Received 31 July 2014 Received in revised form 23 February 2015 Accepted 24 February 2015 Available online 28 February 2015 Keywords: 1,2,3-Triazoles COX inhibition Predictive pharmacometric model Volsurf plus 1. Introduction In the last two decades, the interest around the cyclooxygenases was focused on the inducible isoform COX-2, trying to exalt ther- apeutic over adverse side effects and because deemed solely responsible of inflammation processes in respect to the “constitu- tive” isoenzyme COX-1 [1]. In recent years, the attention around the COX-1 has been growing ever more, especially since it was demonstrated that COX-1 isoform, but not COX-2, is overexpressed in several human pathologies. Particularly, COX-1 is expressed at high levels from the early to advanced stages of human epithelial ovarian cancer, skin and colon, and seems to play a specific key role also in cancer progression. As a consequence, COX-1 might be a novel biomarker for early ovarian cancer detection [2], as well as in other cancer types [1]. * Corresponding author. E-mail address: antonio.scilimati@uniba.it (A. Scilimati). 1 M. G. Perrone and P. Vitale have equally contributed to this project. http://dx.doi.org/10.1016/j.ejmech.2015.02.049 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved. abstract A novel set of 1,4-diaryl-1,2,3-triazoles were projected as a tool to study the effect of both the hetero- aromatic 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 mM 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]benzen- amine (19)} bearing an amino group (NH2) are potent and selective COX-1 inhibitors (IC50 1⁄4 15 and 3 mM, 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 1⁄4 23 mM and was found inactive towards COX-2.

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

FORTUNA, COSIMO GIANLUCA;
2015-01-01

Abstract

Received 31 July 2014 Received in revised form 23 February 2015 Accepted 24 February 2015 Available online 28 February 2015 Keywords: 1,2,3-Triazoles COX inhibition Predictive pharmacometric model Volsurf plus 1. Introduction In the last two decades, the interest around the cyclooxygenases was focused on the inducible isoform COX-2, trying to exalt ther- apeutic over adverse side effects and because deemed solely responsible of inflammation processes in respect to the “constitu- tive” isoenzyme COX-1 [1]. In recent years, the attention around the COX-1 has been growing ever more, especially since it was demonstrated that COX-1 isoform, but not COX-2, is overexpressed in several human pathologies. Particularly, COX-1 is expressed at high levels from the early to advanced stages of human epithelial ovarian cancer, skin and colon, and seems to play a specific key role also in cancer progression. As a consequence, COX-1 might be a novel biomarker for early ovarian cancer detection [2], as well as in other cancer types [1]. * Corresponding author. E-mail address: antonio.scilimati@uniba.it (A. Scilimati). 1 M. G. Perrone and P. Vitale have equally contributed to this project. http://dx.doi.org/10.1016/j.ejmech.2015.02.049 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved. abstract A novel set of 1,4-diaryl-1,2,3-triazoles were projected as a tool to study the effect of both the hetero- aromatic 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 mM 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]benzen- amine (19)} bearing an amino group (NH2) are potent and selective COX-1 inhibitors (IC50 1⁄4 15 and 3 mM, 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 1⁄4 23 mM and was found inactive towards COX-2.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/35380
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