New thiopyrimidine-benzenesulfonamide conjugates as selective carbonic anhydrase II inhibitors: synthesis,in vitro biological evaluation,and molecular docking studies |
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| Institution: | 1. Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, El‐Buhouth St., Dokki, P.O. Box 12622, Cairo, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, New Giza, Km 22 Cairo–Alexandria Desert Road, Cairo, Egypt;4. Università degli Studi di Firenze, Department NEUROFARBA – Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, I-50019, Sesto Fiorentino, Firenze, Italy;5. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) – Helmholtz Centre for Infection Research (HZI), Department of Drug Design and Optimization, Campus Building E8.1, 66123 Saarbrücken, Germany;1. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia;2. College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;4. Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea;5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo P.O. Box 11562, Egypt;6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, New giza, km 22, Cairo–Alexandria Desert Road, Cairo, Egypt;7. Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea;8. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;9. Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt;10. Department of Orthopedics and Traumatology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;11. Clinical Pharmacy Department, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia;12. Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia;1. University of Pisa, Department of Pharmacy, Via Bonanno 6, 56126 Pisa, Italy;2. University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;3. Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt;4. NEUROFARBA Department – Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;5. NEUROFARBA Department – Pharmaceutical and Nutraceutical Section, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;1. Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan;2. Institut für Organische Chemie, Schneiderberg 1 B, 30167 Hannover, Germany;3. Institute of Biochemistry, University of Sindh, Jamshoro 76080, Pakistan;4. Department of Physiology, University of Sindh, Jamshoro 76080, Pakistan;5. Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 32588, Republic of Korea;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia;2. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;3. Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt;1. Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Saul?tekio al. 7, Vilnius LT-10257, Lithuania;2. Department of Organic Chemistry, Faculty of Chemistry and Geosciences, Vilnius University, Naugarduko 24, Vilnius LT-03225, Lithuania;3. Department of Bioinformatics, Institute of Biotechnology, Vilnius University, Saul?tekio al. 7, Vilnius LT-10257, Lithuania |
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| Abstract: | In the present work, a new series of thiopyrimidine-benzenesulfonamide conjugates was designed, synthesized and tested as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Our design strategy was based on the molecular hybridization of the benzenesulfonamide moiety as a zinc binding group (ZBG), an alkylated thiopyrimidine moiety as a spacer and (un)substituted phenyl moieties with various electronic and hydrophobic environments as a tail. The designed and synthesized compounds were evaluated against four human (h) CA isoforms hCA I, hCA II, hCA IX and hCA XII. Series 6 showed promising activity and selectivity toward the cytosolic isoforms hCA I and hCA II versus the membrane bound isoforms hCA IX and hCA XII. Compounds 6e and 6f showed Ki of 0.04 µM against hCA II with a selectivity of 15.8- to 980-fold towards hCA II over hCA I, hCA IX, hCA XII isoforms. Molecular docking in the hCA II active site attributed the promising inhibitory activity of series 6 to the interaction of their sulfonamide moiety with the active site Zn2+ ion as well as its hydrogen bonding with the key amino acids Thr199 and Thr200. Through hydrophobic interaction, the benzenesulfonamide and the thiopyrimidine moieties interact with the hydrophobic side chains of the amino acids Val121/Leu198 and Ile91/Phe131, respectively. These results indicated that the designed and synthesized series is an interesting scaffold that can be further optimized for the development of selective antiglaucoma drugs. |
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| Keywords: | Synthesis Thiopyrimidine-benzenesulfonamide conjugates Carbonic anhydrase Molecular docking |
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