ARTICLE Download: 19| View: 154| Comments: 0 | doi:10.20944/preprints201905.0131.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Citrus aurantium L. blossoms; total phenolics; ultrasonic-assisted extraction; Box-Behnken design; free radical scavenging activity; anti-HMG-CoA reductase activity
Online: 10 May 2019 (14:41:59 CEST)
The objective of this study was to develop an ultrasonic-assisted procedure for the extraction of total phenolics from Citrus aurantium L. blossoms (CAB) and evaluate the free radical scavenging activity, anti-HMG-CoA reductase activity of total phenolics. In this work, a Box-Behnken design based on the single-factor experiments was used to explore the optimum extraction process. Under the optimum conditions (extraction solvent 70.31% ethanol, extraction temperature 61.94 °C, extraction time 51.73 min and liquid-to-solid ratio 35.63 mL/g), the extraction yield of total phenolics was 95.84 mg gallic acid equivalents (GAE)/g dry matter (DM), which was highly consistent with the theoretical value (96.12 mg GAE/g DM). The total phenolic extract showed excellent free radical scavenging properties against DPPH·, ABTS+·, ·OH and ·O2-, with the IC50 values of 197.007, 83.878, 218.643 and 158.885 μg/mL, respectively, and the extracts also showed good inhibition of HMG-CoA reductase activity, with the IC50 value of 117.165 μg/mL. Total phenolics from CAB could be a potential source of natural free radical scavenger and HMG-CoA reductase inhibitor.
Mon, 6 May 2019
REVIEW Download: 123| View: 149| Comments: 0 | doi:10.20944/preprints201905.0066.v1
Subject: Chemistry, Medicinal Chemistry Keywords: chitin; chitosan; cosmetics; biodegradability; biomaterials; polysaccharides; green technology; marine cosmetic ingredients; marine green source; marine resources
Online: 6 May 2019 (12:37:44 CEST)
Huge amounts of chitin and chitosans can be found in the biosphere as important constituent of the exoskeleton of many organisms, as well as waste by worldwide seafood companies. Nowadays, politicians, environmentalists, and industrialists encouraged the use of these marine polysaccharides as renewable source, particularly when developed by alternative eco-friendly processes, especially in the production of regular cosmetics. The aim of this review is to outline the physicochemical and biological properties and the different bioextraction methods of chitin and chitosans sources, focusing on enzymatic deproteinization, bacteria fermentation, and enzymatic deacetylation methods. Thanks to their biodegradability, non-toxicity, biocompatibility, and bioactivity, the application of these marine polymers is widely used in the contemporary manufacturing of biomedical and pharmaceutical products. In the end, advanced cosmetic products based on chitin and chitosans are presented, analyzing different therapeutic aspects about skin, hair, nail, and oral care. The innovative formulations described can be considered as excellent solutions regarding problems in the various body anatomical sectors.
ARTICLE Download: 53| View: 104| Comments: 0 | doi:10.20944/preprints201905.0046.v1
Subject: Chemistry, Medicinal Chemistry Keywords: aminopeptidases; inhibitors; aminophosphonate; phenylglycine analogues; fluorine substituted; molecular modeling
Online: 6 May 2019 (10:16:45 CEST)
Inhibitory activity of 14 phosphonic analogues of phenylglycine, substituted in aromatic ring by fluorine and chlorine, was determined towards porcine aminopeptidase N. The obtained data served as a basis for studying their interaction with the enzyme as modelled by the use of Schrödinger Release 2018 program. The observed linearity between modelled Gibbs free energy differences and inhibitory constants indicated the usefulness of this program. The obtained binding mode was compared with this modelled for bovine lens leucine aminopeptidase. Although both enzymes differ in the number of zinc ions present in the active site, they are considered to exhibit similar activity towards substrates and inhibitors. Our studies seem to support that supposition since the modes of binding of the studied inhibitors are quite similar. Additionally, inhibitory activity of the phosphonic analogues of phenylglycine towards barley aminopetpidase was determined showing that this enzyme could be considered as neutral aminopeptidase.
ARTICLE Download: 13| View: 82| Comments: 0
Subject: Chemistry, Medicinal Chemistry Keywords: azolines synthesis; quorum sensing; Chromobacterium violaceum CV026; molecular docking; molecular dynamics
Online: 6 May 2019 (08:59:08 CEST)
The increasingly common occurrence of antibiotic-resistant bacteria has become an urgent public health issue. There are currently some infections without any effective treatment, which require new therapeutic strategies. An attractive alternative is the design of compounds capable of disrupting bacterial communication known as quorum sensing (QS). In gram-negative bacteria, such communication is regulated by acyl-homoserine lactones (AHLs). QS allows bacteria to proliferate before expressing virulence factors. Our group previously reported that hexyloxy phenyl imidazoline (9) demonstrated 71% inhibitory activity of QS at 100 µM (IC50=90.9 µM) in Chomobacterium violaceum, a gram-negative bacterium. The aim of the present study was to take 9 as a lead compound to design and synthesize three 2-imidazolines (13-15) and three 2-oxazolines (16-18), to be evaluated as quorum sensing inhibitors on C. violaceum CV026. We were looking for compounds with a higher affinity towards the Cvi receptor of this bacterium and the ability to inhibit QS. The binding mode of the test compounds on the Cvi receptor was explored with docking studies and molecular dynamics. It was found that 8-pentyloxyphenyl-2-imidazoline 13 reduced the production of violacein (IC50=56.38 µM) without affecting bacterial growth, suggesting inhibition of quorum sensing. Indeed, compound 13 is apparently one of the best QS inhibitors known to date. Molecular docking revealed the affinity of compound 13 for the orthosteric site of the N-hexanoyl homoserine lactone (C6-AHL) on the CviR protein. Ten aminoacid residues in the active site of C6-AHL interacted with 13, and 7 of these are the same as those interacting with AHL. Contrarily, 8-octyloxyphenyl-2-imidazoline 14, 8-decyloxyphenyl-2-imidazoline 15 and 9-decyloxyphenyl-2-oxazoline 18 bound only to an allosteric site and thus did not compete with C6-AHL for the orthosteric site.
Wed, 24 April 2019
ARTICLE Download: 54| View: 151| Comments: 0 | doi:10.20944/preprints201904.0262.v1
Subject: Chemistry, Medicinal Chemistry Keywords: total synthesis; antitumor activity; structure-activity relationship
Online: 24 April 2019 (05:29:48 CEST)
(-)-Zeylenone is a promising cytotoxic agent，which is a natural product isolated from Uvaria grandiflora Roxb. Though substantial antitumor mechanism has been researched , little has focused on its enantiomer (+)-Zeylenone.This article will try to find a gram scale synthesis method of (+)-Zeylenone and explain the structure-activity relationship of this kind of compound. Total synthesis of (+)-zeylenone was completed in 13 steps with quinic acid as starting material in 8.8% overall yield. The highlight of the route was the control of the three carbon’s chirality by clever use of single step dihydroxylation under the direction of the key C-3 chirality. In addition, zeylenone derivatives were designed and synthesized and their antitumor activity were evaluated against three human cancer cell lines using the CCK8 assay. Structure-activity relationship suggested compounds with both two absolute configurations exhibited good activity. Besides, hydroxyls at C-1/2 position were crucial for the activity and esterification of C-1 hydroxyl with large groups made the activity disappeared. Hydroxyl at C-3 position was also important as proper ester substituent could increase the potency.
Fri, 29 March 2019
ARTICLE Download: 47| View: 167| Comments: 0
Online: 29 March 2019 (09:13:02 CET)
Astragalus is a very interesting plant genus well-known for content of flavonoids, triterpenes and polysaccharides. Its secondary metabolites are described as biologically active compounds showing a number of activities, like immunomodulating, antibacterial, antiviral and hepatoprotective. This inspired us to analyze the Bulgarian endemic A. aitosensis (Ivanisch.) to obtain deeper information about its phenolic components. We used extensive chromatographic separation of A. aitosensis extract to obtain seven phenolic compounds (1–7), which were identified using combined LC-MS and NMR spectral studies. The 1D and 2D NMR analysis and HR-MS allowed us to resolve the structures of known compounds 5–7 as isorhamnetin-3-O-robinobioside, isorhamnetin-3-O-(2,6-di-O-α-rhamno-pyranosyl-β-galactopyranoside), and alangiflavoside, respectively, and further comparison of these spectral data with available literature helped us with structural analysis of newly described flavonoid glycosides 1–4. These were described in plant source for the first time.
Tue, 19 March 2019
REVIEW Download: 66| View: 238| Comments: 0
Subject: Chemistry, Medicinal Chemistry Keywords: Simaroubaceae; Picrasma javanica; quassionoids; phytochemicals; pharmacological properties
Online: 19 March 2019 (10:49:34 CET)
Picrasma javanica Blume or also known as Picrasma nepalensis or Picrasma philippinensis is a plant belongs to the Simaroubaceae family, which is known for its secondary metabolites namely quassinoids with various pharmacological properties including antitumor, antimalarial and antiviral. The plant traditionally used as medicine for different diseases in Myanmar, Thailand and Indonesia. The purpose of this study is to discern the phytochemical constituents and pharmacological activities of Picrasma javanica. The background, phytochemical constituents and pharmacological benefits of Picrasma javanica were reviewed and supported from previous studies, including in vivo and in vitro studies. The literature used in the review comprises of published books, journals, reviews and articles published from the year of 1969 to 2018, which are available in ScienceDirect, PubMed, Scopus and GoogleScholar. Chemical structures presented in this paper are either drawn with ACD/ChemSketch. Picrasma javanica possesses several phytochemical constituents, including quassinoids, alkaloids and triterpenoids. Compounds of the plant were isolated and studied for their pharmacological activities such as antimalarial, antiproliferative, antiviral, antimicrobial and membrane stabilising activity. Most importantly, these studies showed that the key players for the pharmacological benefits are quassinoids and alkaloids present in the plant.Picrasma javanica indeed has therapeutic potentials which may be beneficial for people. However, further extensive studies must be done on the plant as the detailed information on its pharmacological activities are still lacking.
Fri, 15 March 2019
ARTICLE Download: 68| View: 381| Comments: 0 | doi:10.20944/preprints201903.0166.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Structure-based design; glycogen phosphorylase inhibitor; glycogen metabolism; type 2 diabetes; X-ray crystallography; N-acyl-β-D-glucopyranosylamine
Online: 15 March 2019 (14:06:06 CET)
Structure-based design and synthesis of two biphenyl-N-acyl-β-D-glucopyranosylamine derivatives as well as their assessment as inhibitors of human liver glycogen phosphorylase (hlGPa, a pharmaceutical target for type 2 diabetes) is presented. X-ray crystallography revealed the importance of structural water molecules and that the inhibitory efficacy correlates with the degree of disturbance caused by the inhibitor binding to a loop crucial for the catalytic mechanism. The in silico derived models of the binding mode generated during the design process corresponded very well with the crystallographic data.
Wed, 27 February 2019
ARTICLE Download: 52| View: 208| Comments: 0 | doi:10.20944/preprints201902.0248.v1
Subject: Chemistry, Medicinal Chemistry Keywords: 10-methoxycanthin-6-one; quaternization; antibacterial; SARs
Online: 27 February 2019 (05:08:02 CET)
Natural products are an important source of antibacterial agents. Canthin-6-one alkaloids have displayed potential antibacterial activity based on our previous work. In order to improve the activity, twenty-two new 3-N-benzylated 10-methoxy canthin-6-ones were designed and synthesized through quaternization reaction. The in vitro antibacterial activity against three bacteria was evaluated by double dilution method. Four compounds (6f, 6i, 6p and 6t) displayed 2-fold superiority (minimum inhibitory concentration (MIC) = 3.91 µg/mL) against agricultural pathogenic bacteria R. solanacearum and P. syringae than agrochemical propineb. Moreover, the structure–activity relationships (SARs) were also carefully summarized in order to guide the development of antibacterial canthin-6-one agents.
Wed, 6 February 2019
ARTICLE Download: 113| View: 756| Comments: 0 | doi:10.20944/preprints201902.0064.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Dopamine receptors, Molecular Docking, Molecular Dynamics, Receptor-Ligand Interactions
Online: 6 February 2019 (13:54:13 CET)
Background: Selectively targeting dopamine receptors has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases evolving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like receptors). Fifteen structurally diverse ligands were docked to these models. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for DR sub-type specificity. Results: We showed that the number of conformations for a receptor:ligand complex was associated to unspecific interactions > 2.5 Å and hydrophobic contacts, while the decoys binding energy was influenced by specific electrostatic interactions. Known residues such as 3.32Asp, the serine microdomain and the aromatic microdomain were found interacting in a variety of modes (HB, SB, π-stacking). Purposed TM2-TM3-TM7 microdomain was found to form a hydrophobic network involving Orthosteric Binding Pocket (OBP) and Secondary Binding Pocket (SBP). T-stacking interactions revealed as especially relevant for some large ligands such as apomorphine, risperidone or aripiprazole. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, key for the design of more specific ligands.
