In silico ADMET study,docking, synthesis and antimalarial evaluation of thiazole-1,3,5-triazine derivatives as Pf-DHFR inhibitor |
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| Affiliation: | 1. Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, India;2. School of Pharmacy, Graphic Era Hill University Dehradun, Uttarakhand, India;3. Drug Design and Discovery Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture Technology and Sciences, Allahabad, India;4. Regional Medical Research Centre, ICMR, Dibrugarh, Assam, India;1. Key Laboratory for Green Chemical Process of Ministry of Education, Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Hubei Engineering Research Center for Advanced Fine Chemicals, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, PR China;2. Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Hong Kong;1. Organic Research Laboratory, Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong, 4331, Bangladesh;2. Department of Biochemistry and Molecular Biology, Faculty of Biological Science, University of Chittagong, Chittagong, 4331, Bangladesh;3. Wazed Miah Science Research Centre (WMSRC), Jahangirnagar University, Savar, Dhaka, Bangladesh;4. Department of Applied Chemistry and Biochemical Engineering, Shizuoka University, 3-5-1, Johoku, Hamamatsu, 432-8561, Japan;1. College of Chemical Engineering, Nanjing Forestry University, 159 Long Pan Road, Nanjing 210037, China;2. Chia Tai Tianqing Pharmaceutical Group Co., Ltd., 369 South Yuzhou Road, Haizhou District, Lianyungang 222062, Jiangsu Province, China;3. Jiangsu Kanion Pharmaceutical Co., Ltd., 58 Haichang South Road, Lianyungang 222001, Jiangsu Province, China;1. Biorganic & Medicinal Chemistry Laboratory, Department of Chemistry, Faculty of Science, University of Chittagong, Chattogram, 4331, Bangladesh;2. Department of Applied Chemistry and Biochemical Engineering, Shizuoka University, 3-5-1, Johoku, Hamamatsu, 432-8561, Japan;3. Wazed Miah Science Research Centre (WMSRC), Jahangirnagar University, Savar, Dhaka, Bangladesh;4. Department of Anaesthesia and Intensive Care Medicine, Chittagong Medical College, Chattogram, 4203, Bangladesh;1. Pharmaceutical Sciences Research Center, Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran;2. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran;3. Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran;4. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran |
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| Abstract: | BackgroundPlasmodium falciparum dihydrofolate reductase (Pf-DHFR) is an essential enzyme in the folate pathway and is an important target for antimalarial drug discovery. In this study a modern approach has been undertaken to identify new hits of thiazole-1,3,5-triazine derivatives as antimalarials targeting Pf-DHFR.MethodsThe library of 378 thiazole-1,3,5-triazines were designed and subjected to ADME analysis. The compounds having optimal ADME score, was then evaluated by docking against wild and mutant Pf-DHFR complex. The resultant compound after screening from above these two methods were synthesized, and assayed for in vitro antimalarial against chloroquine-sensitive (3D-7) and chloroquine resistant (Dd-2) strains of P. falciparum.ResultsTwenty compounds were identified from the dataset based on considerable AlogP98 vs. PSA_2D confidence ellipse, ADME filter and TOPKAT toxicity analysis. Majority of compounds showed interaction with Asp54, Arg59, Arg122 and Ile 164 in docking analysis. Entire set of tested derivatives exhibited considerable activity at the tested dose against sensitive strain with IC50 values varying from 10.03 to 54.58 μg/ml. Furthermore, against chloroquine resistant strain, eight compounds showed IC50 from 11.29 to 40.92 μg/ml. Compound A5 and H16 were found to be the most potent against both the strains of P. Falciparum.ConclusionResults of the study suggested the possible utility of thiazole-1,3,5-triazines as new lead for identifying new class of Pf-DHFR inhibitor. |
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| Keywords: | Thiazole 1,3,5-Triazine Antimalarial ADMET Docking Synthesis |
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