Synthesis,evaluation and in silico molecular modeling of pyrroyl-1,3,4-thiadiazole inhibitors of InhA |
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| Affiliation: | 1. Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T’s College of Pharmacy, Sangolli Rayanna Nagar, Dharwad 580 002, India;2. Centre for Research and Development, Prist University, Thanjavur, Tamil Nadu 613 403, India;1. SRSMC UMR 7565, Université de Lorraine, BP 70239, F-54506 Vandœuvre-lès-Nancy, France;2. SRSMC UMR 7565, CNRS, BP 70239, F-54506 Vandœuvre-lès-Nancy, France;3. CRAN UMR 7039, Université de Lorraine, BP 70239, F-54506 Vandœuvre-lès-Nancy, France;4. CRAN UMR 7039, CNRS, BP 70239, F-54506 Vandœuvre-lès-Nancy, France;5. CRM2 UMR 7036, Université de Lorraine, BP 70239, F-54506 Vandœuvre-lès-Nancy, France;6. CRM2 UMR 7036, CNRS, BP 70239, F-54506 Vandœuvre-lès-Nancy, France;7. IMoPA UMR 7365, Université de Lorraine, CS 50184, F-54505 Vandoeuvre-lès-Nancy, France;8. UMR 7503 LORIA, BP 70239, 54506 Vandoeuvre-lès-Nancy, France;1. Postovsky Institute of Organic Synthesis of Ural Branch of Russian Academy of Sciences, Sofia Kovalevskoy St. 22/20, Ekaterinburg, 620108, Russia;2. Ural Federal University, Department of Organic and Biomolecular Chemistry, Mira St. 19, Ekaterinburg, 620002, Russia;1. Key Laboratory of Biomedical Polymers, Engineering Research Centre of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China;2. Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055, China;3. School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China;1. Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan;2. Technical Support Center, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan |
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| Abstract: | Enoyl acyl carrier protein reductase (ENR) is an essential type II fatty acid synthase (FAS-II) pathway enzyme that is an attractive target for designing novel antitubercular agents. Herein, we report sixty-eight novel pyrrolyl substituted aryloxy-1,3,4-thiadiazoles synthesized by three-step optimization processes. Three-dimensional quantitative structure–activity relationships (3D-QSAR) were established for pyrrolyl substituted aryloxy-1,3,4-thiadiazole series of InhA inhibitors using the comparative molecular field analysis (CoMFA). Docking analysis of the crystal structure of ENR performed by using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of pyrrolyl substituted aryloxy 1,3,4-thiadiazole into hydrophobic pocket of InhA enzyme. Based on docking and database alignment rules, two computational models were established to compare their statistical results. The analysis of 3D contour plots allowed us to investigate the effect of different substituent groups at different positions of the common scaffold. In vitro testing of ligands using biological assays substantiated the efficacy of ligands that were screened through in silico methods. |
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| Keywords: | Pyrrolyl aryloxy 1,3,4-thiadiazoles Antitubercular activity Enoyl ACP reductase CoMFA Surflex-Docking |
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