title: Design and Synthesis of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Treatment of Rheumatoid Arthritis.
abstract: We report the synthesis of a series of hybrid compounds incorporating 6- and 7-substituted coumarins (carbonic anhydrase, CA inhibitors) derivatized with clinically used NSAIDs (indomethacin, sulindac, ketoprofen, ibuprofen, diclofenac, ketorolac, etc., cyclooxygenase inhibitors) as agents for the management of rheumatoid arthritis (RA). Most compounds were effective in inhibiting the RA overexpressed hCA IX and XII, with KIvalues in the low nanomolar-subnanomolar ranges. The antihyperalgesic activity of such compounds was assessed by means of the paw-pressure and incapacitance tests using an in vivo RA model. Among all tested compounds, the 7-coumarine hybrid with ibuprofen showed potent and persistent antihyperalgesic effect up to 60 min after administration.
authors.affiliation: NEUROFARBA, Sezione di Scienze Farmaceutiche, University of Florence , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bua
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, NEUROFARBA-Pharmacology and Toxicology Section, University of Florence , 50019 Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Polo Scientifico, Laboratorio di Chimica Bioinorganica, University of Florence , Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, NEUROFARBA-Pharmacology and Toxicology Section, University of Florence , 50019 Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: NEUROFARBA, Sezione di Scienze Farmaceutiche, University of Florence , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bartolucci
authors.affiliation: Polo Scientifico, Laboratorio di Chimica Bioinorganica, University of Florence , Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.affiliation: NEUROFARBA, Sezione di Scienze Farmaceutiche, University of Florence , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.identifier: 0000-0003-4262-0323
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: NEUROFARBA, Sezione di Scienze Farmaceutiche, University of Florence , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Fabrizio
authors.identifier: 0000-0002-1141-6146
authors.initials: F
authors.lastname: Carta
mesh_terms: D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D051381:Rats
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002257:Carbonic Anhydrase Inhibitors