Abstract: HIV/AIDS and Mycobacterial tuberculosis (Mtb) are the leading cause of deaths world-wide. Thus, better medicaments are required to manage these diseases. Quinolines have shown great potential due to their broad spectrum of biological activity. Thus, quinoline-1,2,3-triazole-aniline hybrids were synthesised in moderate to good yields. Compounds 11g (IC50 = 0.388 µM), 11h (IC50 = 0.01032 µM) and 11i (IC50 = 0.167 µM) ex-hibited the most promising in vitro activities against the wild-type HIV-1 subtype B, with 11h being 9-fold more active than AZT (IC50 = 0.0909 µM), the reference drug. Fur-thermore, compound 11h displayed moderate activity with MIC90 of 88μM against Mtb’s H37Rv strain. Cytotoxicity studies on TMZ-bl-cell lines revealed that most of the tested compounds were generally non-cytotoxic; the selectivity index (SI) for 11h, the front runner, is > 2472. Molecular docking studies revealed that 11h interacted with Phe112, Tyr108, Glu283, and Trp86 amino acid residues in the active site of the HIV-1. DFT studies revealed that 11h has the ability to donate and accept electrons to and from available orbitals. The predicted ADMET studies showed that these compounds pos-sess drug-likeness, and 11h has the potential to be further optimisation as anti-HIV-1 agent.

Abstract: Glycosylation is a critical enzymatic modification that involves the attachment of sugar moieties to target compounds, considerably influencing their physicochemical and biological characteristics. This review explored the role of two primary enzyme classes—glycosyltransferases (GTs) and glycoside hydrolases (GHs)—in catalyzing the glycosylation of natural products, with a specific focus on Ganoderma triterpenoids. While GTs typically use activated sugar donors, such as uridine diphosphate glucose, certain GHs can leverage more economical sugar sources, such as sucrose and starch, through transglycosylation. This paper also reviewed strategies for producing novel terpenoid glycosides, particularly recently isolated bacterial GTs and GHs capable of glycosylating terpenoids and flavonoids. It summarized the newly synthesized glycosides’ structures and biotransformation mechanisms, enhanced aqueous solubility, and potential applications. The regioselectivity and substrate specificity of GTs and GHs in catalyzing O-glycosylation at distinct hydroxyl and carboxyl groups were compared. Furthermore, a special case in which the novel glycosylation reactions were mediated by GHs, including the formation of unique glycoside anomers, was included. The advantages and specific capabilities of GT/GH enzymes were evaluated for their potential in biotechnological applications and future research directions.

Abstract: A new series of 6-arylaminoflavones was synthesized via the Buchwald-Hartwig cross-coupling reaction, aiming to functionalize the flavone core efficiently. Reaction optimization revealed that Pd₂(dba)₃/XantPhos with Cs₂CO₃ in toluene provided the best yields, with isolated yields ranging from 8% to 95%, depending on the arylamine structure. Steric hindrance and electron-withdrawing groups at the arylamine ring negatively impacted the reaction. Cytotoxicity assays indicated that specific substituents at the 6-position influenced biological activity, with trifluoromethyl- (13c) and chlorine-containing (13g) derivatives showing higher selectivity towards prostate cancer cells (PC3). These findings provide insights into the structure-activity relationship of 6-arylaminoflavones while contributing to the development of synthetic methodologies for functionalized flavones.

Abstract: Childhood neuroblastoma (NB) is a malignant tumour that is a member of a class of embryonic tumours that have their origins in sympathoadrenal progenitor cells. There are five stages in the clinical NB staging system: 1, 2A, 2B, 3, 4S, and 4. For those diagnosed with stage 4 neuroblastoma (NBS4) the treatment options are limited with a survival rate of between 40 to 50%. Since 1975, more than 15 targets have been identified in the search for a treatment for high-risk NBS4. This article is concerned with the search for a multi-target drug treatment for high-risk NBS4 and focuses on four possible treatment targets that research has identified as having a role in the development of NBS4 and includes the inhibitors Histone Deacetylase (HDAC), Bromodomain (BRD), Hedgehog (HH), and Tropomyosin Kinase (TRK). Computer-aided drug design and molecular modelling have greatly assisted drug discovery in medicinal chemistry. Computational methods such as molecular docking, homology modelling, molecular dynamics, and quantitative structure-activity relationships (QSAR) are frequently used as part of the process for finding new therapeutic drug targets. Using these methods, 8 compounds (inhibitors) were identified as possible inhibitors for all four targets. Results revealed that all four targets BRD, HDAC, HH and TRK share similar amino acid sequencing that ranges from 80-100% offering the possibility of further testing for multi-target drug use. Two additional targets were also tested as part of this work, Retinoic Acid (RA) and c-Src (Csk) which showed similarity across their receptors of 80-100% but lower that 80% for the other four targets. The work for these two targets is the subject of a paper currently in progress.