Wed, 30 January 2019
ARTICLE Download: 85| View: 383| Comments: 0 | doi:10.20944/preprints201901.0307.v1
Subject: Chemistry, Medicinal Chemistry Keywords: molecular docking; fluoroquinolones; antimicrobial activity
Online: 30 January 2019 (09:31:52 CET)
An important parameter in the development of a new drug is the drug's affinity to the identified target (protein/enzyme). Predicting the ligand binding to the target (protein/enzyme) by molecular simulation would allow the synthesis to be restricted to the most promising compounds.A restricted hybrid HF-DFT calculation was performed in order to obtain the most stable conformer of each ligand and a series of DFT calculations using the B3LYP levels with 6-31G* basis set has been conducted. The docking studies of the quinolone compounds will be performed with the CLC Drug Discovery Workbench to identify and visualize the ligand-receptor interaction mode.
Fri, 4 January 2019
ARTICLE Download: 101| View: 249| Comments: 0 | doi:10.20944/preprints201901.0046.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Keywords: methotrexate, cubic phase, magnetocubosomes, monoolein, liquid crystalline phase, drug delivery system, alternating magnetic field
Online: 4 January 2019 (14:32:38 CET)
The release profiles of methotrexate, an anticancer drug, from the monoolein liquid crystalline cubic phases were studied. The cubic phases were used either in the form of a lipidic film deposited onto a glassy carbon electrode surface or in the dispersed form of magnetocubosomes, which are considered a prospective hybrid drug delivery system. Commonly, cubosomes or liposomes are employed, but not in the case of toxic methotrexate, known to block receptors responsible for folate transport into the cells. The release profiles of the drug from the lipidic films were monitored electrochemically and described using the Higuchi model. They were also modified via changes in temperature; the release was faster, although deviating from the model when the temperature was increased. Magnetocubosomes - cubic phase nanoparticles containing hydrophobic magnetic nanoparticles placed in an alternating magnetic field of low frequency and amplitude, stimulated drug release from the suspension, which was monitored spectroscopically. These new biocompatible hybrid materials are very promising, allowing to control the release of the drug at the appropriate sites, but do require further investigations into their in vitro cytotoxicity and in vivo biodistribution.
Tue, 18 December 2018
ARTICLE Download: 55| View: 166| Comments: 0 | doi:10.20944/preprints201812.0214.v1
Subject: Chemistry, Medicinal Chemistry Keywords: αβ motif; Abu; chlorotoxin; Cys; disulfide bond; insectotoxin; isosteric substitution; L-α-aminobutyric acid; molecular dynamics; Ser
Online: 18 December 2018 (04:46:38 CET)
Chlorotoxin (CTX) is a 36–amino acid peptide with 8 Cys residues that forms four Cys-Cys bonds. It has high affinity for the glioma-specific chloride channel and matrix metalloprotease-2. Structural and binding properties of CTX analogs with various Cys residue substitutions with L-a-aminobutyric acid (Abu) have been previously reported. Using 4.2 ìs molecular dynamics, we compared the conformational and essential space sampling of CTX and analogs [Abu/Ser2,19]CTX, [Abu/Ser5,28]CTX, [Abu/Ser16,33]CTX, [Abu/Ser20,35]CTX, and [Abu/Ser2,5,16,19,20,28,33,35]CTX. The native and substituted peptides maintained a high degree of a-helix propensity from residues 8 through 21, with the exception of [Ser5,28]CTX and [Abu16,33]CTX. In agreement with previous circular dichroism spectropolarimetry results, the C-terminal b-sheet content varied less from residues 25 through 29 and 32 through 36 and was well conserved in all analogs, except: [Abu16,33]CTX, [Ser20,35]CTX, [Abu2,5,16,19,20,28,33,35]CTX, and [Ser2,5,16,19,20,28,33,35]CTX. The Cys16-Cys33 and Cys20-Cys35 Cys-Cys bonds appear to be required to maintain the ab-motif of CTX. Their selective substitution with Ser16,33 however, may mitigate the destabilizing effect of Cys16-Cys33 substitution by the formation of an inter residue H-bond from OgH of Ser16 to OgH of Ser33 bridged by a water molecule. All peptides shared considerable sampled conformational space, which explains the retained receptor binding of the nonnative analogs.
Mon, 3 December 2018
ARTICLE Download: 71| View: 147| Comments: 0 | doi:10.20944/preprints201812.0027.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Rumex tunetanus; Phenolic compounds; Metabolic profiling; Antioxidant activity; RP-UHPLC-ESI-QTOF-MS
Online: 3 December 2018 (13:58:52 CET)
The present study was designed to investigate the bioactive compound in Rumextunetanus extracts (polygonaceae), a plant growing in GarâaSejnane region (NW-Tunisia). Hydro-methanol extracts of flowers and stems of Rumextunetanus were analyzed by RP-UHPLC-ESI-QTOF-MS in the negative mode to identify the maximum of bioactive compounds. Applied the aforementioned method, a total of 60 bioactive compounds were characterized for the first time in Rumextunetanus between them, 18 photochemical were firstly identified in the Polygonaceae family in negative ionization mode. Quantification of the identified compounds revealed that quercetin-3-O-glucuronide and (-)-epicatechingallate were the most abundant phenolic compounds in flowers and stems, respectively. Moreover, positive correlations were found between the antioxidant activity measured by DPPH and FRAP assays with the total phenolic compounds (r = 0.98; r = 0.99, respectively) and the abundance of some phenolic subfamilies such as hydroxycinnamic acids, hydroxybenzoic acids, flavonols and flavones with r > 0.86. The compounds displaying significant (P < 0.01) and good correlations with the antioxidant activity (r > 0.93) were hydroxybenzoic acid, rutin, quercetin-3-O-glucuronide, quercetin-3-O-glucoside, quercetin and luteolin-7-O-rutinoside. In addition, the flowers and stems of Rumex tunetanus showed different bioactive compound profiles and significant antioxidant properties of extracts. These results highlight the potential of the RP-UHPLC-ESI-QTOF-MS and MS/MS system to identify untargeted metabolic profiling of Rumex tunetanus. Overall, these results contribute to the clear explanation of the past and current usage of genus Rumex in folk medicine. Future investigations are necessary to develop purified antioxidant extracts, with the application of more selective extraction techniques.
Mon, 26 November 2018
ARTICLE Download: 80| View: 203| Comments: 0 | doi:10.20944/preprints201811.0574.v1
Subject: Chemistry, Medicinal Chemistry Keywords: activity cliff; activity landscape plotter; epigenetics; docking; drug discovery; D-tools; molecular dynamics; Epi-polypharmacology; SmART; structure-activity relationships
Online: 26 November 2018 (07:14:05 CET)
In this work we discuss the insights from activity landscape, docking and molecular dynamics towards the understanding of the structure-activity relationships of dual inhibitors of major epigenetic targets: lysine metiltransferase (G9a) and DNA metiltranferase 1 (DNMT1). The study was based on a novel data set of 50 published compounds with reported experimental activity for both targets. The activity landscape analysis revealed the presence of activity cliffs, e.g., pairs of compounds with high structure similarity but large activity difference. Activity cliffs were further rationalized at the molecular level by means of molecular docking and dynamics simulations that led to the identification of interactions with key residues involved in the dual activity or selectivity with the epigenetic targets.
Fri, 16 November 2018
REVIEW Download: 182| View: 138| Comments: 0 | doi:10.20944/preprints201811.0409.v1
Online: 16 November 2018 (11:34:24 CET)
G-quadruplex, a unique secondary structure in nucleic acids found throughout human genome elicited widespread interest in the field of therapeutic research. Being present in key regulatory regions of oncogenes, G-quadruplex structure regulates transcription, translation, splicing, telomere stability etc. Changes in its structure and stability lead to differential expression of oncogenes causing cancer. Thus, targeting G-Quadruplex structures with small molecules/ other biologics has shown elevated research interest. Covering previous reports, in this review we try to enlighten the facts on the structural diversity in G-quadruplex ligands aiming to provide newer insights to design first-in-class drugs for the next generation cancer treatment.
ARTICLE Download: 131| View: 80| Comments: 0 | doi:10.20944/preprints201811.0371.v1
Subject: Chemistry, Medicinal Chemistry Keywords: biosynthesis; nanoparticles; plant extracts; Citrus reticulata
Online: 16 November 2018 (04:33:22 CET)
Biosynthesis of nanoparticles for delivery of therapeutic agents has introduced new opportunities in upgrading medical treatment. Plant extracts contains different capping and reducing agents naturally thus provided simpler and less expensive way to synthesize AgNPs. In present work, Citrus reticulata mediated stabilised AgNPs was synthesized. Optimum concentration of reactants was achieved by varying the amount of extracts (1-11 ml) and AgNO3 concentration (0.5-3 mM). Surface Plasmon peak of Citrus reticulata mediated AgNPs was determined by UV-visible spectrophotometer and functional groups of capping agents were examined by FTIR analysis. Surface Plasmon peaks of Citrus reticulata fresh peel, seed, and juice extracts were observed at 420 nm. But in dry peel extract, absorption peak of AgNPs appeared at 410 nm. Colour of different extracts was changed after the reduction of AgNO3 to AgNPs by reducing agents present in the extracts. FTIR analysis showed band peaks at 3316 cm-1 correspond to amide (N-H and O-H) stretching vibrations while alkanes peaks was observed at 1638 cm-1 which showed C=C stretching aromatic ring (flavonoids). Furthermore, Citrus reticulata fresh peel mediated AgNPs showed impressive stability up-to 112 days. In conclusion, Citrus reticulata fresh peel extract provided an excellent source of reducing agents for synthesizing stabilized AgNPs.
Wed, 14 November 2018
ARTICLE Download: 63| View: 74| Comments: 0 | doi:10.20944/preprints201811.0330.v1
Subject: Chemistry, Medicinal Chemistry Keywords: hyperpigmentation; tyrosinase inhibitors; 3-(2,4-dihydroxyphenyl)propionic acid; structure-activity relationship study; B16-F10 cellular melanogenesis inhibition
Online: 14 November 2018 (09:59:45 CET)
Compounds with tyrosinase inhibitory efficacy could be effective as depigmenting agents. Although a large number of natural and synthetic tyrosinase inhibitors have been reported, few of them are used as skin-whitening agents due to poor activity and safety concerns. 3-(2,4-Dihydroxyphenyl)propionic acid (DPPA), a naturally occurring compound isolated from Ficus carica, was previously discovered as a moderate tyrosinase inhibitor. In this study, the structure-activity relationship study of DPPA was conducted. Compound 3g, with the 2,4-resorcinol subunit and terminal hydrophobic di-butylamino group, was identified with low nanomolar enzymatic IC50 value. Additionally, compound 3g could effectively reduce melanin levels in B16-F10 melanoma cells treated with α-melanocyte-stimulating hormone (α-MSH) without affecting cell viability and proliferation. All these results indicated that compound 3g could be considered as a promising candidate for the treatment of diseases associated with hyperpigmentation.
Thu, 8 November 2018
ARTICLE Download: 56| View: 103| Comments: 0 | doi:10.20944/preprints201811.0221.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Fatty Acid Amide Hydrolase; cannabinoid; carboxamide inhibitors; 3D-QSAR; CoMSIA.
Online: 8 November 2018 (14:52:23 CET)
Fatty Acid Amide Hydrolase (FAAH) is one of the enzymes responsible of endocannabinoids metabolism. The inhibition of FAAH is a useful and indirect strategy to raise endogenous cannabinoid concentrations, which would be useful for the treatment of various pathological processes in which cannabinoid concentrations are lowered. In the present work, we present an extensive 3D-QSAR/CoMSIA study on a series of 90 irreversible inhibitors of FAAH of pyrimidinyl-piperazine-carboxamide structure. The final model obtained was extensively validated (q2 = 0.734; r2test = 0.966; r2m = 0.723), and based on the information derived from the contour maps we reported a series of 10 new compounds designed as powerful FAAH inhibitors (pIC50 of the best-proposed compounds = 12.196; 12.416).
Tue, 6 November 2018
ARTICLE Download: 57| View: 80| Comments: 0 | doi:10.20944/preprints201811.0137.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Streptomyces; angucycline; saquayamycin; cytotoxicity
Online: 6 November 2018 (10:55:42 CET)
Four angucycline glycosides including three new compounds landomycin N (1), galtamycin C (2) and vineomycin D (3), and a known homologue saquayamycin B (4), along with two alkaloids 1-acetyl-β-carboline (5) and indole-3-acetic acid (6), were identified from the fermentation broth of an intertidal sediments derived Streptomyces sp. Their structures were mainly established by IR, HR-ESI-MS, 1D and 2D NMR techniques. Among the isolated angucyclines, saquayamycin B displayed potent cytotoxic activity against hepatoma carcinoma cells HepG-2, SMMC-7721 and plc-prf-5, with IC50 values 0.135, 0.033 and 0.244 μM respectively, superior to positive drug doxorubicin. Saquayamycin B treatment to SMMC-7721 cells led to the typical morphological signs of apoptosis in 4',6-diamidino-2-phenylindole (DAPI) staining experiment.
Fri, 2 November 2018
ARTICLE Download: 76| View: 63| Comments: 0 | doi:10.20944/preprints201811.0008.v1
Subject: Chemistry, Medicinal Chemistry Keywords: neuroinflammation; microglia; carbon-11; radiochemistry; positron emission tomography
Online: 2 November 2018 (02:55:47 CET)
Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia. AZ683 has high affinity for CSF1R (Ki = 8 nM; IC50 = 6 nM) and >250-fold selectivity over 95 other kinases and, in this paper, we report the radiosynthesis of [11C]AZ683 and initial evaluation of its use in CSF1R PET. [11C]AZ683 was synthesized by 11C-methylation of the desmethyl precursor with [11C]MeOTf in 3.0% non-corrected activity yield (based upon [11C]MeOTf), >99% radiochemical purity and high specific activity. Preliminary PET imaging with [11C]AZ683 revealed no brain uptake in rodents and nonhuman primates suggesting that [11C]AZ683 is a poor candidate for imaging neuroinflammation, but that it could still be useful for peripheral imaging of inflammation.
