title: 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.
authors.affiliation: Department of Chemistry, University of Delhi , Delhi 110 007, India.
authors.forename: Hemlata
authors.initials: H
authors.lastname: Nimesh
authors.forename: Souvik
authors.initials: S
authors.lastname: Sur
authors.forename: Devapriya
authors.initials: D
authors.lastname: Sinha
authors.forename: Pooja
authors.initials: P
authors.lastname: Yadav
authors.forename: Prachi
authors.initials: P
authors.lastname: Anand
authors.forename: Priyanka
authors.initials: P
authors.lastname: Bajaj
authors.forename: Jugsharan S
authors.initials: JS
authors.lastname: Virdi
authors.forename: Vibha
authors.initials: V
authors.lastname: Tandon
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D027081:DNA Gyrase / Q000737:chemistry; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000150:complications / Q000188:drug therapy; D005260:Female; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009503:Neutropenia / Q000150:complications; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D018805:Sepsis / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000591346:5-(4-propylpiperazin-1-yl)-2-(2'-(4-ethoxyphenyl)-5'-benzimidazolyl)benzimidazole; D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D010879:Piperazines; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D027081:DNA Gyrase