Abstract: Histone deacetylases (HDACs) are key regulators of gene expression, influencing chromatin remodeling and playing a crucial role in various physiological and pathological processes. Aberrant HDAC activity has been linked to cancer, neurodegenerative disorders, and inflammatory diseases, making these enzymes attractive therapeutic targets. HDAC inhibitors (HDACis) have gained significant attention, particularly those containing zinc-binding groups (ZBGs), which interact directly with the catalytic zinc ion in the enzyme’s active site. The structural diversity of ZBGs profoundly impacts the potency, selectivity, and pharmacokinetics of HDACis. While hydroxamic acids remain the most widely used ZBGs, their limitations, such as metabolic instability and off-target effects, have driven the development of alternative scaffolds, including ortho-aminoanilides, mercaptoacetamides, alkylhydrazides, oxadiazoles and more. This review explores the structural and mechanistic aspects of different ZBGs, their interactions with HDAC isoforms, and their influence on inhibitor selectivity. Advances in structure-based drug design have allowed the fine-tuning of HDACi pharmacophores, leading to more selective and efficacious compounds with improved drug-like properties. Understanding the nuances of ZBG interactions is essential for the rational design of next-generation HDACis, with potential applications in oncology, neuroprotection, and immunotherapy.

Abstract: Bioactive sphingolipids (SLs) are a category of lipids with sphingoid bases (SB) as their basic backbone structure. These molecules exhibit distinct pharmacological effects by targeting esterases, amidases, kinases, phosphatases, and membrane receptors. The SLs constitute highly complex metabolic pathway interconnections called Sphingolipidome. Each pathway signifies specific subcellular localizations that regulate the functions of SLs. These Sphingolipidome networks control critical functions of the cell involving cell growth by regulating apoptosis, senescence, cell migration, and inflammatory responses. These cellular functions are implicated in cardiovascular diseases, metabolic disorders, neurodegenerative disorders, autoimmune diseases, and cancers. Imbalances in SL metabolic pathways significantly contribute to the development and progression of these diseases. The pharmacological significance of sphingolipids has resulted in several sphingoid-based inhibitors, activators, and modulators for translational drug discovery efforts. Most of these medicinal agents possess close structural similarity with sphingolipids. This review covers the enantioselective syntheses and drug development efforts of sphingolipid-based medicinal agents of preclinical and clinical studies. These agents include Myriocin, Fingolimod, Fenretinide, Safingol, Spisulosine (ES-285), jaspine B, D-e-MAPP, B13, and α-Galactosylceramide. These agents were subjected to molecular modeling studies to understand the binding interactions with the biological target. The rationale discussion of these medicinal agents will help future drug discovery endeavors based on sphingolipid biochemistry.

Abstract: Bromodomain and Extra-Terminal (BET) proteins are crucial epigenetic regulators involved in transcriptional processes linked to cancer progression. Inhibiting these proteins has emerged as a promising therapeutic strategy, with OTX015, a potent BET inhibitor, showing promising efficacy against various cancer types. However, accurately predicting drug sensitivity across cancer cell lines remains a challenge. In this study, we present a machine learning-based approach to predict the half-maximal inhibitory concentration (IC₅₀) of OTX015 across various cancer cell lines using their gene expression profiles. By employing regression-based machine learning models, including Support Vector Machine (SVM), K-Nearest Neighbor (KNN), Extreme Gradient Boosting (XGB), Elastic Net (EN), and Neural Networks (NNET), we aimed to optimize prediction accuracy. The dataset was divided into subsets containing 10, 25, 50, 75, and 100 genes based on their correlation with IC₅₀ values, enabling a comprehensive evaluation of model performance across different data dimensions. The SVM model consistently demonstrated the best performance, achieving the lowest Mean Absolute Error (MAE) scores across all datasets, thereby proving most effective for predicting IC₅₀ values. This approach highlights the potential of integrating machine learning algorithms with gene expression data to enhance drug discovery and personalized medicine, particularly in the context of cancer research. Future work should focus on expanding datasets, optimizing feature selection, and evaluating additional machine learning approaches to improve prediction reliability and generalizability.

