TY - JOUR
T1 - Synthesis, biological evaluation, and structure-activity relationships for 5-[(E)-2-arylethenyl]-3-isoxazolecarboxylic acid alkyl ester derivatives as valuable antitubercular chemotypes
AU - Pieroni, Marco
AU - Lilienkampf, Annamaria
AU - Baojie, Wan
AU - Yuehong, Wang
AU - Franzblau, Scott G.
AU - Kozikowski, Alan P.
PY - 2009/10/22
Y1 - 2009/10/22
N2 - 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 multidrugresistant 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.
AB - 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 multidrugresistant 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.
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U2 - 10.1021/jm900513a
DO - 10.1021/jm900513a
M3 - Article
C2 - 19757815
AN - SCOPUS:70350075455
SN - 0022-2623
VL - 52
SP - 6287
EP - 6296
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 20
ER -