Thu, 1 November 2018
ARTICLE Download: 43| View: 69| Comments: 0 | doi:10.20944/preprints201810.0768.v1
Subject: Chemistry, Medicinal Chemistry Keywords: silybin; prostate cancer; 2,3-dehydrosilybin; cell proliferation; cell apoptosis.
Online: 1 November 2018 (18:16:29 CET)
As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic approaches to 7-O-substituted-3,5,20-O-trimethyl- 2,3-dehydrosilybins through a five-step procedure and to 3-O-substituted-5,7,20-O-trimethyl-2,3- dehydrosilybins via a four-step transformation have been developed. Thirty-two nitrogen-containing derivatives of silybin have been achieved through these synthetic methods for the evaluation of their antiproliferative activities towards both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145) using WST-1 cell proliferation assay. These derivatives exhibited greater in vitro antiproliferative potency than silybin. Among them, 11, 29, 31, 37, and 40 were identified as five optimal derivatives with IC50 values in the range of 1.40–3.06 µM, a 17- to 52-fold improvement in potency as compared with silybin. All these five optimal derivatives can arrest the PC-3 cell cycle in the G0/G1 phase and promote PC-3 cell apoptosis. Derivatives 11, 37, and 40 are more effective than 29 and 31 in activating PC-3 cell apoptosis.
Wed, 17 October 2018
ARTICLE Download: 68| View: 72| Comments: 0 | doi:10.20944/preprints201810.0381.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Biginelli reaction; dihydropyrimidin-2-thiones; synthesis, virtual screening, drug design; LaSOM 282
Online: 17 October 2018 (09:34:06 CEST)
The Biginelli reaction is a highly versatile reaction, which leads to dihydropyrimidinones/thiones. This scaffold is reported as being a privileged structure due to its ability to interact with biological targets. Synthesis of ethyl 4-(2-fluorophenyl)-6-methyl-2-thioxo-1-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate was achieved through the Biginelli reaction using a functionalized thiourea. In silico studies demonstrated that the compound title showed good potential for interacting with ecto-5’-nucleotidase, which has been considered as a target in designs for anti-cancer drugs.
ARTICLE Download: 88| View: 102| Comments: 0 | doi:10.20944/preprints201810.0375.v1
Subject: Chemistry, Medicinal Chemistry Keywords: endophytic fungi; sesterterpene; cytotoxic activity; pancreatic cancer
Online: 17 October 2018 (06:39:51 CEST)
As a part of our ongoing research on endophytic fungi, we have isolated a sesterterpene mycotoxin, fusaproliferin (FUS), from Fusarium solani strain associated with the plant Aglaonema hookerianum Schott. FUS showed rapid and sub-micromolar IC50 against pancreatic cancer cell lines. Time dependent survival analysis and microscopy imaging showed rapid morphological changes in cancer cell lines 4 hours after incubation with FUS. This provides a new chemical scaffold that can be further developed to obtain more potent synthetic agents against pancreatic cancer.
Tue, 16 October 2018
REVIEW Download: 193| View: 122| Comments: 0 | doi:10.20944/preprints201810.0360.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Molecular Dynamics, CoSolvent Molecular Dynamics, Drug design, Fragment Screening, Docking
Online: 16 October 2018 (12:15:17 CEST)
Molecular dynamics(MD) simulations are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals the solvent structure and preferential interaction sites (hot spots) on the protein surface. This information is largely transferable across all classes of protein ligands (from water to drugs) and can be used very effectively to understand ligand recognition and improve the predictive capability of well-established methods such as molecular docking. MD simulations for protein and drug or drug-like compounds are now being used but are still computationally expensive and can only be applied to specific cases. On the other hand, MDmix simulations can now be used in SBDD and we will describe the latest developments and implementations. We expect to see an increase in the application of these techniques to a plethora of protein targets to identify new drug candidates with the advent of new tools and faster computers.
ARTICLE Download: 137| View: 96| Comments: 0 | doi:10.20944/preprints201810.0355.v1
Subject: Chemistry, Medicinal Chemistry Keywords: assay; diarrhea; isolate; hydrolysis; proteins; inhibition zone
Online: 16 October 2018 (11:26:59 CEST)
The study compared antibacterial potential of hydrolysates of casein and alpha-lactalbumin from cow and goat milk on diarrhea-causing Escherichia coli and Staphylococcus aureus. Milk samples were aseptically obtained from lactating cows and goats. The samples were skimmed; casein was isolated using acetic acid and alpha-lactalbumin by filtrate thermoprecipitation at 75 °C. 50% of each isolate was reconstituted in a buffer and hydrolyzed with papain at 55 °C for 2 hours. The hydrolysates were heated to 75 °C to inactivate papain, cooled and their antibacterial activity determined by disc diffusion method. Results showed alpha-lactalbumins had higher degrees of hydrolysis and antibacterial activity than caseins; goat alpha-lactalbumin had the highest antibacterial activity with mean inhibition zones of 19.60 mm and 19.50 mm on E. coli and S. aureus. Cow alpha-lactalbumin inhibited E. coli more than S. aureus with inhibition zones of 16.80 mm and 12.50 mm. Cow and goat milk casein hydrolysates inhibited E. coli with mean inhibition zones of 8.00 mm and 10.90 mm and inhibited S. aureus with inhibition zones of 4.13 mm and 1.90 mm respectively. The research showed that the milk hydrolysates can be a source of antibiotics for diarrhea treatment. Research should be done to establish the peptide fractions associated with the observed bioactivity.
Fri, 28 September 2018
ARTICLE Download: 107| View: 85| Comments: 0 | doi:10.20944/preprints201809.0564.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Pritimerin; target fishing; druggability; network pharmacology
Online: 28 September 2018 (11:54:58 CEST)
Pristimerin (PM) is a naturally occurring quinonemethide triterpenoid compound that isolated from the Celastraceae and Hippocrateaceae families. Its anticancer effects have attracted a great deal of attention, but the mechanisms of action remain obscure. In this study, we screened for the active compounds of Pristimerin using a drug-likeness approach. Potential protein targets of Pristimerin were predicted by PharmMapper and Coremine database. Candidate protein targets were then uploaded to GeneMANIA and GO pathway analysis. Finally, compound-target, target-pathway, and compound-target-pathway networks were constructed using Cytoscape 3.3. The results showed that Pristimerin had good drug ability and identified 13 putative protein targets. Network analysis revealed that these targets are associated with cancer, inflammation and other physiological processes. In summary, Pristimerin is predicted to target a variety of proteins and pathways to form a network that exerts systemic pharmacological effects.
Mon, 3 September 2018
ARTICLE Download: 141| View: 217| Comments: 0 | doi:10.20944/preprints201809.0048.v1
Subject: Chemistry, Medicinal Chemistry Keywords: pretargeting; Fusarinine C; rituximab; click chemistry; multimerization; PET; gallium-68
Online: 3 September 2018 (15:55:44 CEST)
Among extensive studies on click chemistry the inverse electron-demand Diels-Alder reaction between 1,2,4,5-tetrazine (Tz) and trans-cyclooct-2-en (TCO) has gained increasing attraction due to its exceptionally fast reaction kinetics and high selectivity for in vivo pretargeting applications including PET imaging. The facile two-step approach utilizing TCO-modified antibodies as targeting structures has not made it into clinic though as the increase in blood volume from mice to human seems to be the major limitation. This study aimed to show if the design of multimeric Tz-ligands by chelator scaffolding can improve the binding capacity and may lead to enhanced PET imaging with gallium-68. For this purpose we utilized the macrocyclic siderophore Fusarinine C (FSC) which allows to conjugate up to three Tz-residues due to three primary amines available for site specific modification. The resulting mono- di- and trimeric conjugates were radiolabelled with gallium-68 and characterized in vitro (logD, protein binding, stability, binding towards TCO modified rituximab (RTX)) and in vivo (biodistribution- and imaging studies in normal BALB/c mice using a simplified RTX-TCO tumour surrogate). The 68Ga-labelled FSC-based Tz-ligands showed suitable hydrophilicity, high stability, high targeting specificity and the binding capacity to RTX-TCO was increased by the grade of multimerization. Corresponding in vivo studies showed a multimerization typical profile but generally suitable pharmacokinetics with low accumulation in non-targeted tissue. Imaging studies in RTX-TCO tumour surrogate bearing BALB/c mice confirmed this trend and revealed improved targeting by multimerization as increased accumulation in RTX-TCO positive tissue was observed.
Thu, 30 August 2018
ARTICLE Download: 147| View: 155| Comments: 0 | doi:10.20944/preprints201808.0516.v1
Subject: Chemistry, Medicinal Chemistry Keywords: ALK5 inhibitor; TGF-β; kinase assay; selectivity; docking
Online: 30 August 2018 (05:52:08 CEST)
The transforming growth factor-β (TGF-β), in which overexpression have been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Three series of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14a–h, 15a–h, 16a–h, 22a, 22b, 22d, 23a, 23b, 23d, 24b, and 24d were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38α mitogen activated protein (MAP) kinase inhibitory activity in an enzymatic assays. Among these compounds, the most active compound 16f inhibited ALK5 phosphorylation with an IC50 value of 0.28 µM, with 98% inhibition at 10 µM. Compound 16f also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound 3 (LY-2157299). Molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.
Wed, 29 August 2018
REVIEW Download: 195| View: 122| Comments: 0 | doi:10.20944/preprints201808.0488.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Sarcophyton; Sinularia; Lobophytum; new compounds; anti-microbial; anti-inflammatory; anti-tumoral
Online: 29 August 2018 (09:03:48 CEST)
Work reviews the new isolated isolated cembranoid diterpene derivatives from species belonging to the family Alcyoniidae, which comprises the genera Sarcophyton, Sinularia, and Lobophytum as well as their biological properties, during 2016–2017. The compilation permitted to conclude that much more new cembranoid diterpenes were found in the soft corals of the genus Sarcophyton sp. (33 new compounds) than in those belonging to the genera Lobophytum (17) or Sinularia (8). Several methods have been used for identifying these new compounds, after extraction with organic solvents and fractionation. The fractions obtained, in some cases, were followed by TLC, and again subjected to chromatographic procedures, including semi-preparative HPLC. Beyond the chemical composition, the biological properties were also evaluated, namely anti-microbial against several Gram-positive and Gram-negative bacteria and fungi, anti-inflammatory and anti-tumoral against several types of cancer cells. Although the biological activities detected in almost all samples, they were not outstanding ones.
Mon, 27 August 2018
ARTICLE Download: 159| View: 191| Comments: 0 | doi:10.20944/preprints201808.0463.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Factor Xa ( F-Xa), Cardiovascular diseases (CD), Coronary heart disease (CHD), Tissue plasminogen activator (t-PA), Urokinase (UK), Streptokinase (SK), N,N-Dimethyl formamide (DMF)
Online: 27 August 2018 (14:54:10 CEST)
A new series of 1,3,4-oxadiazoles derivatives was synthesized, characterized and evaluated for their in vitro and in vivo anti-thrombotic activity. Compounds (3a-3i) exhibited significant clot lysis with respect to negative control and reference drug streptokinase (30,000 IU) while enhanced clotting time (CT) values were observed (130-342 sec) for these tested compounds than the standard drug heparin (110 sec.). High affinity towards 1NFY with greater docking score was observed for the compounds (3a, 3i, 3e, 3d and 3h) than the control ligand RPR200095. In addition, very good inhibitory potential against factor Xa (F-Xa) was observed with higher docking scores (5612-6270) with ACE values (–189.68 to –352.28 kcal/mol) than the control ligand RPR200095 (Docking score 5192; ACE –197.81 kcal/mol. In vitro, in vivo and in silico results proposed that these newly synthesized compounds can be used as anti-coagulant agents.
Thu, 2 August 2018
REVIEW Download: 505| View: 173| Comments: 0 | doi:10.20944/preprints201808.0032.v1
Subject: Chemistry, Medicinal Chemistry Keywords: caffeine; methylxanthine; chlorogenic acid; caffeic acid; inflammation; antimutagen; anticancer; antioxidant
Online: 2 August 2018 (05:14:02 CEST)
Tea and coffee are the most commonly used beverages throughout the world. Both decoctions are rich in small organic molecules such as phenolics/polyphenolics, purine alkaloids, many methylxanthines, substituted benzoic and cinnamic acids. Many of these molecules are physiologically chemopreventive and chemoprotective agents against many severe conditions such as cancer, Alzheimer, Parkinsonism, inflammation, sleep apnea, cardiovascular disorders, bradycardia, fatigue, muscular relaxation, and oxidative stress. Caffeine, a purine alkaloid, is a common metabolite of both tea and coffee aqueous decoctions and its concentration in tea/coffee depends on the fermentation process, preparation of the water extract and quality of tea leaves/coffee beans. A 250 ml of a coffee cup contains 100-150 mg caffeine while the same volume of strong tea contains 25-40 mg caffeine. The present paper presents the potential of caffeine as a potent chemopreventive agent that can be used for numerous physiological disorders.