Abstract: Surface Plasmon Resonance (SPR) aptasensors benefit from the SPR phenomenon in measuring aptamer interactions with specific targets. Integrating aptamers into SPR detection enables extensive applications in clinical analysis. Specifically, virus design aptasensing platforms are highly desirable to face the ongoing challenges of virus outbreaks. This study systematically reviews the latest advances in SPR aptasensors for virus detection according to PRISMA guidelines. The literature search recovered 322 original articles from the Scopus (n = 152), Web of Science (n = 83), and PubMed (n = 87) databases. The selected articles (29) deal with the binding events between the aptamers immobilized on the sensor surface and their target molecule: virus proteins or intact viruses according to different SPR configurations. The methodological quality of each study was assessed using QUADAS-2, and a meta-analysis was conducted with the Cochrane RevMan software. Data were analyzed focusing on the types of viruses, the virus target, and the reference method. The pooled sensitivity was 1.89 (95%, CI 1.29, 2.78, I2 = 49%). The analysis of different types of plasmonic sensors showed the best diagnostic results with the least heterogeneity for SPR conventional configurations: 3.23 (95% CI [1.80, 5.79]; I2 = 0%, p = 0.65). These findings show that even though plasmonic biosensors effectively analyze viruses through aptamer approaches, there are still big challenges to using them regularly for diagnostics. Practical considerations for measuring label-free interactions revealed functional capabilities, technological boundaries, and future outlooks of SPR virus aptasensing.

Abstract:

In this study we evaluated in situ click chemistry as platform for discovering boronic acid-based β-lactamase inhibitors (BLIs). Unlike conventional drug discovery approaches requiring multi-step synthesis, protection strategies, and extensive screening, the in situ method can allow the generation and identification of potent β-lactamase inhibitors in a rapid, economic and efficient way. Using KPC-2 (class A carbapenemase) and AmpC (class C cephalosporinase) as templates, we demonstrated their ability to catalyse azide-alkyne cycloaddition, facilitating the formation of triazole-based β-lactamase inhibitors. Initial screening of various β-lactamases and boronic warheads identified compound 3 (3-azidomethylphenyl boronic acid) as the most effective scaffold for Kinetic Target-Guided Synthesis (KTGS). KTGS experiments with AmpC and KPC-2 yielded triazole inhibitors with K_i values as low as 140 nM (compound 10a, AmpC) and 730 nM (compound 5, KPC-2). Competitive inhibition studies confirmed triazole formation within the active site, while LC-MS analysis verified that the reversible covalent interaction of boronic acids did not affect detection of the in situ synthesised product. While KTGS successfully identified potent inhibitors, limitations in amplification coefficients and spatial constraints highlight the need for optimised warhead designs. This study validates KTGS as a promising strategy for BLI discovery and provides insights for further refinement in fighting β-lactamase-mediated antibiotic resistance.

Abstract: Auger electrons are low-energy, high-linear-energy-transfer particles that deposit their energy over nanometers distances. Their biological impact depends heavily on where the radionuclide is localized within the cell. To verify the hypothesis that the cell membrane may be a better molecular target than the cytoplasm in Auger electron therapy, we investigated whether the radiotoxicity of 99mTc varied depending on its location in the cell. The behavior of peptide radiopharmaceuticals 99mTc-TECANT targeted the cell membrane was compared with 99mTc-TEKTROTYD directed to the cytoplasm. Our findings confirmed that 99mTc-TECANT-1 displayed greater binding to AR-42-J cells than 99mTc-TEKTROTYD. Additionally, it was demonstrated that the receptor agonist 99mTc-TEKTROTYD is localized in more than 90% of the cytoplasm, while 99mTc-TECANT-1 is found in 60-80% of the cell membrane. When evaluating cell survival using the MTS assay, we observed that toxicity was significantly higher when 99mTc was targeted to the membrane compared to the cytoplasm. This indicates that, for 99mTc, as with 161Tb, the membrane is a more sensitive target for Auger electrons than the cytoplasm. Our results also suggest that receptor antagonists labelled with highly-radioactive 99mTc may be effective in treating certain cancers. However, further detailed studies, particularly dosimetric investigations, are necessary to validate these findings.

