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JAC Advance Access originally published online on April 20, 2007
Journal of Antimicrobial Chemotherapy 2007 59(6):1194-1196; doi:10.1093/jac/dkm085
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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

Dharmarajan Sriram*, Perumal Yogeeswari, Murugesan Dinakaran and Rathinasababathy Thirumurugan

Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science, Pilani-333031, India

Received 5 December 2006; returned 29 January 2007; revised 8 February 2007; accepted 27 February 2007

* Corresponding author. Tel: +91-1596-245073 (266); Fax: +91-1596-244183; E-mail: dsriram{at}bits-pilani.ac.in

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-(2'-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.

Keywords: antimycobacterial activity , antitubercular activity , thiourea derivatives , oxazole derivatives


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