1. Aryl-4,5-dihydro-1H-pyrazole-1-carboxamide Derivatives Bearing a Sulfonamide Moiety Show Single-digit Nanomolar-to-Subnanomolar Inhibition Constants against the Tumor-associated Human Carbonic Anhydrases IX and XII
- Author
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Claudiu T. Supuran, Mrunmayee P. Toraskar, Andris Kazaks, Nikhil K. Tadge, Janis Leitans, Priya S. Hargunani, Alessio Nocentini, Kaspars Tars, Paola Gratteri, and Mariangela Ceruso
- Subjects
Docking ,Human carbonic anhydrase ,Inhibition ,Pyrazoline ,Selectivity ,Sulfonamide ,Models, Molecular ,Molecular Conformation ,Carboxamide ,Pyrazole ,01 natural sciences ,lcsh:Chemistry ,chemistry.chemical_compound ,Moiety ,Carbonic Anhydrase Inhibitors ,lcsh:QH301-705.5 ,Spectroscopy ,Carbonic Anhydrases ,Molecular Structure ,biology ,General Medicine ,inhibition ,Computer Science Applications ,Isoenzymes ,docking ,Protein Binding ,Stereochemistry ,medicine.drug_class ,human carbonic anhydrase ,Antineoplastic Agents ,Isozyme ,Article ,Catalysis ,Inorganic Chemistry ,Structure-Activity Relationship ,Carbonic anhydrase ,sulfonamide ,medicine ,Humans ,Physical and Theoretical Chemistry ,pyrazoline ,Molecular Biology ,Binding Sites ,010405 organic chemistry ,Aryl ,Organic Chemistry ,selectivity ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,Docking (molecular) ,biology.protein ,Pyrazoles - Abstract
A series of new 3-phenyl-5-aryl-N-(4-sulfamoylphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide derivatives was designed here, synthesized, and studied for carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity against the human (h) isozymes I, II, and VII (cytosolic, off-target isoforms), and IX and XII (anticancer drug targets). Generally, CA I was not effectively inhibited, whereas effective inhibitors were identified against both CAs II (KIs in the range of 5.2&ndash, 233 nM) and VII (KIs in the range of 2.3&ndash, 350 nM). Nonetheless, CAs IX and XII were the most susceptible isoforms to this class of inhibitors. In particular, compounds bearing an unsubstituted phenyl ring at the pyrazoline 3 position showed 1.3&ndash, 1.5 nM KIs against CA IX. In contrast, a subset of derivatives having a 4-halo-phenyl at the same position of the aromatic scaffold even reached subnanomolar KIs against CA XII (0.62&ndash, 0.99 nM). Docking studies with CA IX and XII were used to shed light on the derivative binding mode driving the preferential inhibition of the tumor-associated CAs. The identified potent and selective CA IX/XII inhibitors are of interest as leads for the development of new anticancer strategies.
- Published
- 2020
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