REVIEW | doi:10.20944/preprints202305.2159.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: carbonylation; cyclization; double cyclization; fused heterocycles; heterocyclization; heterocycles; homogeneous catalysis; metal-catalyzed reactions; palladium; polycyclic heterocycles
Online: 30 May 2023 (14:10:04 CEST)
This short review is aimed at giving an overview of catalytic carbonylative double cyclization reactions, which are processes in which suitable organic substrates and carbon monoxide are sequentially activated by a promoting catalyst to afford the formation of two new cycles with concomitant incorporation of carbon monoxide as a carbonyl function into the final product. Paradigmatic examples of this powerful synthetic methodology, which allows the one-step synthesis of complex molecular architectures from simple building blocks using the simplest and readily available C-1 unit (CO) are illustrated and discussed. The review is divided into five sections: 1) Introduction; 2) Functionalized Olefinic Substrates; 3) Functionalized Acetylenic Substrates; 4) Functionalized Halides; 5) Conclusions and Future Perspectives.
ARTICLE | doi:10.20944/preprints202302.0062.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: heterocycles; thiourea dioxide; TDO; mechanochemistry
Online: 3 February 2023 (08:40:14 CET)
The synthesis of nitrogen-based heterocycles has always been considered essential in the development of pharmaceuticals in medicine and agriculture. This explains why various synthetic approaches have been proposed in recent decades. However, performing as methods often imply harsh conditions or the employment of toxic solvents and dangerous reagents. Mechanochemistry is undoubtedly one of the most promising technologies currently used for reducing any possible environmental impact due to the worldwide interest in developing solvent-free synthetic pathways. Following this line, we propose a renewed mechanochemical protocol for synthesizing various heterocyclic classes by exploiting the reducing proprieties and the electrophilic nature of thiourea dioxide (TDO). Simultaneously using the ready availability and low cost of a component of the textile industry such as TDO and all the advantages brought by a green technique such as mechanochemistry, we plotted the route towards a more sustainable and eco-friendly methodology for obtaining heterocyclic moieties.
REVIEW | doi:10.20944/preprints202305.1247.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: Sequential Reactions; Aminolkynes; Heterocycles; Metal catalysis.
Online: 17 May 2023 (12:25:48 CEST)
Sequential reactions of aminoalkynes represent a powerful tool to easily assembly biologically important polyfunctionalized nitrogen heterocyclic scaffolds. Metal catalysis often plays a key role in terms of selectivity, efficiency, atom economy and green chemistry of these sequential approaches. This review examines the existing literature on the applications of reactions of aminoalkynes with carbonyls which are emerging for their synthetic potential. Aspect concerning the features of the starting reagents, the catalytic systems, alternative reaction conditions and the pathways as well as the possible intermediates are provided.
SHORT NOTE | doi:10.20944/preprints201712.0165.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: aromatic hydrazide condensation; phosphorus heterocycles; cytotoxicity;
Online: 25 December 2017 (07:00:47 CET)
5-Methyl-3,8-di-(2-amino-4-bromophenyl)-4,9-dioxa-1,2,6,7-tetraaza-5λ5-phosphaspiro[4.4]nona-2,7-diene was obtained in a condensation reaction of 2-amino-5-bromobenzohydrazide and methylphosphonyl dichloride in the presence of triethylamine. An initial biological screening was performed for the obtained product. The synthesized compound possesses two aromatic primary amine groups and two bromine atoms within the structure, which are suitable for further structural modifications.
ARTICLE | doi:10.20944/preprints202010.0077.v1
Subject: Chemistry And Materials Science, Analytical Chemistry Keywords: acetamide; pyridine; pyrrolidine; piperidine; antibacterial activity; heterocycles
Online: 5 October 2020 (11:51:12 CEST)
A sequence of new acetamide derivatives 9-15 of primary, secondary amine, and para-toluene sulphinate sodium salt have been synthesized under microwave irradiation and assessed in vitro for their antibacterial activity against one Gram-positive and two Gram-negative bacterial species such as S. pyogenes, E. coli, and P.mirabilis using the Mueller-Hinton Agar diffusion (well diffusion) method. The synthesized compounds with significant differences in inhibition diameters and MICs were compared with those of amoxicillin, ampicillin, cephalothin, azithromycin and doxycycline. All of the evaluated acetamide derivatives were used with varying inhibition concentrations of 6.25, 12.5, 37.5, 62.5, 87.5, 112.5 and 125 µg/ml. The results show that the most important antibacterial properties exercised by the synthetic compounds 9 and 11 bearing para-chlorophenyl moiety incorporated into the 2-position moiety of acetamide 2. The molecular structures of the new compounds were determined using FT-IR, 1H-NMR techniques.