Abstract: The development of gadolinium-based magnetic resonance imaging (MRI) contrast agents (CAs) is a highly challenging and demanding research field in metal-coordination medicinal chemistry. The recognized high capacity of hydroxypyridinone (HOPO)-based compounds to coordinate Gd(III) led us to evaluate a set of physic-chemical-biological properties of a new Gd(III)-complex with an hexadentate tripodal ligand (H3L), containing three 3,4-HOPO chelating moieties attached to an anchoring cyclohexane backbone. In particular, the thermodynamic stability constants of the complex were evaluated by potentiometry, showing the formation of a high stable (1:1) Gd-L complex (log GdL = 26.59), with full coordination even in acid-neutral pH conditions. Molecular simulations of the Gd(III) complex revealed a minimum energy structure with somehow distorted octahedral geometry, involving full metal hexa-coordination by the three bidentate moieties of the ligand arms, indicating that extra water molecules should be coordinated to the metal ion, an important feature for the CAs (required enhancement of water proton relaxivity). In vivo biodistribution studies with the 67Ga complex, as surrogate of the corresponding Gd complex, showed in vivo stability and rapid excretion from the animal body. Though deserving further investigation, these results may give an input on future perspectives towards new MRI diagnostic agents.

Abstract: An accurate and rapid analysis of human indoleamine 2,3-dioxygenase (hIDO) is crucial for the development of anticancer pharmaceuticals because of the role of hIDO in promoting tumoral immune escape. However, the conventional assay of hIDO is limited by interference from reductants, which are used to reduce the heme iron to begin the hIDO catalytic reaction. Herein, we report a direct electrochemical method to control the redox state of the heme iron and the electrochemical investigation of hIDO. Although the conventional gold electrode did not offer a visible signal for the electron transfer between the electrode and hIDO, the anodized nanostructured gold electrode exhibited a clear nonturnover electrochemical response in an Ar atmosphere. In the presence of oxygen, the bioelectrocatalytic current for the reduction of oxygen, which competes with the oxidation of tryptophan upon the addition of the substrate, was observed, confirming an electrochemically driven hIDO reaction. A well-known inhibitor of hIDO, epacadostat, hindered this catalytic signal according to its concentration, demonstrating the rapid evaluation of its inhibition activity for the hIDO reaction. Through an in silico study using the proposed electrochemical assay system, we discovered a strong inhibitor candidate with a half-maximal inhibitory concentration of 10 nM, similar to that of epacadostat. This suggests the usefulness of the proposed system in drug discovery for hIDO and kynureine pathway-targeted immunotherapy.

Abstract:

Minoxidil is a medication used for hypertension. Nevertheless, a significant side effect of hypertrichosis was observed, whereby, now it is widely used in formulation of topical medications for treatment of alopecia. However, international regulations prohibit its use in cosmetic products due to its antihypertensive activity and the potential for systemic absorption after application to the scalp. Despite these regulatory restrictions, various studies have reported the presence of minoxidil in cosmetic products. Objectives: to determine the presence of minoxidil and Minoxidil oxothiazolidinecarboxylate in cosmetic products for hair growth, by means of a standardized and validated HPLC-UV method for different cosmetic matrices. Methods: the analytical method was statistically validated by parameters such as selectivity, linearity, precision, accuracy, precision, robustness, limit of detection and limit of quantification according to International Council for Harmonisation (ICH) guidelines. Results: The validated method meets the ICH requirements. Additionally, it was found that presumably 2 of the 9 cosmetic products analyzed contained the banned analyte minoxidil, corresponding to 22.22 % of the products analyzed. Conclusions: It was possible to standardize and validate a HPLC-UV method for identification of minoxidil in cosmetic matrices, which gives reliability to results obtained. However, it is important to verify these results with other techniques such as HPLC-MS, to support these statements.

