Rational design and synthesis of novel thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors |
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| Affiliation: | 1. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CDRI), Jankipuram Extension, Sector-10, Lucknow 226031, Uttar Pradesh, India;2. Toxicology Division, CSIR-Central Drug Research Institute (CDRI), Jankipuram Extension, Sector-10, Lucknow 226031, Uttar Pradesh, India;3. Department of Molecular Virology, National AIDS Research Institute (NARI), Pune 411026, Maharashtra, India;1. Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan;2. Matsumoto Yushi-Seiyaku Co., Ltd, 2-1-3, Shibukawa-cho, Yao-City, Osaka 581-0075, Japan;1. Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, India;2. Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan;1. School of Chemistry and Environment, South China Normal University, Guangzhou 510006, China;2. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;3. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA;4. Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;1. Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan;2. Division of Anaerobe Research, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan;3. United Graduate School of Drug Discovery and Medicinal Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan;4. College of Science and Technology, Nihon University, Chiyoda, Tokyo 101-0062, Japan;1. Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India;2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201 002, India;3. Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, R.R. District, Hyderabad 500078, India;4. Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India;5. Department of Biology, CSIR-National Chemical Laboratory, Pashan Road, Pune, 411008, India;6. Department of Microbiology, CSIR-Central Drug Research Institute, Lucknow, 226021, Uttar Pradesh, India;7. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, 500 037, India;8. Department of Bacteriology, National Institute for Research in Tuberculosis, Chennai, 600031, India;1. Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Chithera, Dadri, Greater Noida, UP, 201314, India;2. Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, Telangana, 500085, India;3. Structural Biology and Bio-informatics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja SC Mullick Road, Kolkata, West Bengal, 700032, India;4. Acubiosys PVT LTD, TBI, BITS-Pilani Campus, Jawahar Nagar, Hyderabad, Telangana, 500078, India;5. Center for Innovation in Molecular and Pharmaceutical Sciences, Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, 500046, India |
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| Abstract: | A series of novel thiazolidin-4-one analogues, characterized by different substitution patterns at positions C-2 and N-3 of the thiazolidin-4-one scaffold for anti-HIV-1 activity has been investigated. Most of the compounds showed anti-HIV-1 activity at micromolar concentrations when tested in TZM-bl cells in vitro. Among the thirty-three compounds tested, compound 16 was the most potent inhibitor of HIV-1 replication against HIV-1IIIB, HIV-1ADA5, HIV-1UG070 and HIV-1VB59 (EC50 = 0.02, 0.08, 0.08 and 0.08 μM, respectively) with selectivity index (SI = 6940, 1735, 1692 and 1692) against tested viral strains, respectively. The results of the present study suggested that the substitution of the nitro group at 6′ position of the C-2 phenyl ring and 4,6-dimethylpyridin-2-yl at the N-3 position of thiazolidin-4-one had a major impact on the anti-HIV-1 activity and was found to lower cytotoxicity. The substitution of the heteroaryl ring with bromo group and bicyclic heteroaryl ring at N-3 thiazolidin-4-one was found to lower anti-HIV-1 activity and increase cytotoxicity. The undertaken docking studies thus facilitated the identification of crucial interactions between the HIV-1 RT enzyme and thiazolidin-4-one inhibitors, which can be used to design new potential inhibitors. |
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