title: General role of the amino and methylsulfamoyl groups in selective cyclooxygenase(COX)-1 inhibition by 1,4-diaryl-1,2,3-triazoles and validation of a predictive pharmacometric PLS model.
abstract: A novel set of 1,4-diaryl-1,2,3-triazoles were projected as a tool to study the effect of both the heteroaromatic triazole as a core ring and a variety of chemical groups with different electronic features, size and shape on the catalytic activity of the two COX isoenzymes. The new triazoles were synthesized in fair to good yields and then evaluated for their inhibitory activity towards COXs arachidonic acid conversion catalysis. Their COXs selectivity was also measured. A predictive pharmacometric Volsurf plus model, experimentally confirmed by the percentage (%) of COXs inhibition at the concentration of 50 μM and IC50 values of the tested compounds, was built by using a number of isoxazoles of known COXs inhibitory activity as a training set. It was found that two compounds {4-(5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)benzenamine (18) and 4-[1-(4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-yl]benzenamine (19)} bearing an amino group (NH2) are potent and selective COX-1 inhibitors (IC50 = 15 and 3 μM, respectively) and that the presence of a methylsulfamoyl group (SO2CH3) is not a rule to have a Coxib. In fact, 4-(4-methoxyphenyl)-5-methyl-1-[4-(methylsulfonyl)phenyl]-1H-1,2,3-triazole (23) has COX-1 IC50 = 23 μM and was found inactive towards COX-2.
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "A.Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Perrone
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "A.Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vitale
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "A.Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Panella
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Cosimo G
authors.initials: CG
authors.lastname: Fortuna
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "A.Moro", Via E. Orabona 4, 70125 Bari, Italy. Electronic address: antonio.scilimati@uniba.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Scilimati
mesh_terms: D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016018:Least-Squares Analysis; D015394:Molecular Structure; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D014230:Triazoles; D051545:Cyclooxygenase 1
keywords: 1,2,3-Triazoles; COX inhibition; Predictive pharmacometric model; Volsurf plus