Wed, 1 August 2018
ARTICLE Download: 124| View: 156| Comments: 1 | doi:10.20944/preprints201808.0011.v1
Subject: Chemistry, Medicinal Chemistry Keywords: chitosan; aldehydes; chalcone; MIC; anti-cancer activity
Online: 1 August 2018 (09:38:35 CEST)
Versatile hybrid organic polymers are prepared using two active intermediates such as cynuric chloride and chitosan derivatives. The prepared chalcones are characterized by using FT-IR, UV, and proton NMR, thermal analysis and Minimum inhibitory Concentration. Thermal stability of the synthesized hybrid polymer is found using TGA and the hybrid chitosan derivative chalcone is thermally stable up to 270 °C. The antimicrobial activity of the prepared chitosan containing chalcone moiety are find out using Minimum Inhibitory Concentration (MIC) method. The synthesized versatile chalcone shows excellent antimicrobial activity against gram-negative bacteria such as Pseudomonas aeruginosa; and Gram-positive bacteria Chalcone containing halogen moiety shows high activity (MIC 7.8 µg/mL) than the hydroxyl containing chalcone. Cytotoxicity activity of the synthesized composites shows high activity.
Sat, 28 July 2018
ARTICLE Download: 118| View: 168| Comments: 0 | doi:10.20944/preprints201807.0552.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Hedgehog signaling; Veratrum californicum; cyclopamine; HPLC-MS; Shh-Light II cells
Online: 28 July 2018 (23:25:31 CEST)
Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine if additional alkaloids in the extracts contribute to Hh signaling inhibition, we replicated the concentrations of these alkaloids observed in extracts using commercially available standards and compared the inhibitory potential of the extracts to alkaloid standard mixtures using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts contribute to Hh signaling inhibition.
Mon, 23 July 2018
ARTICLE Download: 203| View: 202| Comments: 0 | doi:10.20944/preprints201807.0427.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Pharmacophore; 3D-QSAR; virtual screening; D3R selective antagonist; molecular docking; CNS-like
Online: 23 July 2018 (14:09:10 CEST)
The dopamine D3 receptor is an important CNS target for the treatment of a variety of neurological diseases. Selective dopamine D3 receptor antagonists modulate the improvement of psychostimulant addiction and relapse. In this study, five and six featured pharmacophore models of D3R antagonists were generated and evaluated with the post-hoc score combining two survival scores of active and inactive. Among Top 10 models, APRRR215 and AHPRRR104 were chosen based on the coefficient of determination (APRRR215: R2training = 0.80; AHPRRR104: R2training = 0.82) and predictability (APRRR215: Q2test = 0.73, R2predictive = 0.82; AHPRRR104: Q2test = 0.86, R2predictive = 0.74) of their 3D-quantitative structure–activity relationship models. Pharmacophore-based virtual screening of a large compound library from eMolecules (> 3 million compounds) using two optimal models expedited the search process 100-fold speed increase compared to the docking-based screening (HTVS scoring function in Glide) and identified a series of hit compounds having promising novel scaffolds. After the screening, docking scores, as an adjuvant predictor, were added to two fitness scores (from the pharmacophore models) and predicted Ki (from PLSs of the QSAR models) to improve accuracy. Final selection of the most promising hit compounds were also evaluated for CNS-like properties as well as expected D3R antagonism.
Mon, 16 July 2018
ARTICLE Download: 155| View: 149| Comments: 0 | doi:10.20944/preprints201807.0264.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Orotic hydrazide, Arylhydrazone, Mesenchymal Stem Cells, Proliferation
Online: 16 July 2018 (09:06:33 CEST)
Human mesenchymal stem cells (hMSCs) constitute of cells having potential of self-renewal and proliferation and are commonly isolated from bone marrow aspirates of large bones. The osteogenic potential of these stem cells has been extensively exploited by scientists during the last many years for the biological evaluation of synthetic scaffolds with applications in tissue engineering. Current work aimed to synthesize N-arylhydrazone derivatives of orotic acid and their evaluation as stimulators of human mesenchymal stem cells. Some of the analogs show good to moderate proliferation rate.
Sat, 14 July 2018
ARTICLE Download: 178| View: 294| Comments: 0 | doi:10.20944/preprints201807.0251.v1
Subject: Chemistry, Medicinal Chemistry Keywords: docking; epigenetics; epi-informatics; molecular interactions; molecular dynamics; natural products; flavonoids
Online: 14 July 2018 (17:45:16 CEST)
Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative and antineoplastic activities. Recently, different studies have shown that flavonoid have the potential to inhibit BET bromodomains. Previous reports suggest that flavonoids are putative inhibitors of the ZA channel due to their orientation and interactions with P86, V87, L92, L94 and N140. Herein, a comprehensive characterization of the binding mode of the biflavonoid amentoflavone and fisetin is discussed. To this end, both compounds were docked with BRD4 using four docking programs. Results were post-processed with protein-ligand interaction fingerprints. To gain further insights into the binding mode of the two natural products, docking results were further analyzed with molecular dynamics. Results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as basis for scaffold optimization and further characterization of flavonoids as BET inhibitors.
Fri, 13 July 2018
REVIEW Download: 319| View: 223| Comments: 0 | doi:10.20944/preprints201807.0226.v1
Subject: Chemistry, Medicinal Chemistry Keywords: galvanic replacement; photothermal therapy; drug delivery; nanoparticles; cancer treatment
Online: 13 July 2018 (05:11:21 CEST)
Owing to their unique physicochemical properties, nanoparticles are used in a variety of ways in the field of cancer treatment, including imaging, drug delivery, and photothermal and photodynamic therapies. The fascinating properties of nanoparticles are determined by their size, morphology, and constituent elements, and various synthetic methods and post-synthetic techniques have been applied to control these factors. Herein, we present examples of shape and composition control through galvanic replacement, a technique that exploits redox potential differences between elements to induce spontaneous ion-exchange and highlight its specific contributions to cancer treatment applications. The present article identifies the recent advances in nanoparticle formation techniques and discusses the future outlook of the field.
Fri, 6 July 2018
REVIEW Download: 311| View: 351| Comments: 0 | doi:10.20944/preprints201807.0116.v1
Subject: Chemistry, Medicinal Chemistry Keywords: chemical space; chemoinformatics; data mining; databases; DNMT inhibitors; drug discovery; epi-informatics; molecular modeling; similarity searching; virtual screening
Online: 6 July 2018 (10:04:44 CEST)
Naturally occurring small molecules include a large variety of natural products from different sources that have confirmed activity against epigenetic targets. In this work we review chemoinformatic, molecular modeling and other computational approaches that have been used to uncover natural products as inhibitors of DNA metiltransferases, a major family of epigenetic targets with significant potential for the treatment of cancer and several other diseases. Examples of these computational approaches include docking, similarity-based virtual screening, and pharmacophore modeling. It is also commented the chemoinformatic-based exploration of the chemical space of naturally occurring compounds as epigenetic modulators which may have significant implications in epigenetic drug discovery and nutriepigenetics.
ARTICLE Download: 151| View: 239| Comments: 0 | doi:10.20944/preprints201807.0110.v1
Subject: Chemistry, Medicinal Chemistry Keywords: G-quadruplex; oxadiazole/pyridine polyheteroaryls; G4-ligands; FRET-melting; G4-FID; circular dichroism
Online: 6 July 2018 (08:28:22 CEST)
Acyclic olygoheteroaryl-based compounds represent a valuable class of ligands for nucleic acid recognition. In this regard, acyclic pyridyl polyoxazoles and polyoxadiazoles were recently identified as selective G-quadruplex stabilizing compounds with high cytotoxicity and promising anticancer activity. Herein, we describe the synthesis of a new family of polyheteroaryl oxadiazole/pyridine-ligands targeting DNA G-quadruplexes. In order to perform a structure-activity analysis identifying determinants of activity and selectivity, we followed a convergent synthetic pathway to modulate the nature and number of the heterocycles (1,3-oxazole vs 1,2,4-oxadiazole and pyridine vs benzene). Each ligand was evaluated towards secondary nucleic acid structures, which have been chosen as a prototype to mimic cancer-associated G-quadruplex structures (e.g., the human telomeric sequence, c-myc and c-kit promoters). Interesting, heptapyridyl-oxadiazole compounds showed preferential binding towards the telomeric sequence (22AG) in competitive conditions vs duplex DNA. In addition, G4-FID assays suggest a different binding mode from the classical stacking on the external G-quartet. Additionally, CD titrations in the presence of the two most promising compounds for affinity, TOxAzaPy and TOxAzaPhen, display a structural transition of 22AG in K-rich buffer. This investigation suggests that the pyridyl-oxadiazole motif is a promising recognition element for G-quadruplexes, combining seven heteroaryls in a single binding unit.
Tue, 3 July 2018
ARTICLE Download: 174| View: 192| Comments: 0 | doi:10.20944/preprints201807.0039.v1
Subject: Chemistry, Medicinal Chemistry Keywords: xanthohumol; biotinylated chalcones; anticancer activity; antioxidants
Online: 3 July 2018 (11:42:41 CEST)
Two biotinylated derivatives of the main hop chalcone xanthohumol (1) were prepared by a one-step synthesis via esterification using biotin and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) and 4-dimethylaminopyridine (DMAP) as coupling reagents. The products were characterized spectroscopically and their antiproliferative activity toward MCF-7, MCF-10A, HepG2, MDA-MB-231, 4T1 and Balb/3T3 cell lines was investigated using the SRB assay. For all three tested compounds the best activity was noted in the case of human (MCF-7) and mice (4T1) breast cancer cell lines (IC50 values < 9 μM). Both biotinylated derivatives showed higher anticancer activity than xanthohumol (1) towards all types of tested breast cancer cells. Double biotinylated xanthohumol (3) proved to be the most active in inhibiting cell growth, with IC50 values equal to 5.35 ± 1.5 μM for 4T1 and 8.03 ± 0.53 µM for MCF-7 cell lines. Compound 3 was also more active than 1 and 2 against liver cancer cells HepG2 (IC50 = 17.37 ± 5.1 μM), while the IC50 values for 1 and 2 were equal to 21.5 ± 2.7 and 22.1 ± 3.9 µM, respectively. 4‑O‑biotinylxanthohumol (2) was the second most active growth inhibitor, particularly with respect to MCF-7 (IC50 = 6.19 ± 1.7 μM) and 4T1 (IC50 = 6.64 ± 0.4 μM) cell lines. The antioxidant activity was evaluated using the 1.1-diphenyl-2-picrylhydrazyl radical (DPPH) method. All tested compounds (1-3) have antioxidant activity between 2.73 and 3.38 mM. It was reported for the first time that new prenylated chalcones containing the biotin moiety effectively inhibited proliferation of cancer cells in vitro.
Mon, 4 June 2018
ARTICLE Download: 226| View: 192| Comments: 0 | doi:10.20944/preprints201711.0091.v2
Subject: Chemistry, Medicinal Chemistry Keywords: asymmetrical mono-carbonyl analogs of curcumin (AMACs); synthesis; cytotoxicity, Vero; HeLa; MCF7; cell lines
Online: 4 June 2018 (08:19:03 CEST)
A series of novel asymmetrical mono-carbonyl analogs of curcumin (AMACs) were synthesized and evaluated for cytotoxic activity using the brine shrimp lethality test (BSLT) and the methyl thiazolyl tetrazolium assay against Vero, HeLa, and MCF7 cell lines. The structures of the synthesized compounds were confirmed by Fourier transform infrared spectrophotometry (FTIR), 1H-nuclear magnetic resonance (NMR), 13C-NMR, and mass spectral data. The results of the cytotoxicity evaluation showed that the synthesized compounds exhibited moderate to very high toxic activity in BSLT, requiring a concentration of 13.06–714.49 µg/mL to kill half the population. Most of the compound exhibited cytotoxic activity against HeLa cell lines, comparable to the activity of cisplatin with a concentration of the synthesized compounds required to inhibit 50% of the growth of the cell lines (IC50) value of 40.65–95.55 µM, and most of the compounds tested against MCF7 cell lines exhibited moderate to very high cytotoxic activity (IC50 value 7.86–35.88 µM). However, the selectivity index of the compounds was low, less than 1–1.96. Among the synthesized compounds, compound 1b showed the highest cytotoxicity and selectivity against MCF7 cell lines. Compound 1b could be considered for further development to obtain more active and selective chemotherapeutic agents against breast cancer.
