Investigation of new quinoline derivatives as promising inhibitors of NTPDases: Synthesis,SAR analysis and molecular docking studies |
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| Institution: | 1. Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;2. Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan;3. H.E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75720 Pakistan;4. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia;5. Département de microbiologie-infectiologie et d''immunologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada;6. Centre de Recherche du CHU de Québec – Université Laval, Québec, QC G1V 4G2, Canada;1. Departmentof Chemistry, Quaid-i-Azam University, 45320 Islamabad, Pakistan;2. Sulaiman Bin Abdullah Aba Al-Khail – Centre for Interdisciplinary Research in Basic Science (SA-CIRBS), Faculty of Basic and Applied Sciences, International Islamic University, Islamabad, Pakistan;3. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;4. School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom;5. Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom;6. Département de microbiologie-infectiologie et d''immunologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada;7. Centre de Recherche du CHU de Québec – Université Laval, Québec, QC G1V 4G2, Canada;1. The Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine, Department of Organic Chemistry, Jagiellońska 4, 41-200 Sosnowiec, Poland;2. The Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine, Department of Cell Biology, Jedności 8, 41-200 Sosnowiec, Poland;3. Faculty of Mathematics and Natural Sciences, Cardinal Stefan Wyszyński University, K. Wóycickiego 1/3, 01-938 Warszawa, Poland;4. A.M. Butlerov Institute of Chemistry, Kazan Federal University, Kremlevskaya ul. 18, Kazan 420008, Russia;1. Chemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia;2. Center of Excellence for Advanced Materials Research (CEAMR), King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia;3. Department of Chemistry, Faculty of Sciences, Shree Guru Gobind Singh Tricentenary University, Gurugram 122505, Haryana, India;4. Chemistry Department, Faculty of Science, University of Jeddah, P.O. Box 80327, Jeddah 21589, Saudi Arabia;1. Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China;2. Guangdong Province Engineering Technology Research Institute of T. C. M., Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou 510095, People’s Republic of China;3. School of Biotechnology and Health Sciences, Wuyi University, 99 Yingbin Road, Jiangmen 529020, People’s Republic of China;4. Guangzhou University of Chinese Medicine, Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou 510095, People’s Republic of China;5. Molecular Laboratory, School of Biomedical Science, University of Western Australia, Perth, Western Australia, Australia;1. Department of Physics, Virginia Tech, Blacksburg;2. Department of Cell & Molecular Physiology, Loyola University Chicago, Chicago;1. School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia 750004, People’s Republic of China;2. School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, People’s Republic of China;3. School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People’s Republic of China |
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| Abstract: | Nucleoside triphosphate diphosphohydrolases (NTPDases), an important class of ectonucleotidases, are responsible for the sequential hydrolysis of extracellular nucleotides. However, over-expression of NTPDases has been linked with various pathological diseases e.g. cancer. Thus, to treat these diseases, the inhibitors of this class of enzyme are of interest. The significance of this class of enzyme encouraged us to synthesize a new class of quinoline derivatives with the aim to find selective and potent inhibitors of NTPDases. Therefore, a mild and efficient synthetic route was established for the synthesis of quinoline derivatives. The reaction was catalyzed by molecular iodine to afford the substituted quinoline derivatives. All the synthetic derivatives (3a-3w) were evaluated for their potential to inhibit the h-NTPDase1, 2, 3 and 8. Most of the compounds were identified as dual inhibitors of h-NTPDase1 and 8 with lower effects on h-NTPDase2 and 3. Two compounds i.e. 3f and 3t were identified as selective inhibitor of h-NTPDase1 whereas the compound 3s inhibited the h-NTPDase8 selectively. Moreover, the compounds 3p (IC50 = 0.23 ± 0.01 µM), 3j (IC50 = 21.0 ± 0.03 µM) 3d (IC50 = 5.38 ± 0.21 µM) and 3c (IC50 = 1.13 ± 0.04 µM) were found to be the most potent inhibitors of h-NTPDase1, 2, 3 and 8, respectively. To determine the binding interaction, molecular docking studies were also carried out. |
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| Keywords: | Quinoline synthesis Iodine catalysis NTPDase inhibitors Structure-activity relationship |
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