REVIEW | doi:10.20944/preprints202306.0402.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: bioreduction; heterocycles; natural products; NQO1; reductases; synthesis; thioredoxin
Online: 6 June 2023 (07:59:36 CEST)
This review uses the National Cancer Institute (NCI) COMPARE program to establish an extensive list of heterocyclic iminoquinones and quinones with similarities in differential growth inhibition across the 60-cell line panel of the NCI Developmental Therapeutic Program (DTP). Many natural products and synthetic analogues are revealed, as potential NAD(P)H:quinone oxidoreductase 1 (NQO1) substrates through correlations to dipyridoimidazo[5,4-f]benzimidazoleiminoquinone (DPIQ), and as potential thioredoxin reductase (TrxR) inhibitors, through correlations to benzo[1,2,4]triazin-7-ones and pleurotin. The strong correlation to NQO1 infers the enzyme has a major influence on the amount of active compound with benzo[e]perimidines, phenoxazinones, benz[f]pyrido[1,2-a]indole-6,11-quinones, seriniquinones, kalasinamide, indolequinones, and furano[2,3-b]naphthoquinones, hypothesized as prodrugs. Compounds with very strong correlations to known TrxR inhibitors had inverse correlations to the expression of both reductase enzymes, NQO1 and TrxR, including naphtho[2,3-b][1,4]oxazepane-6,11-diones, benzo[a]carbazole-1,4-diones, pyranonaphthoquinones (including kalafungin, nanomycin A, and analogues of griseusin A), and discorhabdin C. Quinoline-5,8-dione scaffolds based on streptonigrin and lavendamycin can correlate to either reductase. Inhibitors of TrxR are not necessarily (imino)quinones, e.g., parthenolides, while oxidizing moieties are essential for correlations to NQO1, as with the mitosenes. Herein, an overview of synthetic methods and biological activity of each family of heterocyclic imino(quinone) is provided.
REVIEW | doi:10.20944/preprints202106.0350.v1
Subject: Chemistry And Materials Science, Analytical Chemistry Keywords: Heterocycles; Coumarins; Dihyfropyrimidinones; Imidazoles; Isoxazoles; Benzimidazoles; Green Chemistry
Online: 14 June 2021 (10:39:56 CEST)
Heterocycles are unique precursors for the synthesis of various pharmaceuticals and agrochemicals particularly those possessing N- or O- moieties. The development of methods to prepare heterocycles is of great importance in synthesis of organic compounds, especially the heterocycles which can be found in natural products. The synthesis of nitrogen and oxygen containing heterocycles viz. coumarins, dihydropyrimidinones, imidazoles, isoxazoles and benzimidazoles represented an attractive and demanding work for chemists as these nucleus has found extensive applications in several fields such as material science, analytical chemistry and most importantly in medicinal chemistry. Organic synthesis has been attracted towards the development of new environmental friendly procedures to achieve the goals of green chemistry. The fundamental aspects of green chemistry are use of biocatalysts and environmental benign solvents under mild conditions. The present review article summarized the green synthetic methods and biological activities of nitrogen and oxygen containing heterocycles.
