4-Substituted benzenesulfonamides featuring cyclic imides moieties exhibit potent and isoform-selective carbonic anhydrase II/IX inhibition |
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| Institution: | 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 Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia;2. Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia;2. Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;3. Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, AlKharj, Saudi Arabia;4. Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt;5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt;1. Erzurum Technical University, Faculty of Science, Department of Basic Sciences, Erzurum, Turkey;2. Ataturk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey;3. King Saud University, College of Science, Department of Zoology, Riyadh, Saudi Arabia;4. Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey;5. Faculty of Science and Arts, Department of Chemistry, Sutcu Imam University, Kahramanmaras, Turkey;6. Dipartimento di Chimica Ugo Schiff, Universita degli Studi di Firenze, Sesto Fiorentino (Firenze), Italy;7. Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, Universita degli Studi di Firenze, Sesto Fiorentino (Florence), Italy;1. NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Sesto Fiorentino (Firenze), Italy;2. Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;3. Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy |
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| Abstract: | The synthesis, characterization and biological evaluation of series of cyclic imides incorporating the 4-sulfamoylbenzamide scaffold (16–29) is disclosed. The compounds were designed by application of the “tail approach” to the aromatic sulfonamide scaffold and prepared by reacting the proper acid anhydride with 4-(hydrazinecarbonyl)benzenesulfonamide (15). Phtalimides and cyclic imides are biologically privileged scaffolds, endowed with versatile biological activity, such as an anti-proliferative action. The compounds were investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), and more specifically against the cytosolic hCA I and II and the transmembrane hCA IV and IX. Most screened sulfonamides exhibited great potency in inhibiting CA isoforms II, widely involved in glaucoma and other pathologies (KIs in the range of 0.7–62.3 nM), and IX, that is a validated anti-tumor target (KIs in the range of 3.0–50.9 nM), whereas interesting hydrophilicity-dependent inhibitory profiles were measured against isoform CA IV (KIs in the range of 3.9–428.6 nM). In silico studies were carried out to assess the binding mode of selected derivatives to hCA II, IV and IX. |
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| Keywords: | Carbonic anhydrase Inhibition Heterocycle Imide Sulfonamide Anti-glaucoma Anti-tumor |
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