Abstract: Ginsenosides with less sugar groups which were called minor ginsenosides might have greater pharmacological activity and a better adsorptive ability, but their content in nature is extremely low. In this study, a strain of Penicillium fimorum with strong saponin transformation ability was isolated from fresh Gastrodia elata. A comparative biotransformation experiment of the major saponins from Panax notoginseng root were conducted using crude enzyme from P. fimorum and commercial β-glucosidase to product minor ginsenosides. Specifically, the crude enzyme from P. fimorum was able to transform the major saponins from P. notoginseng root into 13 minor saponins within 72 hours, while commercial β-glucosidase was able to transform the same major saponins into 15 minor saponins within 72 hours. The most significant difference between their two enzymes is the ability to transform Rb1. To the best of our knowledge, the biotransformation ability of crude enzyme from P. fimorum is reported for the first time. These two enzymes have the potential to improve the economic value of P. notoginseng root and expand the methods for preparing minor saponins by transforming the major saponins in the total saponins of P. notoginseng root.

Abstract: Histone deacetylases (HDACs) become one of the main targets in cancer therapy due to their involvement in various biological processes, including gene regulation, cell proliferation and differentiation. On the other hand, microtubules as key elements of the cell cytoskeleton also represent an important therapeutic target in anticancer drugs research. These proteins are implied in diverse cellular functions, especially mitosis, cell signaling and intracellular trafficking. With the emergence of multi-target therapy during the last decades, the association of HDAC and tubulin inhibitors has been envisioned as a practical approach for optimizing the therapeutic efficacy of antitumor molecules. The HDAC/tubulin dual-targeting inhibitors offer the advantages of a synergistic action of both compounds, along with a significant decrease of their respective toxicities and drug resistance. This review will detail the major recent advancements in the development of HDAC/tubulin dual inhibitors over the last decade, with their impact in anticancer drugs discovery.

Abstract:

Alzheimer’s disease (AD) exerts a great socioeconomic burden, because of its increasing prevalence and the lack of effective therapies. The multifactorial nature of AD prompted researchers to search for new strategies for discovering disease-modifying therapeutics. To this extent, the multitarget approach holds the potential of synergic or cooperative activities arising from compounds properly designed to address two or more pathogenetic mechanisms. As a privileged and nature-friendly scaffold, coumarin has successfully been enrolled as the heterocyclic core for designing multipotent anti-Alzheimer’s agents. Herein, we summarized the most recent literature (2018-2023) covering the rational design and the discovery of coumarin-containing multitarget directed ligands (MTDLs) whose anti-AD profile encompassed at least two different biological activities relevant for disease onset and progression. To enhance the clarity of presentation, coumarin-based MTDLs are categorized into four clusters based on their substitution pattern and reported bioactivities: i) mono-, ii) di-, and iii) poly-substituted coumarins directed to protein targets; iv) coumarins directed to protein targets with additional metal-chelating features. Before discussing multimodal coumarins, the rationale for addressing each biological target has been briefly presented.

Abstract: Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising target for cancer diagnosis and therapy. However, high pancreas uptake of current clinically evaluated GRPR-targeted radiopharmaceuticals limits their applications. In this study, we replaced the Pro14 residue in our previously reported GRPR-targeted LW02056 and ProBOMB5 with 4,4-difluoroproline (diF-Pro) to obtain an agonist LW02060 (DO-TA-Pip-[D-Phe6,Tle10,NMe-His12,diF-Pro14]Bombesin(6-14)) and an antagonist LW02080 (DO-TA-Pip-[D-Phe6,NMe-Gly11,Leu13(ψ)diF-Pro14]Bombesin(6-14)), respectively. The binding affinities (Ki) of Ga-LW02060, Ga-LW02080, Lu-LW02060, and Lu-LW02080 were measured by in vitro competition binding assays using PC-3 cells and were 5.57 ± 2.47, 21.7 ± 6.69, 8.00 ± 2.61, and 32.1 ± 8.14 nM, respectively. The 68Ga- and 177Lu-labeled ligands were obtained in 36 - 75% decay-corrected radiochemical yields with > 95% radiochemical purity. PET imaging, SPECT imaging, and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice. Both [68Ga]Ga-LW02060 and [68Ga]Ga-LW02080 enabled clear tumor visualization in PET images at 1 h post-injection (pi). Tumor uptake values of [68Ga]Ga-LW02060 and [68Ga]Ga-LW02080 at 1 h pi were 16.8 ± 2.70 and 7.36 ± 1.33 %ID/g, respectively, while their pancreas uptake values were 3.12 ± 0.89 and 0.38 ± 0.04 %ID/g, respectively. Compared to [177Lu]Lu-LW02080, [177Lu]Lu-LW02060 showed higher tumor uptake at all time points (1, 4, 24, 72 and 120 h pi). However, fast tumor clearance was observed for both [177Lu]Lu-LW02060 and [177Lu]Lu-LW02080. Our data demonstrate that [68Ga]Ga-LW02060 is promising for clinical translation for the detection of GRPR-expressing tumor lesions. However, further optimizations are needed for [177Lu]Lu-LW02060 and [177Lu]Lu-LW02080 to prolong tumor retention for therapeutic applications.

