N ,2,6-Trisubstituted 1 H -benzimidazole derivatives as a new scaffold of antimicrobial and anticancer agents: design, synthesis, in vitro evaluation, and in silico studies

• Published in: RSC advances 2022-12, Vol.13 (1), p.399-420
• Main Authors: Pham, Em Canh, Le Thi, Tuong Vi, Ly Hong, Huong Ha, Vo Thi, Bich Ngoc, Vong, Long B, Vu, Thao Thanh, Vo, Duy Duc, Tran Nguyen, Ngoc Vi, Bao Le, Khanh Nguyen, Truong, Tuyen Ngoc
• Format: Article
• Language: English
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/D2RA06667J

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 sodium metabisulfite catalyzed condensation of aromatic aldehydes with -phenylenediamines to form 2-arylbenzimidazole derivatives followed by -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), -benzyl), 3l (2-(4-chlorophenyl), -(4-chlorobenzyl)), 4c (2-(4-chlorophenyl), 6-methyl, -benzyl), 4g (2-(4-nitrophenyl), 6-methyl, -benzyl), and 4j (2-(4-nitrophenyl), 6-methyl, -(4-chlorobenzyl)) with MIC of 4-16 μg mL . In addition, compound 4c showed good antimicrobial activities (MIC = 16 μg mL ) against the bacteria strains and . 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 μM IC (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 and with compound 4c having IC of 2.35 μM.