Antimycobacterial activity of novel 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(sub)phenyl/pyridylthiourea compounds endowed with high activity toward multidrug-resistant Mycobacterium tuberculosis

Abstract

Objectives: The objective of this work was to synthesize 15 new 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(sub)- phenyl/pyridylthiourea compounds and evaluate their in vitro and in vivo antimycobacterial activities. Methods: 5-Cyclobutyloxazol-2-amine was reacted with 1,1′-thiocarbonyldiimidazole, followed by various substituted anilines and 2-amino pyridines to yield the 15 compounds, which were subjected to in vitro and in vivo evaluation against Mycobacterium tuberculosis H37Rv (MTB) and a clinical isolate of multidrug-resistant M. tuberculosis (MDR-TB). Results: Among the 15 compounds screened, 7 compounds inhibited both MTB and MDR-TB in vitro with MICs of <1 μM. In the in vivo screening, compound 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(20-trifluoromethyl) phenylthiourea (compound 8) was equally active as isoniazid at the same dose level. Conclusions: Compound 8 was found to be the most active, with an in vitro MIC of 0.14 μM and was 2.5 and 80 times more active than isoniazid against MTB and MDR-TB, respectively. Compound 8 was non-toxic to Vero cells up to 183 μM, with a selectivity index of >1307. In the in vivo animal model, compound 8 decreased the mycobacterium load in lung and spleen tissues with 2.8 and 3.94 log10 reductions, respectively. © The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.