REVIEW | doi:10.20944/preprints202308.1064.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: Cancer; phytomolecules; fused oxygen-based heterocycles; anticancer; flavonoids; coumarins
Online: 16 August 2023 (09:57:17 CEST)
Oxygen based heterocyclic moieties hold an ample range of therapeutic activities. Heterocyclic molecules are nominated as vital components of an extensive array of structural motifs with both biological and pharmaceutical significance. The oxygen-based scaffolds act as anticancer candidates and are also present in numerous phytomolecules viz; irinotecan, camptothecin, topotecan, taxol, taxotere, podophylotoxin, etoposide, daunorubicin and teniposide. The architectural design of numerous structural motifs for amelioration of cancer has become progressively amplified in recent past years. Until now presently there is no strategic treatment which is so capable that can cure cancer from its roots. Henceforth, it is very indispensible to design novel anticancer structural motifs with least side effects. The oxygen containing heterocyclic scaffolds includes flavonoids, pyrans, xanthones and coumarins are of utmost importance in medical chemistry for the mitigation of cancer. This assemblage offers several recent developments as anticancer oxygen containing heterocyclic molecules all-round the globe and attracted the structural motifs of auspicious molecules, along with their mechanistic insights, IC50 values, structure–activity relationships, and molecular docking studies. The encouraging properties discovered by these oxygen-based scaffolds unconditionally engaging them at frontline in invention of potential drug candidates. Consequently, these probably will be of amazing attention to scientists working on the design and synthesis of antitumor candidates.
ARTICLE | doi:10.20944/preprints202012.0594.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: benzoxazines; polybenzoxazines; diaminodiphenylmethane; 3,3’-dichloro-4,4’-diaminodiphenylmethane; heterocycles; thermosetting binders
Online: 23 December 2020 (15:30:55 CET)
As a result of this work, a previously unreported benzoxazine monomer based on 3,3'-dichloro-4,4'-diaminodiphenylmethane was obtained, characterized by 1H and 13C NMR spectroscopy, and its thermal and rheological properties were studied. A comparison between the properties of benzoxazines based on diamines (3,3'-dichloro-4,4'-diaminodiphenylmethane and 4,4’-diaminodimethylmethane). The effect of the reaction medium on the structure of the oligomeric fraction and the overall yield of the main product was studied. The synthesized monomers can be used as thermo- and fire-resistant binders for polymer composite materials, as well as hardeners for epoxy resins.
ARTICLE | doi:10.20944/preprints201706.0128.v1
Subject: Chemistry And Materials Science, 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.
ARTICLE | doi:10.20944/preprints202308.2124.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: Sustainable chemistry; Bicyclic N,S-heterocycles; Biomass-based Green Solvents; Sabinene.
Online: 31 August 2023 (08:50:16 CEST)
Following on from work already carried out in our laboratory on a new biomass-derived green solvent, eucalyptol, we are now turning our attention to sabinene as a new green solvent. Sabinene is also derived from biomass. We have shown that it can be used as such or distilled to synthesize thiazolo[5,4-b]pyridine heterocycles by thermal or microwave activation. This new solvent was compared with various conventional and green solvents. The conditions were optimized to enable us to carry out the syntheses in good yields, and we were able to show that sabinene, a natural bicyclic monoterpene, could be used effectively as a solvent.
REVIEW | doi:10.20944/preprints202309.0856.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: Penicillin-binding protein 2a (PBP2a); Mur enzymes; heterocycles; High-throughput screenings; transpeptidation
Online: 13 September 2023 (09:01:12 CEST)
Staphylococcus aureus is a common pathogen in human. Methicillin resistant Staphylococcus aureus (MRSA) infection poses a big and perplexing difficulty in terms of therapy. The acquisition of the non-native gene PBP2a, which has a decreased tolerance for β-lactam antibiotics, frequently confers resistance. PBP2a has a less attraction for methicillin and it helps bacteria to continue peptidoglycan biosynthesis, and it is cell wall’s core component in bacteria. So, even in the presence of methicillin or any other antibiotic, bacteria develop resistance. Due to resistance-causing genes, S. aureus becomes MRSA. The main premise of the resistance mechanism is well understood. The current demand for novel antibiotics is legitimate in the face of therapeutic concerns posed by resistant micro-organisms. The emphasis of this review is on PBP2a scaffolds and the different screening approaches used to find PBP2a inhibitors. Penicillin, Cephalosporins, Pyrazole-Benzimidazole based derivatives, Oxadiazole containing derivatives, non-β-lactam allosteric inhibitors, 4-(3H)-Quinazolinones, Pyrrolylated chalcone, Bis-2-Oxoazetidinyl macrocycle (β-lactam antibiotics with 1, 3-Bridges), Macrocycle-embedded β-lactams as novel inhibitors, Pyridine-Coupled Pyrimidinones, novel Naphthalimide corbelled aminothiazoximes, non-covalent inhibitors, Investigational-β-lactam antibiotics Carbapenem, novel Benzoxazole derivatives, Pyrazolylpyridine analogues, and other miscellaneous classes of scaffolds for PBP2a are also represented as well as with their biological activity is discussed. The penicillin-binding protein is also discussed, which is the crucial target for the cell wall of MRSA. Various aspects of PBP2a, the cell wall of bacteria, peptidoglycans, different crystal structures of PBP2a, synthetic routes for PBP2a inhibitors, and future perspectives of MRSA inhibitors are also enumerated.