Abstract:

Antimicrobial chemotherapeutic failure as a result of pathogenic resistance stain is great concern across the globe, there is need to search for an effective antimicrobial agent from synthetic sources to wipe microbial resistant in clinical practice. The phenylhydrazone derivatives were scientifically found to have wide application in area of drug discovery due to their anticancer, anti-tubercular, anti-bacterial and anti-fungal activities. Five (5) novel (E)-Substituted-N-(phenylhydrazones) derivatives’ were obtained by condensation reaction through one step reaction, here are the five compounds, HS1 (E)-1-(1-(4-bromophenyl)ethylidene)-2-(2,4dinitrophenyl)hydrazine),HS2 (E)-1-(1-(4-bromophenyl)ethylidene)-2-(4-nitrophenyl)hydrazine), HS3(E)-1-(4nitrophenyl)-2-(1-(3-nitrophenyl)ethylidene)hydrazine), HS4 (E)-1-(2,4-dinitrophenyl)-2-(1-(3nitrophenyl)ethylidene)hydrazine), and HS5 (E)-1-(1-(3-nitrophenyl)ethylidene)-2-phenylhydrazine) and their structural elucidation were established on the basis of FTIR, 1D and 2D NMR spectra and the Insilco prediction of physicochemical properties found within the lipinski’s rule of five and the newly synthesized compounds were evaluated for antimicrobial assessment via an in-vitro test model using inhibition zone technique, MIC, MBC and MFC.

Abstract:

Indole-chalcone hybrids are a large group of compounds known for their excellent biological properties against diverse pathogens. The current research describes a rapid synthetic pathway for the synthesis of ten (10) indole-chalcone hybrids 3(a-j), from 1-Boc-3-formylindole (1) and acetophenone derivatives (2), in a one-pot approach. The Boc was deprotected during the reaction and occurred automatically at the end of the reaction. 1H-NMR, 13C-NMR, and MS were used to elucidate the structures of the compounds. Contrary to previous methods for the synthesis of indole-chalcone hybrids, this novel synthetic method, which involves using a Boc-protected indole via microwave-assisted synthesis, is advantageous because it is a one-pot approach making it facile, and rapid.

Abstract: N-containing carbon-based materials have been employed with claimed improved performance as adsorbent of acidic molecules, VOC and metallic ions, catalyst, electrocatalyst and supercapacitor. In this context, the present work provides valuable insights into the preparation of N-doped activated carbons (ACs) by thermal treatment in NH3 atmosphere (ammonization). A commercial AC was submitted to two kinds of pre-treatment: (i) reflux with dilute HNO3; (ii) thermal treatment up to 800 oC in inert atmosphere. The original and modified ACs were subjected to ammonization up to different temperatures. ACs with N content up to 8% were achieved. Nevertheless, the amount and type of inserted nitrogen depended on ammonization temperature and surface composition of the starting material. Remarkably, oxygenated acidic groups on the surface of the starting material favored nitrogen insertion at low temperatures, with formation of mostly aliphatic (amines, imides, and lactams), pyridinic and pyrrolic nitrogens. In turn, high temperatures provoked the decomposition of labile aliphatic functions. Therefore, the AC prepared from the sample pre-treated with HNO3, which had the highest content of oxygenated acidic groups among the materials submitted to ammonization, presented the highest N content after ammonization up to 400 oC, but the lowest content after ammonization up to 800 oC.