title: A trisubstituted benzimidazole cell division inhibitor with efficacy against Mycobacterium tuberculosis.
abstract: Trisubstituted benzimidazoles have demonstrated potency against Gram-positive and Gram-negative bacterial pathogens. Previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against M. tuberculosis H37Rv and clinical isolates, and were not toxic to Vero cells. A new series of 2-cyclohexyl-5-acylamino-6-N, N-dimethylaminobenzimidazoles derivatives has been developed based on SAR studies. Screening identified compounds with potency against M. tuberculosis. A lead compound from this series, SB-P17G-A20, was discovered to have an MIC of 0.16 µg/mL and demonstrated efficacy in the TB murine acute model of infection based on the reduction of bacterial load in the lungs and spleen by 1.73 ± 0.24 Log10 CFU and 2.68 ± Log10 CFU, respectively, when delivered at 50 mg/kg by intraperitoneal injection (IP) twice daily (bid). The activity of SB-P17G-A20 was determined to be concentration dependent and to have excellent stability in mouse and human plasma, and liver microsomes. Together, these studies demonstrate that SB-P17G-A20 has potency against M. tuberculosis clinical strains with varying susceptibility and efficacy in animal models of infection, and that trisubstituted benzimidazoles continue to be a platform for the development of novel inhibitors with efficacy.
authors.affiliation: Mycobacteria Research Laboratories, Department Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Divya
authors.initials: D
authors.lastname: Awasthi
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Kunal
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Infectious Disease Therapeutic Strategic Unit, Sanofi-Aventis R&D, Toulouse, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Carreau
authors.affiliation: Infectious Disease Therapeutic Strategic Unit, Sanofi-Aventis R&D, Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Goullieux
authors.affiliation: Infectious Disease Therapeutic Strategic Unit, Sanofi-Aventis R&D, Toulouse, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lagrange
authors.affiliation: Infectious Disease Therapeutic Strategic Unit, Sanofi-Aventis R&D, Montpellier, France.
authors.forename: Hélèn
authors.initials: H
authors.lastname: Vermet
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, New York, United States of America; Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.affiliation: Mycobacteria Research Laboratories, Department Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001562:Benzimidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D055503:Protein Multimerization / Q000187:drug effects; D012294:Rifamycins / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001562:Benzimidazoles; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D012294:Rifamycins; C031000:benzimidazole
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