Identification, synthesis, and pharmacological evaluation of tetrahydroindazole based ligands as novel antituberculosis agents

Songpo Guo, Yang Song, Qingqing Huang, Hai Yuan, Baojie Wan, Yuehong Wang, Rong He, Maria G. Beconi, Scott G. Franzblau, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

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 μM, 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.

Original languageEnglish (US)
Pages (from-to)649-659
Number of pages11
JournalJournal of medicinal chemistry
Volume53
Issue number2
DOIs
StatePublished - Mar 1 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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