Sulfonamides incorporating piperazine bioisosteres as potent human carbonic anhydrase I,II, IV and IX inhibitors |
| |
| Affiliation: | 1. University of Florence, Department of Neuroscience, Psychology, Drug Research and Child’s Health, Section of Pharmaceutical and Nutraceutical Sciences, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy;2. University of Florence, Department of Chemistry, via della Lastruccia, 50019 Sesto Fiorentino, Italy;1. Department of Chemistry, School of Technology, GITAM University, Hyderabad 502102, Telangana, India;2. School of Chemical Sciences, SRTM University, Nanded 431606, Maharashtra, India;3. NEUROFARBA Department, Section of Pharmacology and Toxicology, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Florence, Italy;4. Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Alkharj 11942, Saudi Arabia;5. University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;6. Centre of Advanced Research in Bionanoconjugates and Biopolymers Department, “Petru Poni” Institute of Macromolecular Chemistry, Iasi, Romania;1. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), University of Dammam, Dammam 31441, Saudi Arabia;2. Department of Chemistry, University of Wah, Quaid Avenue, Wah Cantt 47000, Pakistan;3. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah, Malaysia;5. Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia;6. Department of Chemistry, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan;7. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;1. Dipartimento CHIBIOFARAM, Università degli Studi di Messina, Viale Palatucci, Polo Didattico SS. Annunziata, 98168 Messina, Italy;2. Istituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, 80134 Napoli, Italy;3. Dipartimento NEUROFARBA, Università di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy;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. Chemistry Dept., Universita degli Studi di Firenze, Florence 50019, Italy;2. Neurofarba Dept., Sezione di Farmacologia, Universita degli Studi di Firenze, Florence 50019, Italy;3. The Ushinsky Yaroslavl State Pedagogical University, Yaroslavl 150000, Russian Federation;4. Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Universita degli Studi di Firenze, Florence 50019, Italy;5. Institute of Chemistry, Saint Petersburg State University, Peterhof 198504, Russian Federation;1. Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany;2. Institute of Organic Chemistry, University of Regensburg, D-93040 Regensburg, Germany |
| |
| Abstract: | Starting from the molecular simplification of (R) 4-(3,4-dibenzylpiperazine-1-carbonyl)benzenesulfonamide 9a, a compound endowed with selectivity for human Carbonic Anhydrase (hCA) IV, a series of piperazines and 4-aminopiperidines carrying a 4-sulfamoylbenzamide moiety as Zn-binding group have been designed and tested on human isoforms hCA I, II, IV and IX, using a stopped flow CO2 hydrase assay. The aim of the work was to derive structure-activity relationships useful for designing isoform selective compounds. These structural modifications changed the selectivity profile of the analogues from hCA IV to hCA I and II, and improved potency. Several of the new compounds showed subnanomolar activity on hCA II. X-ray crystallography of ligand-hCAII complexes was used to compare the binding modes of the new piperazines and the previously synthesized 2-benzyl-piperazine analogues, explaining the inhibition profiles. |
| |
| Keywords: | Carbonic anhydrase Sulfonamides Piperazines Piperazine bioisosteres Carbonic anhydrase inhibitors Isoform selectivity |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
