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Compounds containing benzimidazole moiety occupy privileged chemical space for discovering new bioactive substances. In continuation of our recent work, 69 benzimidazole derivatives were designed and synthesized with good to excellent yields of 46-99% using efficient synthesis protocol i.e. sodium metabisulfite catalyzed condensation of aromatic aldehydes with o-phenylenediamines to form 2-arylbenzimidazole derivatives followed by N-alkylation by conventional heating or microwave irradiation for diversification. Potent antibacterial compounds against MSSA and MRSA were discovered such as benzimidazole compounds 3k (2-(4-nitrophenyl), N-benzyl), 3l (2-(4-chlorophenyl), N-(4-chlorobenzyl)), 4c (2-(4-chlorophenyl), 6-methyl, N-benzyl), 4g (2-(4-nitrophenyl), 6-methyl, N-benzyl), and 4j (2-(4-nitrophenyl), 6-methyl, N-(4-chlorobenzyl)) with MIC of 4-16 mu g mL(-1). In addition, compound 4c showed good antimicrobial activities (MIC = 16 mu g mL(-1)) against the bacteria strains Escherichia coli and Streptococcus faecalis. Moreover, compounds 3k, 3l, 4c, 4g, and 4j have been found to kill HepG2, MDA-MB-231, MCF7, RMS, and C26 cancer cells with low mu M IC50 (2.39-10.95). These compounds showed comparable drug-like properties as ciprofloxacin, fluconazole, and paclitaxel in computational ADMET profiling. Finally, docking studies were used to assess potential protein targets responsible for their biological activities. Especially, we found that DHFR is a promising target both in silico and in vitro with compound 4c having IC50 of 2.35 mu M.

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.

Supplementary methods for the article "Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress".

Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells. ispartof: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY vol:144 issue:7 pages:2905-2920 ispartof: location:United States status: published

A multistep synthesis was developed to prepare new 1,2,3-triazole-amino acid conjugates (6 and 7). These compounds contain the diaryl ether moiety and were synthesized via SNAr reaction under mild condition and in good yield. Their structures were confirmed by spectroscopic analyses (HR-MS, NMR, IR). These compounds showed significant antiproliferative activity (>30%) toward the breast MCF7 and liver HepG2 cancer cells lines at

Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi‐target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure‐based strategy to identify dual‐target ligands of G‐protein‐coupled receptors is presented. We use this approach to design compounds that both antagonize the A2A adenosine receptor and activate the D2 dopamine receptor, which have excellent potential as antiparkinson drugs. Atomic resolution models of the receptors guided generation of a chemical library with compounds designed to occupy orthosteric and secondary binding pockets in both targets. Structure‐based virtual screens identified ten compounds, of which three had affinity for both targets. One of these scaffolds was optimized to nanomolar dual‐target activity and showed the predicted pharmacodynamic effect in a rat model of Parkinsonism., Structure‐based modelling was used to design a single compound with the ability to modulate the activity of two G‐protein‐coupled receptors relevant for Parkinson's disease. The most potent scaffold displayed nanomolar binding affinities for both targets and was active in a rat model of parkinsonism.

Herein we present the use of low catalyst loading of PdCl(C3H5)dppb (1mol%) to directly prepare 4-CHO-2-arylbenzofurans by copper-free tandem Sonogashira coupling-cyclization under microwave irradi ...

Twelve new 2-quinolizinylbenzimidazole and 2-naphthalylbenzimidazole derivatives with various 5- and 6-positioned substituents (aza, H, CH3, Cl, NO2, NH2, OCH3), have been synthesized in moderate to excellent yields via the condensation of 4-oxo-4H-quinolizinecarbaldehyde or naphthalenecarbaldehyde with substituted o-phenylenediamines, o-nitroaniline, and 2,3-pyridinediamine using sodium metabisulfite or sodium hydrosulfite under microwave irradiation. The new benzimidazole derivatives were screened for their cytotoxic activity against the human breast cancer cell line (MCF-7). The results showed on one hand that 2-(substituted quinolizinyl)-1H-benzimidazoles (12b–f) were less active (3–6 fold) than the positive control Tamoxifen (CC50 = 6.52 μM), and on the other hand, among the 2-(substituted naphthalyl)-1H-benzimidazoles series (13a–f), compounds 6,7,8-trimethoxy-3-(5-chloro-1H-benzo[d]imidazol-2-yl)naphthalen-1-ol (13c) (CC50 = 7.48 μM) and 6,7,8-trimethoxy-3-(5-methoxy-1H-benzo[d]imidazol-2-yl)naphthalen-1-ol (13f) (CC50 = 6.43 μM) were found to be as active as Tamoxifen.

A facile synthetic method for the construction of 2-substituted-4-oxo-4H-quinolizine-based core structure has been successfully developed. The synthesis made use of a one-pot Stobbe condensation followed by cyclization starting from the commercially available 2-pyridinecarbaldehyde. The structure of the formed 4-oxo-4H-quinolizine-2-carboxylate was fully confirmed by mass spectra, 1H NMR and 13C NMR, correlation spectrography, heteronuclear multiple bond correlation, and heteronuclear single quantum coherence (HSQC) spectra. The ethyl carboxylate moiety was then further functionalized via direct aminolysis by a range of amines to afford the corresponding 4-oxo-4H-quinolizine-2-carboxamides 4a–i in moderate to good yields.

Twelve new 2-quinolizinylbenzimidazole and 2-naphthalylbenzimidazole derivatives with various 5- and 6-positioned substituents (aza, H, CH3, Cl, NO2, NH2, OCH3), have been synthesized in moderate to excellent yields via the condensation of 4-oxo-4H-quinolizinecarbaldehyde or naphthalenecarbaldehyde with substituted o-phenylenediamines, o-nitroaniline, and 2,3-pyridinediamine using sodium metabisulfite or sodium hydrosulfite under microwave irradiation. The new benzimidazole derivatives were screened for their cytotoxic activity against the human breast cancer cell line (MCF-7). The results showed on one hand that 2-(substituted quinolizinyl)-1H-benzimidazoles (12b–f) were less active (3–6 fold) than the positive control Tamoxifen (CC50 = 6.52 μM), and on the other hand, among the 2-(substituted naphthalyl)-1H-benzimidazoles series (13a–f), compounds 6,7,8-trimethoxy-3-(5-chloro-1H-benzo[d]imidazol-2-yl)naphthalen-1-ol (13c) (CC50 = 7.48 μM) and 6,7,8-trimethoxy-3-(5-methoxy-1H-benzo[d]imidazol-2-yl)naphthalen-1-ol (13f) (CC50 = 6.43 μM) were found to be as active as Tamoxifen.

High-throughput screening has revealed dark chemical matter, a set of drug-like compounds that has never shown bioactivity despite being extensively assayed. If dark molecules are found active at a therapeutic target, their extraordinary selectivity profiles make excellent starting points for drug development. We explored if ligands of therapeutically relevant G-protein-coupled receptors could be discovered by structure-based virtual screening of the dark chemical matter. Molecular docking screens against crystal structures of the A2A adenosine and the D4 dopamine receptors were carried out, and 53 top-ranked molecules were evaluated experimentally. Two ligands of each receptor were discovered, and the most potent had sub-micromolar affinities. Analysis of bioactivity data showed that the ligands lacked activity at hundreds of off-targets, including several that are associated with adverse effects. Our results demonstrate that virtual screening provides an efficient means to mine the dark chemical space, which could contribute to development of drugs with improved safety profiles.