Development of benzo[d]oxazol-2(3H)-ones derivatives as novel inhibitors of Mycobacterium tuberculosis InhA |
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| Affiliation: | 1. Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Shameerpet, Hyderabad 500078, India;2. Department of Chemistry, Sri Krishnadevaraya University, Anantapur 515055, India;1. University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia;2. DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain;3. Medicines Research Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK;1. Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia;2. Diseases of the Developing World, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain;3. GlaxoSmithKline Medicines Research Centre, Stevenage, Herfordshire SG1 2NY, UK;1. Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d''Intérêt Biologique, LSPCMIB, 118 route de Narbonne, F-31062 Toulouse cedex 9, France;2. Taras Shevchenko National University of Kyiv, Department of Chemistry, 64 str. Volodymyrska, Kyiv 01601, Ukraine;3. CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d''Intérêt Biologique, LSPCMIB, UMR-5068, 118 Route de Narbonne, F-31062 Toulouse cedex 9, France;4. University of Pavia, Dipartimento di Biologia e Biotecnologie “Lazzaro Spallanzani”, via Ferrata 1, 27100 Pavia, Italy;1. Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka-shi, Fukuoka 820-8502, Japan;2. Department of Biochemistry & Biophysics, Texas A & M University, College Station, TX 77843-2128, United States;3. Department of Applied Chemistry, Kyushu Institute of Technology, 1-1 Sensui-cho, Tobata-ku, Kitakyushu-shi, Fukuoka 804-8550, Japan;4. Biomedical Informatics Research and Development Center (BMIRC), Kyushu Institute of Technology, 680-4 Kawazu, Iizuka-shi, Fukuoka 820-8502, Japan |
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| Abstract: | 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. |
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| Keywords: | Tuberculosis InhA Enoyl acyl carrier protein reductase Cytotoxicity |
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