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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Guo S,Song Y,Huang Q,Yuan H,Wan B,Wang Y,He R,Beconi MG,Franzblau SG,Kozikowski AP

doi

10.1021/jm901235p

subject

Has Abstract

pub_date

2010-01-28 00:00:00

pages

649-59

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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