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.
OBJECTIVE
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 microM. 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 microM 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 microM, 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 log(10) reductions, respectively.
Sriram
Dharmarajan
D
Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science, Pilani, India. dsriram@bits-pilani.ac.in
Yogeeswari
Perumal
P
Dinakaran
Murugesan
M
Thirumurugan
Rathinasababathy
R
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D005260:Female; D007538:Isoniazid / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D014709:Vero Cells
D000995:Antitubercular Agents; D011725:Pyridines; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; D013890:Thiourea; D007538:Isoniazid