Sriram Dharmarajan, Yogeeswari Perumal, Dinakaran Murugesan, Thirumurugan Rathinasababathy
Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science, Pilani, India.
J Antimicrob Chemother. 2007 Jun;59(6):1194-6. doi: 10.1093/jac/dkm085. Epub 2007 Apr 20.
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.
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).
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.
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.
本研究的目的是合成15种新型1-(5-环丁基-1,3-恶唑-2-基)-3-(取代)苯基/吡啶基硫脲化合物，并评估其体外和体内抗分枝杆菌活性。
5-环丁基恶唑-2-胺与1,1'-硫代羰基二咪唑反应，然后与各种取代苯胺和2-氨基吡啶反应，得到这15种化合物，对其进行针对结核分枝杆菌H37Rv（MTB）和耐多药结核分枝杆菌临床分离株（MDR-TB）的体外和体内评估。
在筛选的15种化合物中，7种化合物在体外对MTB和MDR-TB均有抑制作用，MICs<1 microM。在体内筛选中，化合物1-(5-环丁基-1,3-恶唑-2-基)-3-(2'-三氟甲基)苯基硫脲（化合物8）在相同剂量水平下与异烟肼活性相当。
发现化合物8活性最高，体外MIC为0.14 microM，对MTB和MDR-TB的活性分别比异烟肼高2.5倍和80倍。化合物8在高达183 microM时对Vero细胞无毒，选择性指数>1307。在体内动物模型中，化合物8使肺和脾组织中的分枝杆菌载量分别降低了2.8和3.94 log(10)。
