Pedgaonkar Ganesh S, Sridevi Jonnalagadda Padma, Jeankumar Variam Ullas, Saxena Shalini, Devi Parthiban Brindha, Renuka Janupally, Yogeeswari Perumal, Sriram Dharmarajan
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Shameerpet, R.R. District, Hyderabad 500078, India.
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Shameerpet, R.R. District, Hyderabad 500078, India.
Bioorg Med Chem. 2014 Nov 1;22(21):6134-45. doi: 10.1016/j.bmc.2014.08.031. Epub 2014 Sep 4.
A series of twenty seven substituted 2-(2-oxobenzo[d]oxazol-3(2H)-yl)acetamide derivatives were designed based on our earlier reported Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein reductase (InhA) lead. Compounds were evaluated for MTB InhA inhibition study, in vitro activity against drug-sensitive and -resistant MTB strains, and cytotoxicity against RAW 264.7 cell line. Among the compounds tested, 2-(6-nitro-2-oxobenzo[d]oxazol-3(2H)-yl)-N-(5-nitrothiazol-2-yl)acetamide (30) was found to be the most promising compound with IC50 of 5.12 ± 0.44 μM against MTB InhA, inhibited drug sensitive MTB with MIC 17.11 μM and was non-cytotoxic at 100 μM. The interaction with protein and enhancement of protein stability in complex with compound 30 was further confirmed biophysically by differential scanning fluorimetry.
基于我们早期报道的结核分枝杆菌（MTB）烯酰-酰基载体蛋白还原酶（InhA）先导化合物，设计了一系列27种取代的2-(2-氧代苯并[d]恶唑-3(2H)-基)乙酰胺衍生物。对这些化合物进行了MTB InhA抑制研究、对药物敏感和耐药MTB菌株的体外活性以及对RAW 264.7细胞系的细胞毒性评估。在所测试的化合物中，2-(6-硝基-2-氧代苯并[d]恶唑-3(2H)-基)-N-(5-硝基噻唑-2-基)乙酰胺（30）被发现是最有前景的化合物，对MTB InhA的IC50为5.12±0.44μM，对药物敏感MTB的MIC为17.11μM，在100μM时无细胞毒性。通过差示扫描荧光法进一步从生物物理学角度证实了化合物30与蛋白质的相互作用以及与蛋白质形成复合物时蛋白质稳定性的增强。
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