Wed, 30 May 2018
ARTICLE Download: 197| View: 198| Comments: 0 | doi:10.20944/preprints201805.0437.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Jatropha pelargoniifolia; alkaloids; flavonoids; coumarinolignans; diterpenes; anti-inflammatory; antinociceptive; antipyretic; free radical scavenging
Online: 30 May 2018 (06:15:42 CEST)
Extensive phytochemical and chromatographic analysis of different root fractions of Jatropha pelargoniifolia Courb. (Euphorbiaceae) resulted in the isolation and identification of 22 distinct secondary metabolite compounds. Two new compounds, 6-hydroxy-8-methoxycoumarin-7-O-β-D-glycopyranoside and (3-(2-(methylamino) ethyl)-1H-indol-2-yl) methanol, were isolated and identified for the first time from a natural source. In addition, other known compounds, such as hovetricoside C and N-methyltryptamine were isolated from Euphorbiaceae, and hordenine, N-methyltyramine, their salts, cynaroside and linarin were identified in Jatropha spp. for the first time. Some isolated metabolites, such as β-sitosterol, β-sitosterol glucoside, curcusons D and C, naringenin, apigenin, cleomiscosins B and A, spruceanol, propacin, jatrophadiketone, and uracil were previously identified in various Jatropha species. The structures of the isolated compounds were determined using different spectroscopic techniques. The anti-inflammatory, antinociceptive, antipyretic, and antioxidant activities were evaluated for some adequately available isolated compounds. Compounds showed significant antinociceptive activity compared with the standard analgesic drug indomethacin. The edema size was significantly reduced (p< 0.05–0.001) in the animals treated with low doses (5 and 10 mg/kg) of the isolated compounds compared with those treated with a high dose (100 mg/kg) of standard anti-inflammatory drug (phenylbutazone). Furthermore, all tested compounds showed a significant (p< 0.05–0.001) reduction in the rectal temperature of hyper-thermic mice.
Tue, 29 May 2018
ARTICLE Download: 210| View: 250| Comments: 0 | doi:10.20944/preprints201805.0419.v1
Online: 29 May 2018 (08:54:56 CEST)
A heterobifunctional reactive oxygen species (ROS)-responsive linker for directed drug assembly onto and delivery from a quantum dot (QD) nanoparticle carrier was synthesized and coupled to doxorubicin using EDC/sulfo-NHS coupling. The doxorubicin conjugate was characterized using 1H NMR and LC-MS and subsequently reacted under conditions of ROS formation (Cu2+/H2O2) resulting in successful and rapid thioacetal oxidative cleavage which was monitored using 1H NMR. The deprotected amine linker is amenable to peptide or protein conjugation prior to QD assembly or to direct conjugation to cognate reactive groups on ligands that cap the QD surface.
Mon, 14 May 2018
ARTICLE Download: 254| View: 256| Comments: 0 | doi:10.20944/preprints201805.0189.v1
Subject: Chemistry, Medicinal Chemistry Keywords: G-quadruplex DNA; interactions; berberine and palmatine analogues; chemotherapy; NMR; FRET and MST assays
Online: 14 May 2018 (11:44:10 CEST)
In this article/review, the selective interactions of several berberine and palmatine derivatives with various DNA G-quadruplex structures are reported. These derivatives were constructed starting from two natural compounds, berberine and palamatine, through specific synthetic passages following two different schemes for each of them and using several substituents. The details of these synthesis are also described. Indeed, the study of the interactions of these derivative compounds with various G-quadruplex forming sequences was carried out by means of various structural and biochemical techniques. The results show that the presence of suitable side chains are very useful to improve the interaction of the ligands with G-quadruplex structures. Thus, since G-quadruplex formation is promoted by these compounds, which have never been reported before, these may be tested as potential anticancer drugs.
Tue, 8 May 2018
ARTICLE Download: 191| View: 260| Comments: 0 | doi:10.20944/preprints201805.0133.v1
Subject: Chemistry, Medicinal Chemistry Keywords: antioxidant potential; molecular docking; molecular descriptors; binding free energy; free radicals; oxidative stress
Online: 8 May 2018 (15:38:38 CEST)
The antioxidant activity of molecules constitutes an important factor for the regulation of redox homeostasis and reduction of oxidative stress. Cells affected by oxidative stress can undergo genetic alteration, causing structural changes and promoting the onset of chronic diseases, such as cancer. The in silico study performed here was developed to evaluate the antioxidant potential of two molecules, ZINC08706191 (Z91) and ZINC08992920 (Z20), with recognized epithelial anticancer potential. Molecular docking, chemical-quantum calculations and Pearson's correlation were performed. The Z91 and Z20 molecules showed lower binding free energy (ΔG) values for the receptor-ligand interaction than the reference molecules (caffeine – CAF and ascorbic acid – AA), and better results for values of molecular descriptors correlated with ΔG, resulting in a decrease of ΔG. Strong correlations were observed between ΔG values for the five receptors evaluated and ΔG values of the potential epithelial anticancer activity available in literature. These results attest to the significant antioxidant potential of the Z91 and Z20 molecules and their strong relation with the potential epithelial anticancer activity and may be indicated for further analysis in relation to the control of oxidative stress and epithelial anticancer activity.
Fri, 4 May 2018
ARTICLE Download: 206| View: 262| Comments: 0 | doi:10.20944/preprints201805.0085.v1
Subject: Chemistry, Medicinal Chemistry Keywords: 7-acetamido-2-aryl-5-bromoindoles; trifluoroacetylation; cytotoxicity; apoptosis; tubulin polymerization; molecular docking
Online: 4 May 2018 (07:47:06 CEST)
Structurally related 7-acetyl-2-aryl-5-bromoindoles 2a–d and the 7-acetamido-2-aryl-5-bromoindoles 4a–d as well as their corresponding 3-trifluoroacetyl–substituted derivatives 5a–d and 5e–h were evaluated for potential antigrowth effect in vitro against the human lung cancer (A549) and cervical cancer (HeLa) cells. All of the 3-trifluoroacetyl–substituted 7-acetamido-2-aryl-5-bromoindoles 5e–h were found to be more active against both cell lines when compared to the chemotherapeutic drug, Melphalan. The most active compound 5g induced apoptosis in a caspase dependent manner for both cell lines. Compounds 5e–h were found to significantly inhibit tubulin polymerization. Molecular docking of 5g into the colchicine-binding site suggests that the compounds bind to tubulin by different type of interactions including pi-alkyl, amide-pi stacked and alkyl interactions as well as hydrogen bonding with the protein residues to elicit anticancer activity.
Mon, 23 April 2018
ARTICLE Download: 214| View: 201| Comments: 0 | doi:10.20944/preprints201804.0282.v1
Subject: Chemistry, Medicinal Chemistry Keywords: aminosteroid; aminocycloartane; alkaloid; 3D-QSAR; CoMFA; antitrypanosomal activity; cytotoxicity
Online: 23 April 2018 (11:02:16 CEST)
As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr) with low toxicity against mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena alkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were obtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in terms of statistical characteristics (R2, Q2 and P2 for partial least squares (PLS) regression, internal cross-validation (leave-one-out) and external predictions (test set), respectively, as well as the corresponding SDEP and F-values). With R2=0.99, Q2=0.83 and P2=0.79 for anti-Tbr activity and R2=0.94, Q2=0.64, P2=0.59 for cytotoxicity against L6 rat skeletal myoblasts, both models were of good internal and external predictive power. The regression coefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr and for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing suggestions for possible modification of the aminosteroids to further increase the antitrypanosomal potency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena alkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds recently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these structurally similar natural products share a common SAR and, possibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in plausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroid- and aminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent a starting point for lead optimization.
Thu, 5 April 2018
REVIEW Download: 235| View: 230| Comments: 0 | doi:10.20944/preprints201804.0071.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Sulfenic acids; Sulfoxides; Sulfones; Disulfides; Alliin derivatives; Glycoconjugates; Pyrimidine derivatives.
Online: 5 April 2018 (16:30:18 CEST)
Sulfenic acids as small molecules are too unstable to be isolated and their transient nature offers the possibility to involve them in concerted processes that lead to the obtainment of functional groups such as sulfoxides, sulfones and disulfides. All these functions are present in a number of natural and synthetic drugs and can represent structural motives inducing biological relevant properties. In this small review the generation and reactions of sulfenic acid bearing naturally occurring residues are described. Carbohydrate and aminoacid-derived sulfenic acids have been used in concerted addition to triple bonds to obtain alliin derivatives and thiosugars in enantiomerically pure form. Glycoconjugates with sulfinyl, sulfonyl and disulfane functional groups and pyridine-derived disulfides have been obtained from bis and tris-sulfinyl precursors of sulfenic acids. Small families of such compounds have been subjected to preliminary biological tests. Starting from the evidence that the control of molecular architecture and the presence of suitable functional groups can play a significant role on the exhibition of biological properties, apoptotic effects on malignant cells by glycoconjugates and inhibitory activity against the important human pathogen S. aureus by pyrimidine-derived disulfides have been found.
Mon, 19 March 2018
ARTICLE Download: 278| View: 484| Comments: 0 | doi:10.20944/preprints201803.0142.v1
Subject: Chemistry, Medicinal Chemistry Keywords: chitosan; thermoresponsive hydrogel; nitric oxide; s-nitrosothiols; biocompatibility; antimicrobial; Pseudomonas aeruginosa; pluronic F127
Online: 19 March 2018 (07:25:27 CET)
Nitric oxide (NO) is involved in physiological processes, including vasodilatation, wound healing and antibacterial activities. As NO is a free radical, designing drugs to generate therapeutic amounts of NO in controlled spatial and time manners is still a challenge. In this study, the NO donor S-nitrosoglutathione (GSNO) was incorporated into the thermoresponsive Pluronic F-127 (PL) - chitosan (CS) hydrogel, with an easy and economically feasible methodology. CS is a polysaccharide with known antimicrobial properties. Scanning electron microscopy, rheology and differential scanning calorimetry techniques were used for hydrogel characterization. The results demonstrated that the hydrogel has a smooth surface, thermoresponsive behavior and good mechanical stability. The kinetics of NO release and GSNO diffusion from GSNO-containing PL/CS hydrogel demonstrated a sustained NO/GSNO release, in concentrations suitable for biomedical applications. The GSNO-PL/CS hydrogel demonstrated a concentration-dependent toxicity to Vero cells, and antimicrobial activity to Pseudomonas aeruginosa (minimum inhibitory concentration and minimum bactericidal concentration values of 0.5 µg·mL-1 of hydrogel, which corresponds to 1 mmol·L-1 of GSNO). Interestingly, the concentration range in which the NO-releasing hydrogel demonstrated an antibacterial effect was not found to be toxic to the Vero mammalian cell. Thus, the GSNO-PL/CS hydrogel is a suitable biomaterial for topical NO delivery applications.
Wed, 7 March 2018
ARTICLE Download: 258| View: 507| Comments: 2 | doi:10.20944/preprints201803.0050.v1
Subject: Chemistry, Medicinal Chemistry Keywords: carboxamide; carbohydrazine; antibacterial; antifungal; molecular docking; Schiff base; NMR; IR
Online: 7 March 2018 (05:11:10 CET)
The article describes facile one-pot, hi-yielding reactions to synthesize substituted 3,4-dimethyl-1H-pyrrole-2-carboxamide (3a–m) and carbohydrazide analogues (5a–l) as potential antifungal and antimicrobial agents. The structural integrity and purity of the synthesized compounds were assigned based on appropriate spectroscopic techniques. Synthesized compounds were assessed in vitro for antifungal and antibacterial activity. The compound 5h, 5i and 5j were found to be the most potent against A. fumigatus, with MIC value of 0.031 mg/mL. The compound 5f bearing a 2,6-dichloro group on the phenyl ring was found to be the most active broad spectrum antibacterial agent with MIC value of 0.039 mg/mL. The mode of action of the most promising antifungal compounds (one representative from each series; 3j and 5h) was established by their molecular docking to the active site of sterol 14α-demethylase. Molecular docking studies revealed a highly spontaneous binding ability of the tested compounds in the access channel away from catalytic heme iron of the enzyme, which suggested that the tested compounds inhibit this enzyme and would avoid heme iron related deleterious side effects observed with existing antifungal compounds.
Thu, 1 March 2018
ARTICLE Download: 366| View: 316| Comments: 0 | doi:10.20944/preprints201803.0003.v1
Subject: Chemistry, Medicinal Chemistry Keywords: derivatives of N-phenylanthranilic acids; anti-inflammatory activity; flexible molecular docking; microsomal prostaglandin E synthase-1
Online: 1 March 2018 (04:58:58 CET)
The aim of the study was to determine the possibility of suppression of the prostaglandin synthesis by new derivatives of N-phenylanthranilic acids; they inhibit the activity of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme using the method of a flexible molecular docking. For the docking studies the crystallographic structural models with high resolution from Protein Data Bank were used: mPGES-1 in the complex with glutathione (pdb code 4AL0). A flexible molecular docking was carried out using the Molecular Operating Environment (MOE) software package. According to the results of the docking studies four scoring functions were calculated (Affinity dG Scoring, Alpha HB Scoring, London dG Scoring, GBVI/WSA dG Scoring). The values of the scoring functions calculated indicate the thermodynamic probability and energy favorability of forming complexes between molecules of the substances under research and the specified receptor, in which arrangement of ligands in the active site of the receptor and residues of amino acids of side chains are of similar geometry and types of binding of the known inhibitors of mPGES-1 determined on the basis of the crystallographic studies.
