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Focused compound libraries are well-established tools for hit identification in drug discovery and chemical probe development. We present the compilation and application of a focused ...screening library of fatty acid mimetics (FAMs), which are compounds designed to bind the orthosteric site of proteins that endogenously accommodate natural fatty acids and lipid metabolites. This set complies with chemical properties of FAM and was found suitable for use also in cellular setting. Several hits were retrieved in screening the focused library against diverse fatty acid binding targets including the enzymes soluble epoxide hydrolase (sEH) and leukotriene A4 hydrolase (LTA4H), the nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RXRα), the carrier proteins fatty acid binding protein 4 and 5 (FABP4 and FABP5), as well as the G-protein coupled receptors leukotriene B4 receptor 1 (BLT1) and free-fatty acid receptor 1 (FFAR1). Thus, the focused FAM library is suitable to obtain chemical starting matter for fatty acid binding proteins and provides a valuable extension to available screening collections.
Benzoxazine is one of the most important privileged scaffolds in medicinal chemistry. Compounds bearing benzoxazine moiety usually have a variety of biological activities, such as anti-inflammatory, ...anti-microbial, anti-tuberculosis, anti- oxidant and anti-cancer activities. The fascinating bioactivity profile of benzoxazine scaffold in various fields has prompted medicinal chemists to design and discover novel benzoxazine derivatives as potential therapeutic candidates with the desired biological properties.
This review aimed to provide a comprehensive elucidation on the recent advances of benzoxazine derivatives in medicinal chemistry.
We have searched the recent literature about benzoxazine derivatives from the online resources and databases, such as PubMed, SciFinder and Google Scholar.
Many benzoxazine derivatives with a wide range of bioactivities, such as anti- microbial, anti-cancer, anti-tuberculosis, anti-oxidant and anti-inflammatory, were summed up. Many compounds displayed good biological activities.
Benzoxazine is a versatile structure and building block in medicinal chemistry. Benzoxazine derivatives have gained considerable attention from medicinal chemists due to their various pharmacological properties and multiple modification sites. This review might help medicinal chemists to seek new drug candidates with better bioactivities and pharmacokinetics properties.
In the design and discovery of anticancer drugs, various natural heterocyclic scaffolds have attracted considerable interest as privileged structures. For rational drug design, some of the natural ...scaffolds such as chromones have exhibited wide acceptability due to their drug‐like properties. Among the approved anticancer drugs, the scaffolds with high selectivity for a small group of closely related targets are of importance. In the development of selective anticancer agents, the natural, as well as synthetic, can generate highly selective compounds toward cancer targets. The present manuscript includes more particularly the development of cancer inhibitors incorporating the chromone scaffold, with a strong emphasis on their molecular interactions in the anticancer mechanism. It also includes the structure‐activity relationship studies and related examples of lead optimization.
In the design and discovery of anticancer drugs, various natural heterocyclic scaffolds have attracted considerable interest as privileged structures. In the development of selective anticancer agents, the natural, as well as synthetic chromones, can be utilized to generate highly selective compounds towards cancer targets.
The Co(II)Cl2·6H2O catalyzed C–H activation/direct arylation of imidazo1,2‐apyridine with aryl/heteroaryl iodide is reported. The cost effective, ligand and additive free protocol using KOAc ...successfully afforded 3‐arylimidazo1,2‐apyridines in good yields. Imidazo1,2‐apyridines with electron withdrawing and electron donating substituents with various aryl iodides are well tolerated. The reaction is performed in a Screw‐top V‐Vial® to expedite the synthesis. The antibacterial 3‐naphthyl imidazo1,2‐apyridine is smoothly prepared using this protocol.
A practical protocol for the C‐3 arylation of imidazo1,2‐apyridines with aryl/heteroaryl iodides using Co(II)Cl2·6H2O is reported. The reaction can be performed in a Screw‐top V‐Vial® to expedite the synthesis.
•Anxiolytic activity of six new compounds was evaluated.•DAB-21 was found to be a promising candidate.•In several aspects, DAB-21 is superior to diazepam.•DAB-21 was verified to acts through a ...GABA-ergic mechanism.
