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.