Discovery of thiazolin-4-one-based aromatic sulfamates as a new class of carbonic anhydrase isoforms I,II, IV,and IX inhibitors |
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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;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. Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;2. Università degli Studi di Firenze, Department NEUROFARBA – Pharmaceutical and Nutraceutical Section, University of Firenze, via Ugo Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy;3. 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;1. Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, via Ospedale 72, Cagliari I, 09124, Italy;2. Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Birmingham, B15 2TT, UK;3. Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK;4. Medicinal Chemistry & Drug Discovery, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK;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. Department of Pharmacology, Faculty of Pharmacy, Adiyaman University, 02040 Adiyaman, Turkey;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. Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Saulėtekio al. 7, Vilnius LT-10257, Lithuania;2. Department of Organic Chemistry, Faculty of Chemistry and Geosciences, Vilnius University, Naugarduko 24, Vilnius LT-03225, Lithuania |
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| Abstract: | Herein we report the synthesis of a new series of aromatic sulfamates investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IV, and IX. The reported derivatives, obtained by a sulfamoylation reaction of the corresponding phenolic precursors, bear arylthiazolin-4-one moieties as spacers between the benzenesulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor. Thiazolin-4-ones are biologically privileged scaffolds, endowed with versatile biological activity, such as an anti-proliferative action. Phenolic precursors, also evaluated for CA inhibition, did not exhibit noteworthy efficacy in inhibiting the screened hCAs, whereas low nanomolar inhibitors were evidenced within the sulfamates subset mainly against hCA II (KIs in the range of 28.7–84.3 nM) and IX (KIs in the range of 17.6–73.3 nM). The variety of substituents appended at the outer aromatic portion almost generally reduced the inhibitory efficacy against isoforms II and IV, increasing instead that against the tumor-associated isoform IX. |
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| Keywords: | Carbonic anhydrase Zinc-binding group Aromatic sulfamates Phenols Sulfamoylation Nanomolar inhibition |
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