SHORT NOTE | doi:10.20944/preprints202308.1339.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: 1,2,3-triazole; 4-amino-1,2,4-triazole-3-thiol; condensation; heterocycles; crystal structure
Online: 18 August 2023 (08:10:46 CEST)
The reaction of 2-bromo-1-(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)ethan-1-one (1) with 4-amino-5-((2,4-dichlorophenoxy)methyl)-4H-1,2,4-triazole-3-thiol (2) in absolute ethanol in the presence of triethyl amine as catalyst gave 2-((4-amino-5-((2,4-dichlorophenoxy)methyl)-4H-1,2,4-triazol-3-yl)thio)-1-(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)ethan-1-one (3) in 73% yield. The structure of the title heterocycle (3) was confirmed by X-ray single crystal diffraction and spectral analyses (NMR and IR).
REVIEW | doi:10.20944/preprints202308.0379.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: Bimetallic catalysis; multimetallic catalysis; sequential catalysis; N-heterocycles; transition metals; green chemistry
Online: 4 August 2023 (14:50:41 CEST)
Bimetallic (or multimetallic) catalysis has emerged as a powerful tool in modern chemical synthesis, offering improved reaction control and versatility. This review focuses on the recent de-velopments in bimetallic sequential catalysis for the synthesis of nitrogen heterocycles, essential building blocks in pharmaceuticals and fine chemicals. The cooperative action of two (and sometimes more) different metal catalysts enables intricate control over reaction pathways, enhancing selectivity and efficiency of N-heterocyclic compounds synthesis. By activating less reactive substrates, this multimetal catalytic strategy opens new synthetic possibilities for challenging compounds. The use of catalytic materials in bimetallic systems reduces waste and improves atom efficiency, aligning with green chemistry principles. With a diverse range of metal combinations and reaction conditions, bimetallic catalysis provides access to a broad array of N-heterocyclic compounds with various functionalities. This paper highlights the significant progress made in the past decade in this topic, emphasizing the promising potential of bimetallic catalysis in drug discovery and the fine chemical industries.
ARTICLE | doi:10.20944/preprints201911.0364.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: mannich reaction; 1,2,4-triazine; pyrimidine; 1,2,4-triazole; n-heterocycles; anti-microbial activity
Online: 29 November 2019 (02:26:36 CET)
In our tactic to construct bio-active molecules, a series of novel pyrimido[2,1-c][1,2,4]triazine-3,4-diones based heterocycles, were synthesized and evaluated for their in vitro antimicrobial impacts. The exploratory bioassay results declared that, the majority of the evaluated compounds exhibited considerable anti-microbial activity comparable to the reference drugs. Conjugates 15j, 15f, 15i, 15h, 15g and 15a were found to be the most potent antibacterial, indicating that conjugates bearing electron-attracting substituents exhibited higher potency than these with electron-releasing substituents.
REVIEW | doi:10.20944/preprints202209.0320.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: marine natural products; oxygen heterocycles; tetrahydrofuran; total synthesis; biological activity; terpenes; fatty acids.
Online: 21 September 2022 (10:04:09 CEST)
heterocycles are particularly common moieties within marine natural products. Specifically, tetrahydrofuranyl rings are present in a variety of compounds which present complex structures and interesting biological activities. Focusing on terpenoids, a high number of tetrahydrofuran-containing metabolites have been isolated during the last decades. They show promising biological activities, making them potential leads for novel antibiotics, antikinetoplastid drugs, amoebicidal substances or anticancer drugs. Thus, they have attracted the attention of the synthetic community, and numerous approaches to their total syntheses have appeared. Here, we offer the reader an overview of marine-derived terpenoids and related compounds, with a special focus on their isolation, structure determination, biological profiles and total syntheses.