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Synthesis and biological evaluation of novel bisbenzimidazoles as Escherichia coli topoisomerase IA inhibitors and potential antibacterial agents.

Abstract：

:Novel bisbenzimidazole inhibitors of bacterial type IA topoisomerase are of interest for the development of new antibacterial agents that are impacted by target-mediated cross resistance with fluoroquinolones. The present study demonstrates the successful synthesis and evaluation of bisbenzimidazole analogues as Escherichia coli topoisomerase IA inhibitors. 5-(4-Propylpiperazin-1-yl)-2-[2'-(4-ethoxyphenyl)-5'-benzimidazolyl]benzimidazole (12b) showed significant relaxation inhibition activity against EcTopo 1A (IC50 = 2 ± 0.005 μM) and a tendency to chelate metal ion. Interestingly, these compounds did not show significant inhibition of E. coli DNA gyrase and hTop 1 even up to 100 μM. Compound 12b has shown lowest MIC against E. coli strains among 24 compounds evaluated. The binding affinity constant and binding free energy of 12b with EcTopo 1A was observed 6.8 × 10(6) M(-1) and -10.84 kcal mol(-1) from isothermal titration calorimetry (ITC), respectively. In vivo mouse systemic infection and neutropenic thigh model experimental results confirmed the therapeutic efficacy of 12b, suggesting further development of this class of compounds as antibacterial agents.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Nimesh H,Sur S,Sinha D,Yadav P,Anand P,Bajaj P,Virdi JS,Tandon V

doi

10.1021/jm5003028

subject

Has Abstract

pub_date

2014-06-26 00:00:00

pages

5238-57

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

57

pub_type

杂志文章

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