benzimidazole carboxamides / GSK - LARVOL DELTA

Duplexed CeTEAM drug biosensors reveal determinants of PARP inhibitor selectivity in cells. (PubMed, J Biol Chem) - "Our results reveal that most PARPi are equipotent for both PARPs, including the next-generation drug, senaparib. However, benzimidazole carboxamide (niraparib) derivatives demonstrated PARP1-selective tendencies, while pthalazinones (olaparib) favored PARP2. AZD5305, a reported PARP1-selective inhibitor with characteristics of both series, was the exception and appears ∼1600-fold more potent towards PARP1. In agreement with current understanding, we see that trapping-associated S/G2-phase transitions positively correlate with PARP1/2 binding potency, while some potent binders, such as veliparib, did not - likely reflecting their allosteric influence on DNA retention...The PARP1/2 CeTEAM platform thus provides a structural roadmap for the development of selective PARPi and should facilitate the discovery of targeted therapies. Furthermore, our results highlight that multiplexing CeTEAM biosensors and layered genetic perturbations can systematically profile determinants of..."

Journal • Oncology • PARP2

Design and Synthesis of Benzimidazole Carboxamide Cysteine Protease Inhibitors as Promising Anti-leishmanial Agents. (PubMed, Curr Med Chem) - "Both in vitro and in silico studies indicate that the synthesized imidazole carboxamides can act as potent hits and that N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5- yl)benzo[d][1,3]-5-carboxamide-dioxole 4a can be an effective hit molecule which can be further developed into potent lead molecule (s) to fight Leishmania donovani."

Journal • Infectious Disease

Design, Synthesis and Biological Activity of Novel Methoxy- and Hydroxy-Substituted N-Benzimidazole-Derived Carboxamides. (PubMed, Molecules) - "This work presents the design, synthesis and biological activity of novel N-substituted benzimidazole carboxamides bearing either a variable number of methoxy and/or hydroxy groups...However, their antiproliferative activity was not related to their ability to inhibit oxidative stress nor to their ability to induce it. Compound 8 with two hydroxy and one methoxy group on the phenyl ring showed the strongest antibacterial activity against the Gram-positive strain E. faecalis (MIC = 8 μM)."

Journal • Infectious Disease

Benzimidazole derivatives as tubulin polymerization inhibitors: Design, synthesis and in vitro cytotoxicity studies. (PubMed, Bioorg Med Chem Lett) - "Compound 7n dose-dependently arrested the G2/M phase of the cell cycle and the target-based outcomes proposed tubulin polymerization inhibition by 7n (IC of 5.05±0.13 μM). Computational studies were also conducted on the tubulin protein (PDB ID: 3E22) to investigate the stabilized binding interactions of compounds 7n and 7u with tubulin, respectively."

Journal • Preclinical • Oncology • ANXA5

Anticholinesterase and Serotoninergic Evaluation of Benzimidazole-Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease. (PubMed, Pharmaceutics) - "Primary in silico evaluation showed that benzimidazole-carboxamides effectively bind to 5-HTR and 5-HTR. The pool of the obtained data allows us to choose N-[2-(diethylamino)ethyl]-2-oxo-3-(tert-butyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride (compound 13) as the most promising for further experimental development."

Journal • Alzheimer's Disease • CNS Disorders

Benzimidazole-Carboxamides as Potential Therapeutics for Alzheimer's Disease: Primary Analysis In Silico and In Vitro. (PubMed, Bull Exp Biol Med) - "Biochemical analysis showed the ability of the obtained chemicals to inhibit acetyl- and butyrylcholinesterase. A compound with minimal toxicity, high inhibitory ability against butyrylcholinesterase, and low inhibitory ability against acetylcholinesterase has been identified, which is of greatest interest for further experimental development."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Synthesis and Anti-Cancer Applications of Benzimidazole Derivatives - Recent Studies. (PubMed, Anticancer Agents Med Chem) - "This review article will help the medicinal chemists to design and synthesize benzimidazole-based molecules and evaluate them as anti-cancer agents."

Journal • Oncology

Discovery of the PARP (poly ADP-ribose polymerase) inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the treatment of cancer. (PubMed, Bioorg Chem) - "In this work, two series of cyclic amine-containing benzimidazole carboxamide derivatives were designed and synthesized as potent anticancer agents...What's more, further studies revealed that 17d was endowed with an excellent ADME profile. These combined results indicated that 17d could be a promising candidate for the treatment of cancer."

Journal • Oncology

Synthesis, Molecular Docking Studies and Antibacterial Activities of Novel Monocationic Indole-benzimidazole Derivatives. (PubMed, Med Chem) - "This study mainly includes the design, synthesis and optimization of indole-benzimidazole-amidine derivatives. Docking studies confirmed our results, since our most potent hit compound 36 created the necessary interactions between two chains of MRSA-PK. Further optimization can be considered to increase drug ability."

Journal • Immunology

Discovery of 2-(1-(3-(4-Chloroxyphenyl)-3-oxo- propyl)pyrrolidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide: A Potent Poly(ADP-ribose) Polymerase (PARP) Inhibitor for Treatment of Cancer. (PubMed, Molecules) - "A series of benzimidazole carboxamide derivatives have been synthesized and characterized by H-NMR, C-NMR and HRMS. The two compounds also displayed slightly better in vitro cytotoxicities against MDA-MB-436 and CAPAN-1 cell lines than veliparib and olaparib, with values of 17.4 µM and 11.4 µM, 19.8 µM and 15.5 µM, respectively. The structure-activity relationship based on molecular docking was discussed as well."

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