Sulfamide derivatives with selective carbonic anhydrase VII inhibitory action |
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| Institution: | 1. Medicinal Chemistry, Department of Biological Sciences, Faculty of Exact Sciences, National University of La Plata, 47 and 115, La Plata B1900BJW, Argentina;2. Università degli Studi di Firenze, Neurofarba Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;1. CEDECOR, Departamento de Química, Facultad de Ciencias Exactas, CONICET, Universidad Nacional de La Plata. 47 y 115, La Plata 1900, Argentina;2. Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 954 CP 1113, Buenos Aires, Argentina;1. Department of Chemistry, Badji-Mokhtar University, Annaba, Algeria;2. Laboratory of Computational Chemistry and Nanostructures, BP: 401, University of Guelma, Algeria;3. Applied Organic Chemistry Laboratory, Department of Chemistry, Faculty of Science, Badji-Mokhtar University, BP 12 Annaba, Algeria;1. Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, PR China;2. Departments of Biomedical Engineering and Chemistry, Metcalf Center for Science and Engineering, Boston University, Boston, MA 02215, United States;1. Departamento de Química Orgánica and UMYMFOR (CONICET–FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina;2. Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA;3. Departamento de Química Orgánica and CIHIDECAR, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina |
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| Abstract: | A set of N,N′-disubstituted sulfamides and sodium cyclamate have been tested for their inhibitory action against six isoforms of carbonic anhydrase (CA, EC 4.2.1.1) found in the brain, that is, CA I, CA II, CA VII, CA IX, CA XII and CA XIV, some of which are involved in epileptogenesis. The biological data showed interesting results for CA VII inhibition, the isozyme thought to be a novel antiepileptic target. Strong CA VII inhibitors, with Ki values in the low nanomolar–subnanomolar range were identified. Some of these derivatives showed selectivity for inhibition of CA VII versus the ubiquitous isoform CA II, for which the Ki values were in the micromolar range. Molecular modeling approaches were employed to understand the binding interactions between these compounds and the two CA isoforms, since the mechanism of action of such disubstituted sulfamides was not yet investigated by means of X-ray crystallography. |
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| Keywords: | Carbonic anhydrase Sulfamides Docking Epilepsy Sodium cyclamate |
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