Thu, 22 February 2018
ARTICLE Download: 398| View: 493| Comments: 0 | doi:10.20944/preprints201802.0142.v1
Subject: Chemistry, Medicinal Chemistry Keywords: reactive selenium species; arylmethyl selenocyanate; cellular thiolstat; antimicrobial; anticancer; ESKAPE; multidrug resistance
Online: 22 February 2018 (11:34:22 CET)
Selenocyanates form an interesting class of organic selenium compounds as they serve as multifunctional agents (being the precursors of seleninic acids and diselenides in synthetic chemistry and as antimicrobial and cytotoxic agent in biology) and, due to their similarity with better known thiocyanates promise high biological activity. Yet whilst selenocyanates are common in synthetic chemistry, they are rarely considered in pharmaceutical design. Arylmethyl selenocyanates (1-13) have been synthesized and an insight into their structural properties using X-ray crystallography has been obtained. The compounds subsequently have been evaluated for their potential antimicrobial, nematicidal and cytotoxic activity. ADMET properties in vitro, using mutagenicity (AMES) and permeability (PAMPA) tests, have been determined. The compounds exhibit pronounced activity against various strains of bacteria (both Gram-positive and Gram-negative) and yeasts. Among them, benzylselenocyanate (1) represents the most active anti-ESKAPE agent, with potent antibacterial activity, especially against multidrug resistant MRSA strains (HEMSA 5). Our results demonstrate that the arylmethyl selenocyantes are not only non-mutagenic but also possess moderate cytotoxic activity against cancer cells.
Fri, 2 February 2018
ARTICLE Download: 261| View: 357| Comments: 0 | doi:10.20944/preprints201802.0021.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Keywords: one-pot synthesis; single crystal x-ray crystallography; oxovanadium(IV); zinc(II); spectroscopic studies; in vitro antibacterial studies.
Online: 2 February 2018 (16:00:10 CET)
Abstract Antibacterial activities can be improved using mixed ligands. Mixed ligands involved in this research are sodium sulfadiazine (Na-sfz) and dithiocarbamate (ai-dtc). One-pot synthesis was used to synthesize ligand of aniline dithiocarbamate (ai-dtc) and the corresponding coordination compounds of [VO(sfz)(ai-dtc)] and [Zn(sfz)(ai-dtc)]. Crystals of ai-dtc, which grew from the solution when refrigerated after five days, were diffracted with technique of single crystal x-ray crystallography to reveal the structure. Other characterization techniques involving physicochemical parameters, FT-IR, UV-Vis and NMR (1H NMR and 13C NMR) were carried out on ligands of ai-dtc, sfz and corresponding coordination compounds. Differences in results of FT-IR, UV-Vis and NMR between ligands and their respective metal ions confirmed the coordination. The in vitro antibacterial studies showed that the ligands (not the metal complexes) had modest activity against Gram negative bacteria: Staphylococcus aureus, whereas, the coordination compounds had modest activities against the Gram negative bacteria: Escherichia coli and Pseudomonas aeruginosa.
Wed, 31 January 2018
ARTICLE Download: 646| View: 424| Comments: 0 | doi:10.20944/preprints201801.0292.v1
Subject: Chemistry, Medicinal Chemistry Keywords: African medicinal plants; Leishmaniasis; natural products; protozoal diseases; Schistosomiasis; Trypanosomiasis
Online: 31 January 2018 (05:28:15 CET)
Parasitic diseases continue represent a threat on a global scale, particularly among the poorest countries in the world. This is particularly because of the absence of vaccines, and in some cases, resistance against available drugs, currently being used for their treatment. In this review emphasis is laid on natural products and scaffolds from African medicinal plants (AMPs) for lead drug discovery and possible further development of drugs for the treatment of parasitic diseases. In the discussion, emphasis has been laid on alkaloids, terpenoids, quinones, flavonoids and narrower compound classes of compounds with micromolar range activities against Schistosoma, Trypanosoma and Leishmania species. Suggestions for future drug development from African medicinal plants have also been provided.
Wed, 10 January 2018
SHORT NOTE Download: 288| View: 358| Comments: 0 | doi:10.20944/preprints201801.0087.v1
Subject: Chemistry, Medicinal Chemistry Keywords: redox-sensitive; disulfide linker; gemini amphiphiles; gene therapy
Online: 10 January 2018 (09:12:03 CET)
The absence of highly effective delivery systems is a major challenge for gene therapy. Our work was aimed at the development of novel cationic liposomes possessing high transfection efficiency. For this purpose, a novel disulfide polycationic amphiphile 2S4 was synthesized. Cationic liposomes based on 2S4 and a helper lipid DOPE were formed by the thin film hydration method and exhibited effective pDNA delivery into the HEK293 cells, with a maximal transfection activity superior to that of the commercial agent Lipofectamine® 2000. Our results suggest that the polycationic amphiphile 2S4 is a promising candidate for in vitro nucleic acid delivery.
Tue, 9 January 2018
ARTICLE Download: 429| View: 447| Comments: 0 | doi:10.20944/preprints201801.0079.v1
Online: 9 January 2018 (08:54:18 CET)
We synthesized a small series of five 3-[4-arylmethoxy)phenyl]propanoic acids using an easy and short step synthetic route. All compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: GPR40, aldose reductase (AKR1B1), PPARγ and GLUT-4. Compound 1 displayed an EC50 value of 0.075 μM against GPR40 and was an AKR1B1 inhibitor, showing IC50 = 7.4 μM. Compounds 2 and 3 behave as AKR1B1 inhibitors, GPR40 agonists and showed an increase of 2 to 4-times in the mRNA expression of PPARγ, as well as the GLUT-4 levels. Docking studies were conducted in order to explain the polypharmacological mode of action and the interaction binding mode of the most active compounds on these targets. Compounds 1-3 were tested in vivo at 100 mg/kg dose, being 2 and 3 orally actives, reducing glucose levels in a non insulin-dependent diabetes mellitus mice model. Compounds 2 and 3 showed robust in vitro and in vivo efficacy, and could be considered as promising multitarget antidiabetic drug candidates. This is the first report of a single molecule with these four polypharmacological target action.
Tue, 2 January 2018
ARTICLE Download: 342| View: 361| Comments: 0 | doi:10.20944/preprints201711.0177.v2
Subject: Chemistry, Medicinal Chemistry Keywords: Leishmania; thiochroman-4-ones; acyl hydrazone; cytotoxicity
Online: 2 January 2018 (10:11:55 CET)
Cutaneous leishmaniasis (CL) is a neglected tropical disease, which causes severe skin lesions. Due to the lack of effective vaccines, and toxicity or reduced effectiveness of available drugs in addition to complex and prolonged treatments, there is an urgent need to develop alternatives for the treatment for CL with different mechanisms of action. In our effort to search for new promising hits against Leishmania parasites we prepared 18 acyl hydrazone derivatives of thiochroman-4-ones. Compounds were evaluated for their in vitro antileishmanial activity against the intracellular amastigote form of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2). Our results show that derivatization of the thiochroman-4-ones with acyl hydrazones significantly enhances the antileishmanial activity. Among the compounds tested semicarbazone and thiosemicarbazone derivatives of thioflavanone 19 and 20 displayed the highest antileishmanial activities, with EC50 values of 5.4 and 5.1 µM and low cytotoxicities (100.2 and 50.1 µM respectively), resulting in higher indexes of selectivity (IS).
Mon, 11 December 2017
ARTICLE Download: 300| View: 519| Comments: 0 | doi:10.20944/preprints201712.0066.v1
Subject: Chemistry, Medicinal Chemistry Keywords: cancer; cell line; urea derivatives; synthesis; antiproliferative activity
Online: 11 December 2017 (15:10:36 CET)
Synthesis of new series of 1-phenyl-3-(4-(pyridin-3-yl) phenyl) urea derivatives and its in vitro antiproliferative activities against NCI-60 human cancer cell lines of nine different cancer types are described. Fourteen compounds 5a-n have been synthesized with three different hydrogen bondable moieties (4-hydroxylmethylpiperidinyl and trimethoxyphenyloxy and 4-hydroxyethylpiperazine) attached to the core structure 1-phenyl-3-(4-(pyridin-3-yl) phenyl) urea. Different substituents with different π and σ values were added on the terminal phenyl group. Compounds with 4-hydroxymethylpiperidine moiety showed higher mean percentage inhibition values over the 60-cell line panel at 10-µM concentration. They showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 5a elicited some lethal rather than inhibition effects on SK-MEL-5 melanoma cell line, 786-0, A498, RXF 393 renal cancer cell lines, and MDA-MB-468 breast cancer cell line by 146.1, 108.7, 136.2, 134.8, 116.6 % at 10 µM, respectively. Compounds 5a-e exhibited superior antiproliferative activity than Paclitaxel and Gefitinib against the most sensitive cell lines. Two compounds, 5a and 5d showed promising mean growth inhibitions and thus were further tested at five-dose testing mode to determine their IC50 values. The data revealed that 5a and 5d urea compounds are the most active derivatives with significant efficacies and superior potencies than Paclitaxel in 21 different cancer cell lines, belonging particularly to renal cancer and melanoma cell lines. Moreover, 5a and 5d had superior potencies than Gefitinib in 38 and 34 cancer cell lines, respectively; belonging particularly to colon cancer, breast cancer and melanoma cell lines.
Mon, 27 November 2017
ARTICLE Download: 225| View: 281| Comments: 0 | doi:10.20944/preprints201711.0177.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Leishmania; thiochroman-4-ones; acyl hydrazone; cytotoxicity
Online: 27 November 2017 (09:35:23 CET)
Cutaneous Leishmaniasis (CL) is a neglected tropical disease, which causes severe skin lesions. Due to the lack of effective vaccines, treatment can be complex and prolonged, high toxicity, side effects and high cost, there is an urgent need to develop alternatives for the treatment for CL that may have different mechanisms of action. In our effort to search for new promising hits against Leishmania parasites we prepared 18 acyl hydrazone derivatives of thiochroman-4-ones. Compounds were evaluated for their in vitro antileishmanial activity against intracellular amastigotes form of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2); our results show that derivatization with acyl hydrazones significantly enhance the antileishmanial activity, among the compounds tested semicarbazone (19) and thiosemicarbazone (20) derivatives of thioflavanone display the highest antileishmanial activities with EC50 values of 5.4 and 5.1 µM both with low cytotoxicities, 100.2 a 50.1 µM resulting in high selectivity index (SI).
Tue, 14 November 2017
ARTICLE Download: 399| View: 405| Comments: 0 | doi:10.20944/preprints201711.0091.v1
Subject: Chemistry, Medicinal Chemistry Keywords: diethylamine Mannich base; asymmetrical mono-carbonyl analogs of curcumin; AMACs; synthesis; cytotoxicity; antiproliferative activity; Hela cell lines
Online: 14 November 2017 (10:26:47 CET)
A series of diethylamine Mannich base of asymmetrical mono-carbonyl analogs of curcumin (AMACs) were synthesized and evaluated for cytotoxic activity against Hela Cell lines. The structures of the synthesized compounds were confirmed on the basis of FTIR, 1H-NMR, 13C-NMR and mass spectral data. Preliminary cytotoxic test using BSLT showed that all the synthesized compounds exhibited more potent cytotoxic activity than that of curcumin. While results of MTT assay showed that all the synthesized compounds exhibited more potent antiproliferative activity against HeLa cell lines than that of cisplatin. Compound 2b exhibited as the most potent compound of the series. Compound 2a, 2b, 2c, and 2f had IC50 (µM) less than that of compound 1a, 1b, 1c and 1f indicating that the addition of diethylamine Mannich base improves the antiproliferative activity of the parent compound.
Tue, 31 October 2017
ARTICLE Download: 493| View: 356| Comments: 0 | doi:10.20944/preprints201710.0200.v1
Subject: Chemistry, Medicinal Chemistry Keywords: 4-Thiazolidinones; ORAC assay; Metalloproteinase-9; Docking study; Keratinocytes cultures; Nuclear factor -kB.
Online: 31 October 2017 (16:36:16 CET)
Nine 2-(1,2-benzothiazol-3-yl)-N-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl) propanamides were designed and synthesized, combining benzisothiazole and 4-thiazolidinone in one frame. The aim of the study was to verify their effectiveness to contrast the inflammatory/oxidative process in which free oxygen and nitrite (ROS and RNS) radicals, advanced glycation products (AGEs), inflammatory cytokines and matrix metalloproteinases (MMPs) are involved. Docking studies of all the compounds were performed in order to explore their binding mode at the MMP-9 protein. An appreciable anti-inflammatory/wound healing effects of the tested compounds was highlighted. Derivative 23, bearing a 4-carboxyphenyl substituent at C2 of the 4-thiazolidinone ring, exhibited the highest activity, being able to inhibit MMP-9 at nanomolar level (IC50 = 40 nM).
ARTICLE Download: 487| View: 545| Comments: 0 | doi:10.20944/preprints201710.0196.v1
Subject: Chemistry, Medicinal Chemistry Keywords: osteoporosis; herbal medicine; Kukoamine B; osteoblast; osteoclast; bone mineral density; ovariectomized mice
Online: 31 October 2017 (15:35:04 CET)
Osteoporosis is an abnormal bone remodeling condition characterized by decreased bone density, which leads to high risks of broken bones. Previous studies have demonstrated that Lycii Radicis Cortex (LRC) extract inhibits bone loss in ovariectomized (OVX) mice by enhancing the osteoblast differentiation. A bioactive compound, Kukoamine B (KB), was identified from a fractionation of LRC extract as a candidate component responsible for an anti-osteoporotic effect. This study investigated the anti-osteoporotic effects of KB using in vitro and in vivo osteoporosis models. KB treatment significantly increased the osteoblastic differentiation and mineralized nodule formation of osteoblastic MC3T3-E1 cells, while it significantly decreased the osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. The effects of KB on osteoblastic and osteoclastic differentiations under more physiological conditions were also examined. In the co-culture of MC3T3-E1 cells and monocytes, KB promoted osteoblast differentiation but did not affect osteoclast differentiation. For the in vivo experiments, KB significantly inhibited OVX-induced bone mineral density loss and restored the impaired bone structural properties in osteoporosis model mice. These results suggest that KB may be a potential therapeutic candidate for the treatment of osteoporosis.
