Synthesis and biological evaluation of novel pyrazoline-based aromatic sulfamates with potent carbonic anhydrase isoforms II,IV and IX inhibitory efficacy |
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| Institution: | 1. Department NEUROFARBA – Pharmaceutical and Nutraceutical Section, University of Firenze, via Ugo Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy;2. Department of Life and Environmental Sciences – Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, via Ospedale 72, I-09124 Cagliari, Italy;3. Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, via Fossato di Mortara 17/19, I-44100 Ferrara, Italy;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt;3. Università degli Studi di Firenze, Department NEUROFARBA – Pharmaceutical and Nutraceutical section, University of Firenze, via Ugo Schiff 6, I-50019, Sesto Fiorentino, Firenze, Italy;4. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy;5. Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt;6. Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adiyaman University, 02040 Adiyaman, Turkey;2. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;3. University of Pennsylvania, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics, 19104 Philadelphia, United States;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Istanbul, Turkey;2. Department of Biochemistry, School of Medicine, Aydin Adnan Menderes University, Aydın, Turkey;1. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad-22060, Abbottabad, Pakistan;2. Division of Analytical Chemistry, Institute of Chemical Science, Bahauddin Zakariya University, 60800, Multan, Pakistan;3. Institute of Chemistry, University of the Punjab, Lahore, Pakistan;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt;3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy;4. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;5. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;6. Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt;1. University of Veterinary and Pharmaceutical Sciences, Faculty of Pharmacy, Department of Chemical Drugs, Palackého 1-3, CZ-612 42 Brno, Czech Republic;2. Masaryk University, Faculty of Science, Department of Chemistry, Centre for Syntheses at Sustainable Conditions and Their Management, University Campus, Kamenice 753/5, CZ-625 00 Brno, Czech Republic;3. University of Florence, Polo Scientifico, Neurofarba Department, Via Ugo Shiff 6, 500 19 Sesto Fiorentino (Florence), Italy;4. Comenius University in Bratislava, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Odbojárov 10, 832 32 Bratislava, Slovakia |
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| Abstract: | Herein we report the synthesis of a new series of aromatic sulfamates designed considering the sulfonamide COX-2 selective inhibitors celecoxib and valdecoxib as lead compounds. These latter were shown to possess important human carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties, with the inhibition of the tumor-associated isoform hCA IX likely being co-responsible of the celecoxib anti-tumor effects. Bioisosteric substitution of the pyrazole or isoxazole rings from these drugs with the pyrazoline one was considered owing to the multiple biological activities ascribed to this latter heterocycle and paired with the replacement of the sulfonamide of celecoxib and valdecoxib with its equally potent bioisoster sulfamate. The synthesized derivatives were screened for the inhibition of four human carbonic anhydrase isoforms, namely hCA I, II, IV, and IX. All screened sulfamates exhibited great potency enhancement in inhibiting isoform II and IV, widely involved in glaucoma (KIs in the range of 0.4–12.4 nM and 17.7 and 43.3 nM, respectively), compared to the lead compounds, whereas they affected the tumor-associated hCA IX as potently as celecoxib. |
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| Keywords: | Carbonic anhydrase ZInc-binding group Aromatic sulfamates Celecoxib Sulfamoylation Sub-nanomolar inhibition |
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