Novel tetrahydropyrimidinyl-substituted benzimidazoles and benzothiazoles: synthesis, antibacterial activity, DNA interactions and ADME profiling. Issue 12 (16th September 2022)

• Record Type: Journal Article
• Authors: Rep, Valentina; Štulić, Rebeka; Koštrun, Sanja; Kuridža, Bojan; Crnolatac, Ivo; Radić Stojković, Marijana; Paljetak, Hana Čipčić; Perić, Mihaela; Matijašić, Mario; Raić-Malić, Silvana
• Is Part Of: RSC medicinal chemistry. Volume 13:Issue 12(2022)
• Page Start: 1504
• Page End: 1525
• Publication Date: 2022-09-16
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d2md00143h
• Languages: English
• ISSNs: 2632-8682

Abstract

Abstract : The most active benzimidazole 15a against E. coli, M. catarrhalis and both sensitive and resistant strains of S. pyogenes showed preference toward AT-rich sites and minor groove binding mode, which was in line with docking studies. Abstract : A series of tetrahydropyrimidinyl-substituted benzimidazoles attached to various aliphatic or aromatic residues via phenoxymethylene were synthesised to investigate their antibacterial activities against selected Gram-positive and Gram-negative bacteria. The influence of the type of substituent at the C-3 and C-4 positions of the phenoxymethylene linker on the antibacterial activity was observed, showing that the aromatic moiety improved the antibacterial potency. Of all the evaluated compounds, benzoyl-substituted benzimidazole derivative 15a was the most active compound, particularly against the Gram-negative pathogens E. coli (MIC = 1 μg mL −1 ) and M. catarrhalis (MIC = 2 μg mL −1 ). Compound 15a also exhibited the most promising antibacterial activity against sensitive and resistant strains of S. pyogenes (MIC = 2 μg mL −1 ). Significant stabilization effects and positive induced CD bands strongly support the binding of the most biologically active benzimidazoles inside the minor grooves of AT-rich DNA, in line with docking studies. The predicted physico-chemical and ADME properties lie within drug-like space except for low membrane permeability, which needs further optimization. Our findings encourage further development of novel structurally related 5(6)-tetrahydropyrimidinyl substituted benzimidazoles in order to optimize their antibacterial effect against common respiratory pathogens.