ARTICLE Download: 1734| View: 607| Comments: 0 | doi:10.20944/preprints201710.0194.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Africa; Terminalia brownii; antifungal extracts; Aspergillus, Nattrassia, Fusarium; triterpenoids; flavonoids; ellagitannins; stilbenes
Online: 31 October 2017 (09:54:35 CET)
Decoctions, macerations and fumigations of the stem bark and wood of Terminalia brownii Fresen. are used in traditional medicine for fungal infections and as pesticides on field crops and in traditional granaries in Sudan. In addition, T. brownii is commonly used for protecting wooden houses and furniture. Therefore, using agar disc diffusion and macrodilution methods, eight extracts of various polarities from the stem wood and bark were screened for their growth inhibitory effects against filamentous fungi commonly causing fruit, vegetable and grain decay, as well as infections in the immunocompromised host. Ethyl acetate extracts of the stem wood and bark gave the best antifungal activities, with MIC values of 250 µg/ml against Nattrassia mangiferae and Fusarium verticillioides, and 500 µg/ml against Aspergillus niger and Aspergillus flavus. Aqueous extracts gave almost as potent effects as the ethyl acetate extracts against the Aspergillus and Fusarium strains, and were slightly more active than the ethyl acetate extracts against Nattrassia mangiferae. Thin layer chromatography, RP-HPLC-DAD and tandem mass spectrometry (LC-MS/MS), were employed to identify the chemical constituents in the ethyl acetate fractions of the stem bark and wood. The stem bark and wood were found to have a similar qualitative composition of polyphenols and triterpenoids, but differed quantitatively from each other. The stilbene derivatives, cis- (3) and trans- (4) resveratrol-3-O-β-galloylglucoside, were identified for the first time in T. brownii. Moreover, methyl-(S)-flavogallonate (5), quercetin-7-β-O-di-glucoside (8), quercetin-7-O-galloyl-glucoside (10), naringenin-4`-methoxy-7-pyranoside (7), 5,6-dihydroxy-3`,4`,7-tri-methoxy flavone (12), gallagic acid dilactone (terminalin) (6), a corilagin derivative (9) and two oleanane type triterpenoids (1) and (2) were characterized. Our results justify the traditional uses of macerations and decoctions of T. brownii stem wood and bark for crop and wood protection and demonstrate that standardized extracts could have uses for the eco-friendly control of plant pathogenic fungi in African agroforestry systems. Likewise, our results justify the traditional uses of these preparations for the treatment of skin infections caused by filamentous fungi.
Fri, 13 October 2017
ARTICLE Download: 386| View: 496| Comments: 0 | doi:10.20944/preprints201710.0088.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Caesalpinia sappan; cassane diterpenes; N bridge; antimalarial activity
Online: 13 October 2017 (06:30:04 CEST)
One new cassane diterpene possessing an unusual N bridge between C-19 and C-20 named caesalsappanin R (1), as well as another new diterpene caesalsappanin S (2), were isolated from the seeds of Caesalpinia sappan with methanol extract. Their structures were determined by spectroscopic analysis and examined alongside existing data from prior studies. Their biological activities were profiled by their antiplasmodial activity.
Thu, 17 August 2017
ARTICLE Download: 1311| View: 1609| Comments: 0 | doi:10.20944/preprints201708.0057.v1
Subject: Chemistry, Medicinal Chemistry Keywords: [18F]PSMA-1007; fluorine-18; PSMA; automation; prostate cancer; PET
Online: 17 August 2017 (06:10:57 CEST)
Radiolabelled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection we recently developed the fluorine-18 labelled PSMA-ligand [18F]PSMA-1007 as next generation radiofluorinated Glu-ureido PSMA inhibitor after [18F]DCFPyL and [18F]DCFBC. Since radiosynthesis so far was suffering for rather poor yields novel procedures for the automated radiosyntheses of [18F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly used radiosynthesisers. Using the novel one-step procedure the [18F]PSMA-1007 was produced in good radiochemical yields ranging from 30-70 % and synthesis times less than 55 minutes. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and at the same time high yielding production pathway for the next generation PSMA radioligand [18F]PSMA-1007. Actually it turned out that the radiosynthesis is as easily realised as the well-known [18F]FDG synthesis and thus transferable onto all currently available radiosynthesisers. Using the new procedures, clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch.
Tue, 11 July 2017
REVIEW Download: 777| View: 539| Comments: 0 | doi:10.20944/preprints201707.0019.v1
Subject: Chemistry, Medicinal Chemistry Keywords: affective disorders; alzheimer’s disease; l-Deprenyl (Selegiline); donepezil; galantamine; value; inhibitor constant; mechanism-based inhibition; multitarget-directed ligand (MTDL); rasagiline; rivastigmine
Online: 11 July 2017 (05:58:53 CEST)
The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behaviour remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.
Fri, 30 June 2017
ARTICLE Download: 642| View: 718| Comments: 0 | doi:10.20944/preprints201706.0132.v1
Subject: Chemistry, Medicinal Chemistry Keywords: arylamine N-acetyltransferases; cancer; tuberculosis; drug discovery; traditional Chinese medicine; virtual screening; molecular dynamics simulation; MM-PBSA
Online: 30 June 2017 (11:36:22 CEST)
Arylamine N-acetyltransferases (NATs) are cytosolic enzymes, highly polymorphic, present in both eukaryotes and prokaryotes. These enzymes play an important role in the detoxification and activation of xenobiotics as well as in the synthesis of endogenous compounds. Specific NATs have been pointed out in the literature as possible therapeutic targets. In particular, the human NAT1, for the treatment of certain cancers, and the NAT from M. tuberculosis (TBNAT), for the treatment of tuberculosis. This paper describes an in silico approach to prospect and select potentially inhibitors of NAT1 and TBNAT from the Traditional Chinese Medicine (TCM) using free available tools. A library with ligands from TCM was previously screened in order to select only compounds with optimal pharmacological properties. The affinity of the selected ligands with respect to NAT enzymes was then evaluated by virtual screening (VS). Subsequently, the complexes with the best ligands were submitted to molecular dynamics (MD) simulations aiming to obtain better quality information on affinity and selectivity. The results for one specific ligand, ZINC14690579, indicated its potential for affinity and selectivity. ZINC14690579 structure may represent the discovery of a new scaffold for future development of NAT inhibitors.
ARTICLE Download: 624| View: 638| Comments: 0 | doi:10.20944/preprints201706.0128.v1
Subject: Chemistry, Medicinal Chemistry Keywords: steroidal dimer; steroidal N-heterocycles; antiproliferative activity; esophageal cancer cells
Online: 30 June 2017 (07:43:06 CEST)
Following our previous success in identifying new steroid-based anticancer agents, we herein disclosed the structural requirements for retaining high potency against cancer cells and associated modes of action. The structurally novel steroidal dimer by001 inhibited growth of different esophageal cancer cells and colony formation at low micromolar levels, elevated cellular ROS levels and caused mitochondrial dysfunction. Mechanistic studies showed that by001 induced cell death through the mitochondria and death receptor-mediated apoptotic pathways and autophagy induction, as well as inhibited migration.
Fri, 16 June 2017
COMMUNICATION Download: 601| View: 664| Comments: 0 | doi:10.20944/preprints201706.0074.v1
Subject: Chemistry, Medicinal Chemistry Keywords: deep-sea; actinomycete; Microbacterium sp.; indole
Online: 16 June 2017 (04:40:54 CEST)
A novel indole, microindolinone A (1), was isolated from a deep-sea-derived actinomycete Microbacterium sp. MCCC 1A11207, together with 18 known compounds (2–19). By detailed analysis of the 1H, 13C, HSQC, COSY, HMBC, HRESIMS, and CD data, the absolute configuration of 1 was elucidated as 5R-hydroxy-4,5,6,7-tetrahydroindole-4-one. Noteworthily, 1 is the second example of a saturated indole isolated from nature.
Mon, 15 May 2017
REVIEW Download: 2139| View: 1058| Comments: 0 | doi:10.20944/preprints201705.0115.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Palladium; Suzuki cross coupling; natural product; non-natural product
Online: 15 May 2017 (18:30:52 CEST)
New class of biologically active and non-active compounds can be synthesized via transition metal mediated Suzuki cross coupling reaction that has a great impact on the advancement of organic chemistry. These resulted products can lend a helping hand in pharmaceutical and polymer chemistry for the betterment of mankind. Suzuki-Miyaura cross coupling reaction is one of the best tools through which many natural and non-natural compounds can be synthesized.
Mon, 24 April 2017
ESSAY Download: 653| View: 738| Comments: 0 | doi:10.20944/preprints201704.0120.v2
Subject: Chemistry, Medicinal Chemistry Keywords: oleanolic acid derivatives; synthesis; anti-tumor activity; molecular docking; computer-aided drug design
Online: 24 April 2017 (12:08:36 CEST)
Using the techniques of computer-aided drug design, the docking of Survivin and known active small molecules was simulated and then the key amino acid residue fragment of the target protein was analyzed. It led to the discovery of active groups capable of binding to the critical sites. Through the use of the natural product, Oleanolic Acid, as a lead compound, the introduction of the active groups onto the A-ring, and the modification of the carboxyl group at the C-28 position using esterification or amidation, twenty new Oleanolic acid derivatives had been designed and synthesized.A549 and SGC-7901 cells were used to screen the antitumor activity in vitro through the standard MTT method. The compounds, II3, III5 and Ⅳ4, exhibited more potent cytotoxicity than positive drugs.
Wed, 19 April 2017
ESSAY Download: 385| View: 463| Comments: 0 | doi:10.20944/preprints201704.0120.v1
Subject: Chemistry, Medicinal Chemistry Keywords: oleanolic acid derivatives; synthesis; anti-tumor activity; molecular docking
Online: 19 April 2017 (05:00:30 CEST)
With the computer drug-aided design and the key amino acid residue fragment of the target protein analyzed on the basis of simulated docking of Survivin and known active small molecules, the active groups capable of binding to the critical sites were determined. After the natural product Oleanolic acid was used as lead compound, then the active groups were introduced on the ring of A, next the carboxyl group at the C-28 position was modified by esterification or amidation, twenty new Oleanolic acid derivatives had been designed and synthesized. SKOV3 and BGC-823 cells were used to screen the antitumor activity in vitro through the standard MTT method. Among the selection, compounds II3、III5 and Ⅳ4 exhibited more potent cytotoxicity than positive drugs.
Thu, 16 March 2017
REVIEW Download: 883| View: 921| Comments: 0 | doi:10.20944/preprints201703.0118.v1
Subject: Chemistry, Medicinal Chemistry Keywords: dengue; chikungunya; virus enzymes; antiviral; natural products
Online: 16 March 2017 (09:42:52 CET)
Dengue virus (DENV) and chikungunya virus (CHIKV) are reemergent arboviruses that are transmitted by mosquitoes of the Aedes genus. During the last several decades, these viruses have been responsible for millions of cases of infection and thousands of deaths worldwide. Therefore, several investigations were conducted over the past few years to find antiviral compounds for the treatment of DENV and CHIKV infections. One attractive strategy is the screening of compounds that target enzymes involved in the replication of both DENV and CHIKV. In this review, we describe advances in the evaluation of natural products targeting the enzymes involved in the replication of these viruses.
Fri, 10 March 2017
ARTICLE Download: 878| View: 903| Comments: 0 | doi:10.20944/preprints201703.0053.v1
Subject: Chemistry, Medicinal Chemistry Keywords: 1,3,4-Thiadiazole; 1,2,4-Triazole; synthesis; MTT assay; Cytotoxicity of Schiff base
Online: 10 March 2017 (10:11:56 CET)
5-(4-aminophenyl )-2-amino -1,3,4-thiadiazole was prepared by reaction of Thiosemicarbazide with 4-amino benzoic acid under reflux condition for 7 hours. The compound which has been synthesized successfully was subjected to addition reaction with 4-(Dimethylamino) benzaldehyde under reflux condition for 6 hours to synthesize Schiff bases. These compounds was characterized by using FTIR) and evaluated for their anticancer activity. The effect of (1, 3, 4-thiadiazole derivative) on the activity of malignant cells was studied by using different types of cell lines [Breast cancer, and human prostate cancer]. And was used the Electron microscope to show that the effect of the derivative on the cancer cells before and after 3 days of the injection time. It was found that the Schiff base of thiadiazole-1,3,4-(Dimethylamino)benzylidineamino]- [4-2-phenyl]amino was effective in reducing the size and density of malignant cells. That of 46.7 while in breast ) 145(DUprostate for growth inhibition produce of equal 85.9 µg/ml.
