title: Identification, synthesis, and pharmacological evaluation of tetrahydroindazole based ligands as novel antituberculosis agents.
abstract: The resurgence of tuberculosis (TB), the incidence of drug-resistant strains of Mycobacterium tuberculosis (MTB), and the coinfection between TB and HIV have led to serious infections, high mortality, and a global health threat, resulting in the urgent search for new classes of antimycobacterial agents. Herein, we report the identification of a novel class of tetrahydroindazole based compounds as potent and unique inhibitors of MTB. Compounds 6a, 6m, and 6q exhibited activity in the low micromolar range against replicating Mycobacterium tuberculosis (R-TB) phenotype, with minimum inhibitory concentrations (MICs) of 1.7, 1.9, and 1.9 muM, respectively, while showing no toxicity to Vero Ccells. Moreover, studies aimed to assess the in vitro metabolic stability of 6a and 6m in mouse liver microsomes and in vivo pharmacokinetic profiles in plasma levels gave satisfactory results. This research suggests that tetrahydroindazole based anti-TB compounds can serve as a promising lead scaffold in developing new drugs to combat tuberculosis infections.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
authors.forename: Songpo
authors.initials: S
authors.lastname: Guo
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Huang
authors.forename: Hai
authors.initials: H
authors.lastname: Yuan
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: He
authors.forename: Maria G
authors.initials: MG
authors.lastname: Beconi
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002522:Chlorocebus aethiops; D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D008024:Ligands; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D007191:Indazoles; D008024:Ligands