Novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and biological evaluation
Abstract A series of novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents were designed, synthesized and characterized by IR, NMR and HRMS spectra. The biological evaluation in vitro revealed that some of the target compounds exerted good antibacterial and antifungal activity in comparison with the reference drugs. Noticeably, compound 7d could effectively inhibit the growth of A. flavus , E. coli DH52 and MRSA with MIC values of 1, 1 and 8 μg/mL, respectively. Further studies revealed that pyrimidine derivative 7d could exhibit bactericidal mode of action against both Gram positive ( S. aureus and MRSA) and Gram negative ( P. aeruginosa ) bacteria. The active molecule 7d showed low cell toxicity and did not obviously trigger the development of resistance in bacteria even after 16 passages. Furthermore, compound 7d was able to beneficially regulate reactive oxygen species (ROS) generation for an excellent safety profile. Molecular docking study revealed that compound 7d could bind with DNA gyrase by the formation of hydrogen bonds. The preliminary exploration for antimicrobial mechanism disclosed that compound 7d could effectively intercalate into calf thymus DNA to form a steady supramolecular complex, which might further block DNA replication to exert the powerful bioactivities. The binding investigation of compound 7d with human serum albumins (HSA) revealed that this molecule could be effectively transported by HSA. Highlights Novel aminopyrimidinyl benzimidazoles with good antimicrobial potency were developed. Compound 7d showed broad spectrum and beneficial regulation for ROS generation. Compound 7d with low toxicity did not trigger the resistance development in bacteria. MEPs and molecular docking rationalized the antimicrobial activity. Compound 7d could intercalate into DNA and be effectively stored and carried by HSA. Graphical abstract A series of novel aminopyrimidinyl benzimidazoles were synthesized and screened for their antimicrobial activities. Molecular modeling and experimental investigation with DNA suggested the possible antibacterial mechanism. [DISPLAY OMISSION]
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