title: In vitro-in vivo activity relationship of substituted benzimidazole cell division inhibitors with activity against Mycobacterium tuberculosis.
abstract: Structure based drug design was used to develop a compound library of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles. Three structural analogs, SB-P1G10, SB-P8B2 and SB-P3G2 were selected from this library for advanced study. In vitro studies revealed that SB-P8B2 and SB-P3G2 had sigmoidal kill-curves while in contrast SB-P1G10 showed a narrow zonal susceptibility. The in vitro studies also demonstrated that exposure to SB-P8B2 or SB-P3G2 was bactericidal, while SB-P1G10 treatment never resulted in complete killing. The dose curves for the three compounds against clinical isolates were comparable to their respective dose curves in the laboratory strain of Mycobacterium tuberculosis. SB-P8B2 and SB-P3G2 exhibited antibacterial activity against non-replicating bacilli under low oxygen conditions. SB-P3G2 and SB-P1G10 were assessed in acute short-term animal models of tuberculosis, which showed that SB-P3G2 demonstrated activity against M. tuberculosis. Together, these studies reveal an in vitro-in vivo relationship of the 2,5,6-trisubstituted benzimidazoles that serves as a criterion for advancing this class of cell division inhibitors into more resource intensive in vivo efficacy models such as the long-term murine model of tuberculosis and Pre-IND PK/PD studies. Specifically, these studies are the first demonstration of efficacy and an in vitro-in vivo activity relationship for 2,5,6-trisubstituted benzimidazoles. The in vivo activity presented in this manuscript substantiates this class of cell division inhibitors as having potency and efficacy against M. tuberculosis.
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Kunal
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Awasthi
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA; Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA. Electronic address: Richard.Slayden@ColoState.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D004195:Disease Models, Animal; D004338:Drug Combinations; D008826:Microbial Sensitivity Tests / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010100:Oxygen; D012293:Rifampin / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000995:Antitubercular Agents; D001562:Benzimidazoles; D004338:Drug Combinations; C031000:benzimidazole; D010100:Oxygen; D012293:Rifampin
keywords: Benzimidazole; FtsZ inhibitor; In vitro activity; In vivo efficacy; Murine model tuberculosis; Mycobacterium tuberculosis
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