Identification, synthesis, and pharmacological evaluation of tetrahydroindazole based ligands as novel antituberculosis agents.
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.
Guo
Songpo
S
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
Song
Yang
Y
Huang
Qingqing
Q
Yuan
Hai
H
Wan
Baojie
B
Wang
Yuehong
Y
He
Rong
R
Beconi
Maria G
MG
Franzblau
Scott G
SG
Kozikowski
Alan P
AP
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
D000995:Antitubercular Agents; D007191:Indazoles; D008024:Ligands