%0 Journal Article
%A Lilienkampf, Annamaria
%A Pieroni, Marco
%A Wan, Baojie
%A Wang, Yuehong
%A Franzblau, Scott G.
%A Kozikowski, Alan P.
%D 2010
%T Rational Design of 5-Phenyl-3-isoxazolecarboxylic Acid Ethyl Esters as Growth Inhibitors of Mycobacterium tuberculosis. A Potent and Selective Series for Further Drug Development
%U https://acs.figshare.com/articles/journal_contribution/Rational_Design_of_5_Phenyl_3_isoxazolecarboxylic_Acid_Ethyl_Esters_as_Growth_Inhibitors_of_i_Mycobacterium_tuberculosis_i_A_Potent_and_Selective_Series_for_Further_Drug_Development/2796481
%R 10.1021/jm901273n.s001
%2 https://ndownloader.figshare.com/files/4490848
%K Drug DevelopmentNew antituberculosis
%K Selective Series
%K SAR
%K 128 μ M
%K Growth Inhibitors
%K series
%K exhibit nanomolar activity
%K Ethyl Esters
%K INH
%K Mycobacterium tuberculosis
%K phenoxy derivatives
%K RMP
%K Mtb strains
%K Vero cells
%K SM
%K Several compounds
%K TB drug development
%K IC 50
%K drug design approach
%K Rational Design
%K micromolar activity
%K nonreplicating bacteria
%X New antituberculosis (anti-TB) drugs are urgently needed to shorten the 6−12 month treatment regimen and especially to battle drug-resistant Mycobacterium tuberculosis (Mtb) strains. In this study, we have continued our efforts to develop isoxazole-based anti-TB compounds by applying rational drug design approach. The biological activity and the structure−activity relationships (SAR) for a designed series of 5-phenyl-3-isoxazolecarboxylic acid ethyl ester derived anti-TB compounds were investigated. Several compounds were found to exhibit nanomolar activity against the replicating bacteria (R-TB) and low micromolar activity against the nonreplicating bacteria (NRP-TB). The series showed excellent selectivity toward Mtb, and in general, no cytotoxicity was observed in Vero cells (IC50 > 128 μM). Notably, selected compounds also retained their activity against isoniazid (INH), rifampin (RMP), and streptomycin (SM) resistant Mtb strains. Hence, benzyloxy, benzylamino, and phenoxy derivatives of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters represent a highly potent, selective, and versatile series of anti-TB compounds and as such present attractive lead compounds for further TB drug development.
%I ACS Publications