A study on the anxiolytic activity of the new derivatives of 11-dialkylaminoethyl-2,3,4,5-tetrahydrodiazepino1,2-abenzimidazole, containing privileged scaffolds of benzodiazepine and benzimidazole in their structure, was conducted. The cytotoxic properties of low levels of six compounds were preliminary determined in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test. The screening of these substances for anxiolytic activity was conducted using elevated plus maze (EPM) test in vivo, and DAB-21 was found to be the most active compound. The acute toxicity of DAB-21 was determined as less toxic than that of diazepam. The dose-dependent effect of the most active compound revealed a minimum dose of 1.26 mg/kg, which resulted in the maximum counterphobic effect. The effect of DAB-21 was superior in a number of tests compared with that of diazepam, which indicated a high level of tranquilizing activity for DAB-21. The results of in silico docking analysis suggest that DAB-21 should have a slightly lower anxiolytic activity than diazepam, but should exhibit greater specific affinity for the benzodiazepine site of the GABAA receptor, in comparison with its GABA-binding site. The interaction between DAB-21 and flumazenil in terms of EPM verifies the GABAergic mechanism of action of DAB-21. Our results highlight the potential of 11-dialkylaminomethyl-2,3,4,5-tetrahydrodiazepino1,2-abenzimidazoles as promising compounds in the search for new highly effective anxiolytics.
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A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed ...selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a were performed. The binding modes of such compounds were determined assuming their enzymatically active structures (i.e., cinnamic acid) in the thermodynamically favored, and not previously explored, E geometry. Molecular modelling suggests multiple interactions within the enzymatic cavity and may explain the high potency and selectivity reported for the hCAs IX and XII.
Skeletal diversity: The reactions of alkynoic acids (A, common type of substrates) with various scaffold‐building agents (B) under gold catalysis produce a series of multifunctional polyheterocyclic ...structures (see scheme). The approach enables the preparation of compound libraries with high skeletal diversity.
Thiazoles exhibit a wide range of biological activities and therefore represent useful and attractive building blocks. To evaluate their usefulness and pinpoint their liabilities in fragment ...screening campaigns, we assembled a focused library of 49 fragment-sized thiazoles and thiadiazoles with various substituents, namely amines, bromides, carboxylic acids, and nitriles. The library was profiled in a cascade of biochemical inhibition assays, redox activity, thiol reactivity, and stability assays. Our study indicates that when thiazole derivatives are identified as screening hits, their reactivity should be carefully addressed and correlated with specific on-target engagement. Importantly, nonspecific inhibition should be excluded using experimental approaches and in silico predictions. To help with validation of hits identified in fragment screening campaigns, we can apply our high-throughput profiling workflow to focus on the most tractable compounds with a clear mechanism of action.
The development of versatile new routes to bridgehead nitrogen-bearing polycyclic aromatic systems having privileged scaffolds is a synthetic challenge for organic chemists. An efficient synthesis of ...benzo4,5imidazo1,2-aquinazoline derivatives bearing bridgehead nitrogen by the reaction of benzodimidazol-2-amines, aldehydes, and ortho-silyl aryltriflate via 1,4-dipolar cycloaddition is reported under the optimized reaction conditions. The methodology provides easy access to fused benzimidazolo-quinazolines by sequential C-N and C-C bond formation through a one-pot reaction.
The Asinger multicomponent reaction is a versatile synthetic tool which gives access to multiple drug‐like scaffolds such as 3‐thiazolines. The diversity and easy access of its starting materials, ...its operational simplicity combined with mild conditions and relatively good yields, renders the Asinger reaction, today more than ever, a cornerstone not only in heterocyclic chemistry and modern synthesis but also in medicinal chemistry. In this review, we perform a thorough analysis of the scope and limitations on the different reaction variants with their starting materials, the three‐dimensional solid‐state conformations of the Asinger derivatives, and we underline and classify all the major post‐modifications that have been described. In addition, we report all the major applications in drug discovery projects.
Titan of the toolkit: The Asinger multicomponent reaction can play an important role in drug design and discovery due to the diversity and complexity that offers. Here, we present the scope and limitations of the reaction, its orthogonal combination with classic or other MCRs and the applications in drug discovery. We believe that Asinger reaction will find its position in today's sustainable chemistry.
