10.1021/jm901273n.s001 Annamaria Lilienkampf Annamaria Lilienkampf Marco Pieroni Marco Pieroni Baojie Wan Baojie Wan Yuehong Wang Yuehong Wang Scott G. Franzblau Scott G. Franzblau Alan P. Kozikowski Alan P. Kozikowski 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 American Chemical Society 2010 Drug DevelopmentNew antituberculosis Selective Series SAR 128 μ M Growth Inhibitors series exhibit nanomolar activity Ethyl Esters INH Mycobacterium tuberculosis phenoxy derivatives RMP Mtb strains Vero cells SM Several compounds TB drug development IC 50 drug design approach Rational Design micromolar activity nonreplicating bacteria 2010-01-28 00:00:00 Journal contribution 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 New antituberculosis (anti-TB) drugs are urgently needed to shorten the 6−12 month treatment regimen and especially to battle drug-resistant <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) 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 <i>Mtb</i>, and in general, no cytotoxicity was observed in Vero cells (IC<sub>50</sub> > 128 μM). Notably, selected compounds also retained their activity against isoniazid (INH), rifampin (RMP), and streptomycin (SM) resistant <i>Mtb</i> 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.