Synthesis, biological evaluation, and structure-activity relationships for 5-[(E)-2-arylethenyl]-3-isoxazolecarboxylic acid alkyl ester derivatives as valuable antitubercular chemotypes.
Tuberculosis (TB), mostly caused by Mycobacterium tuberculosis (Mtb), is one of the leading causes of death from infectious disease worldwide. Its coinfection with HIV and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains have further worsened the TB pandemic. Despite its global impact, TB is considered a neglected disease and no new anti-TB therapeutics have been introduced over the last four decades. The nonreplicating persistent form of TB (NRP-TB) is responsible for the length of the treatment and is the putative cause of treatment failure. Therefore, new anti-TB agents, which are active against both the replicating form of Mtb (R-TB) and NRP-TB, are urgently needed. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of 5-[(E)-2-arylethenyl]-3-isoxazolecarboxylic acid alkyl esters as potent anti-TB agents. Several compounds had submicromolar minimum inhibitory concentrations (MIC) against R-TB and were active against NRP-TB in the low micromolar range, thus representing attractive lead compounds for the possible development of new anti-TB agents.
Pieroni
Marco
M
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
Lilienkampf
Annamaria
A
Wan
Baojie
B
Wang
Yuehong
Y
Franzblau
Scott G
SG
Kozikowski
Alan P
AP
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry*; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D002264:Carboxylic Acids; D004952:Esters