Tue, 7 March 2017
ARTICLE Download: 622| View: 752| Comments: 0 | doi:10.20944/preprints201703.0037.v1
Subject: Chemistry, Medicinal Chemistry Keywords: hypertension; 4-hydroxy-2-nonenal (4HNE); reactive oxygen species(ROS)
Online: 7 March 2017 (07:00:16 CET)
The oxidative stress is one of the main cause for cardiovascular diseases (like Hypertension) also one of the results of these diseases. This study involved 56 subjects matched ages and sex divided into two groups; 28 hypertensive subject and 28 healthy subject as control group. The following analysis was done: 4-Hydroxy-2-nonenal(4HNE) and albumin. The results show that there is a significant increase in (4HNE) between patients group and control group. The increase in 4HNE which is a product of lipid peroxidation is attributed to destruction in body cell caused by due to the increase in stress events. It has been concluded that is important nappy on ideal weight, because obesity considered main factors for heart disease and hardening of the arteries. The aim of this study was to investigate the relationship between of some oxidative stress markers and cardiovascular diseases.
Thu, 15 December 2016
ARTICLE Download: 1054| View: 931| Comments: 0 | doi:10.20944/preprints201612.0082.v1
Subject: Chemistry, Medicinal Chemistry Keywords: transdermal physical penetration technology; Fu’s Cupping Therapy; pharmacokinetics; SEM; TEM; stratum corneum; mechanism
Online: 15 December 2016 (10:57:46 CET)
Background: in this paper, a new physical penetration technology for transdermal administration with traditional Chinese medicine (TCM) characteristics - Fu’s cupping therapy (FCT) - was established and studied by in-vitro and in-vivo experiments; the penetration effect and mechanism of FCT physical penetration technology (FCT-PPT) was preliminarily discussed. Method: Indomethacin (IM) as a model drug，by transdermal in vitro tests the establishment of the high，medium and low reference were finished as the chemical permeation system；chemical penetration enhancers and iontophoresis as a reference，the percutaneous penetration effect of FCT for IM patch was evaluated with 7 species diffusion kinetics model and in vitro drug distribution；naproxen as an internal standard，using UPLC-MS/MS technology，the IM quantitative analysis method in vivo was established，and pharmacokinetic parameters (AUC0-t，AUC0-∞，AUMC0-t，AUMC0-∞, Cmax and MRT) as indicators were used evaluate to FCT penetration role in vivo；in the same time，the group used 3K factorial design to study joint synergistic penetration effect on FCT and chemical penetration enhancers (CPEs)；by SEM and TEM，the skin micro and ultrastructural changes of the stratum corneum (SC) surface were observed, to explore pay tank penetration mechanism. Results: In vitro and in-vivo skin permeation experiments revealed that both the total cumulative percutaneous amount and in-vivo percutaneous absorption amount (AUC and AUMC) of indomethacin that permeated SD mouse skin using FCT techniques were greater than the amount observed using CPE and iontophoresis: Firstly, in contrast to the control group, the indomethacin percutaneous rate (PR) of the FCT lower group (FCTL) was 35.52%, and the enhancement ratio (ER) at 9h was 1.76X, which was roughly equivalent to the penetration enhancing effect of the CPEs and iontophoresis; secondly, the indomethacin PR of the FCT middle (FCTM) group and the FCT high intensity group (FCTH) were respectively 47.36% and 54.58%, ER at 9h were separately 3.58X and 8.39X; thirdly, pharmacokinetic studies showed that in-vivo indomethacin percutaneous absorption of the FCTs was higher than that of the control group, that of the FCTM group was slightly higher than that of the CPEs group, and that of the FCTM group was significantly higher than that of the others. Meanwhile, the variance analysis indicated that the combination of the FCT penetration enhancement method and the CPE method had beneficial effects in penetration enhancing of the skin: the significance level of the CPE method was 0.0004, which was apparently lower than the 0.001, meaning the difference was markedly significant; the significance level of the FCT was under 0.0001, its difference markedly significant; and the significance level of factor interaction A×B was lower than 0.0001, indicating that its difference of the synergism was markedly significant. Moreover, SEM and TEM images showed that the SC surfaces of SD rats treaded with FCT-PPT was damaged, and hard to observe the complete surface structure with its SC pores growing bigger and its special “brick structure” becoming looser, indicating that it broke the barrier function of skin, which revealed potentially a major route of skin penetration. Conclusion: FCT, as percutaneous penetration new technologies, has penetration effects significantly, with Chinese characteristics and highly clinical value, worth promoting development.
Sun, 27 November 2016
CASE REPORT Download: 975| View: 1106| Comments: 1 | doi:10.20944/preprints201611.0134.v1
Online: 27 November 2016 (04:43:15 CET)
Hyperlipidemia case was described as a rise of lipid profile or lipoproteins in the blood. This study describe briefly investigate the reducing hyperlipideamia impact of Ginkgo biloba on the level of lipid profile.
Mon, 14 November 2016
ARTICLE Download: 857| View: 842| Comments: 0 | doi:10.20944/preprints201611.0072.v1
Subject: Chemistry, Medicinal Chemistry Keywords: aporphine derivatives; antiarrhythmia; 10,11-dibromocrebanine; 3-bromocrebanine; crebanine; stephanine
Online: 14 November 2016 (07:24:04 CET)
Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF), induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d), three bromo-substituted products of crebanine (2a, 2b, 2c), N-methylcrebanine (2d), and dehydrostephanine (4a) displayedantiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p<0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p<0.01), and the number of rats that maintained sinus rhythm for more than 20 minutes (p<0.01). Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50=59.62 mg/kg, mice), simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.
ARTICLE Download: 1195| View: 1061| Comments: 0 | doi:10.20944/preprints201611.0071.v1
Subject: Chemistry, Medicinal Chemistry Keywords: diabetes mellitus; metformin; glibenclamide and lipid profile
Online: 14 November 2016 (07:14:00 CET)
Diabetes mellitus (DM) has been defined as a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. This study includes (84) subjects, their age ranged from (40 to 54) years. (20) subjects were healthy chosen as control group and (64) patients with type 2 diabetes mellitus were divided into three groups according to their type of anti diabetic therapy: (23) newly diagnosed group without therapy (Group1), (20) with metformin therapy (Group2) and (21) with metformin plus glibenclamide therapies (Group3). In the study lipid profile level were quantitatively determine by enzymatic methods, in addition to that fasting plasma glucose (FPG), Glycated hemoglobin (HbA1c%) and body mass index (BMI) were identified in the patients. There is significant increase in the level of lipid profile in patients group. Metformin alone produce a non-significant favorable effect on all lipids profile parameters while metformin plus glibenclamide showed a significant reduction in TC and LDL-C.
Mon, 7 November 2016
ARTICLE Download: 696| View: 886| Comments: 0 | doi:10.20944/preprints201611.0043.v1
Online: 7 November 2016 (08:30:12 CET)
A series of novel isobutylchalcones (A1-A20) were prepared, evaluated for their cytotoxic activity and characterized by FTIR, 1H NMR, 13C NMR, and elemental analysis data. The logic behind the design is to synthesize and compare chalcones containing electron releasing lipophilic isobutyl substituent on aromatic ring A and the B ring with aromatic ring containing a range of electron releasing and electron withdrawing groups as well as heteroaromatic rings for their cytotoxic activity. The compounds were tested against HT-29 (colon cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer) cell lines using methotrexate (IC50 12 ± 1 (HT-29), 9 ±1 (MCF-7) 5 ± 1 (DU-145)) as reference standard. Compound A6 having 2,4-difluorphenyl moiety was most potent of the series against all the three cell lines and notably A6 was mainly effective against DU-145 cell lines with an IC50 value of 18 µg/mL. The critical structural features required for the activity against all the cell lines were identified through pharmacophore model using PHASETM which has recognised a 5 point AHHRR model and is consistent with the cytotoxic activity of the tested compounds.
Mon, 31 October 2016
ARTICLE Download: 1026| View: 882| Comments: 1 | doi:10.20944/preprints201610.0137.v1
Subject: Chemistry, Medicinal Chemistry Keywords: glibenclamide therapies; glycemic; Glucose-6-phosphatase
Online: 31 October 2016 (08:35:41 CET)
Glucose-6-phosphatase (G6Pase), an enzyme found mostly in the kidneys and the liver, acting significant role of supplying glucose through starvation. This study includes (84) subjects, their age ranged from (40 to 54) years. (20) subjects were healthy chosen as control group and (64) patients with type 2 diabetes mellitus were divided into three groups according to their type of anti diabetic therapy : (23) newly diagnosed group without therapy (Group1), (20) with metformin therapy (Group2) and (21) with metformin plus glibenclamide therapies( Group3). The study found that G-6-Pase activity is increased, thereby leading to an increase in endogenous glucose production (EGP) in patients with type 2 diabetes and, therefore FPG will increase. The result found that increasing G-6-Pase activity will increase the concentration of glucose in the blood and that will increase the long-term glycemic control (HbA1c%).
Thu, 29 September 2016
ARTICLE Download: 1150| View: 1195| Comments: 0 | doi:10.20944/preprints201609.0122.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Cancer; FGFR; Inhibitor; 4‐Substituted‐1H‐indazole
Online: 29 September 2016 (15:42:08 CEST)
Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles derivatives as potent FGFR inhibitors. Compound 10a was first identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that compound 13a is the most potent FGFR1 inhibitor in this series with the enzyme inhibitory activity about 30.2 nM of IC50 value.
Mon, 15 August 2016
ARTICLE Download: 1452| View: 1063| Comments: 0 | doi:10.20944/preprints201608.0145.v1
Subject: Chemistry, Medicinal Chemistry Keywords: methyl 3,4-dihydroxybenzoate; oxidative stress; apoptosis; neuroprotection; nuclear factor erythroid 2-related factor 2
Online: 15 August 2016 (10:42:05 CEST)
This study investigated the neuroprotective effects of methyl 3,4-dihydroxybenzoate (MDHB) against t-butylhydroperoxide(TBHP) induced oxidative damage in SH-SY5Y (human neuroblastoma cells) and the underlying mechanisms. SH-SY5Y were cultured in DMEM+10% FBS for 24 hours and pretreated with different concentrations of MDHB or N-acetyl-L-cysteine (NAC) for 4 hours prior to the addition of 40 μM TBHP for 24 hours. Cell viability was analyzed using the methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays. An annexin V-FITC assay was used to detect cell apoptosis rate. The 2',7'-dichlorofluorescin diacetate (DCFH-DA) assay was used to determine intracellular ROS levels. The activities of antioxidative enzymes (GSH-Px and SOD) were measured using commercially available kits. The oxidative DNA damage marker 8-OHdG was detected using ELISA. Western blotting was used to determine the expression of Bcl-2, Bax, caspase 3, p-Akt and Akt proteins in treated SH-SY5Y cells. Our results showed that MDHB is an effective neuroprotective compound that can mitigate oxidative stress and inhibit apoptosis in SH-SY5Y cells
Thu, 11 August 2016
ARTICLE Download: 1497| View: 1247| Comments: 0 | doi:10.20944/preprints201608.0119.v1
Subject: Chemistry, Medicinal Chemistry Keywords: thiazoles; thiadiazoles; hydrazonoyl chlorides; anticancer activity; structure activity relationship
Online: 11 August 2016 (11:05:21 CEST)
A novel series of thiazole based-1,3,4-thiadiazoles were designed and prepared via the reaction of the 2-(4-methyl-2-phenylthiazole-5-carbonyl)-N-phenylhydrazinecarbothioamide with the appropriate hydrazonoyl chlorides. The structures of the newly synthesized compounds were established based on spectroscopic evidences and their alternative syntheses. Thirteen new 1,3,4-thiadiazoles have been evaluated for their anticancer activity against liver carcinoma cell line (HepG2). Also, their structure activity relationship (SAR) was studied. The 1,3,4-thiadiazoles 12d, 12c, 6g,18b, 6c, and 6f(IC50 = 0.82, 0.91, 1.06, 1.25, 1.29 and 1.88 µM, respectively) have promising antitumor activity against liver carcinoma cell line (HepG2).
Tue, 9 August 2016
ARTICLE Download: 1144| View: 1128| Comments: 0 | doi:10.20944/preprints201608.0086.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Acid hydrolysis; Degradation product; Saikosaponin a
Online: 9 August 2016 (11:32:29 CEST)
Saikosaponin (SS) a is a compound with various pharmacological properties and easily degraded into SSb1 and SSg in acid condition. In present work another two new degradation products of SSa formed under acid hydrolytic condition were detected and isolated by analytical and semi-preparative liquid chromatography technology, furthermore their structures were characterized as hydroxyl-saikosaponin a and SSb2 by spectral analysis, which is not only essential in stability-indicating method development and validation but also could be used as a worst case to assess the analytical method performance of SSa. Moreover their structural transformation pathways were also proposed.
Tue, 2 August 2016
ARTICLE Download: 1521| View: 1286| Comments: 0 | doi:10.20944/preprints201608.0013.v1
Subject: Chemistry, Medicinal Chemistry Keywords: α-mangostin; antibacterial; antifungal; food packaging; semi-synthetic modification
Online: 2 August 2016 (09:02:09 CEST)
The microbial contamination in food packaging have been a major concern that paved the way for the search for natural based new anti-microbial agents, such as modified α-mangostin. In the present work, twelve synthetic analogs were obtained via semi-synthetic modification of α-mangostin by Ritter reaction, reduction by palladium-carbon (Pd-C), alkylation, and acetylation. The evaluation of the anti-microbial potential of the synthetic analogs showed higher therapeutic value than the parent molecule. The anti-microbial studies proved that I E showed higher antibacterial activity whereas I I showed most significant antifungal activity. Due to their microbial properties, modified α-mangostin can be utilized as active anti-microbial agents in food packaging.