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Novel tetrahydropyrimidinyl-substituted benzimidazoles and benzothiazoles: synthesis, antibacterial activity, DNA interactions and ADME profiling

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 phenoxymethylene linker on antibacterial activity was observed, showing that 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 pathogen E. coli (MIC = 1 µg/mL) and M. catrrhalis (MIC = 2 µg/mL). Compound 15a also exhibited the most promising antibacterial activity against sensitive and resistant strains of S. pyogenes (MIC = 2 µg/mL). Significant stabilization effects and positive induced CD bands strongly support binding of biologically most active benzimidazoles inside minor grooves of AT-rich DNA, in line with docking studies. 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.

benzimidazole ; benzothiazole ; antibacterial activity ; ADME ; DNA interaction

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