1. Novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and biological evaluation.
- Author
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Liu HB, Gao WW, Tangadanchu VKR, Zhou CH, and Geng RX
- Subjects
- Animals, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Antifungal Agents chemical synthesis, Antifungal Agents chemistry, Benzimidazoles chemical synthesis, Benzimidazoles chemistry, Cattle, Cell Line, Cell Survival drug effects, DNA chemistry, DNA drug effects, Dose-Response Relationship, Drug, Drug Design, Hep G2 Cells, Humans, Models, Molecular, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Reactive Oxygen Species metabolism, Serum Albumin chemistry, Serum Albumin metabolism, Structure-Activity Relationship, Thermodynamics, Anti-Bacterial Agents pharmacology, Antifungal Agents pharmacology, Bacteria drug effects, Benzimidazoles pharmacology, Fungi drug effects, Pyrimidines pharmacology
- 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., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
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