Diarylheterocycle core ring features effect in selective COX-1 inhibition |
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Authors: | Perrone Maria Grazia Vitale Paola Malerba Paola Altomare Angela Rizzi Rosanna Lavecchia Antonio Di Giovanni Carmen Novellino Ettore Scilimati Antonio |
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Affiliation: | Dipartimento Farmaco-Chimico, Università degli Studi di Bari A. Moro via E. Orabona 4, 70125 Bari, Italy. |
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Abstract: | The COX-1 isoenzyme plays a significant role in a variety of diseases, as it catalyzes the bioprocesses behind many health problems. Among the diarylheterocycle class of COX inhibitors, the isoxazole ring has been widely used as a central heterocycle for the preparation of potent and selective COX-1 inhibitors such as P6 [3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole]. The role of the isoxazole nucleus in COX-1 inhibitor selectivity has been clarified by preparing a set of new diarylheterocycles with various heterocycle cores. Replacement of isoxazole with isothiazole or pyrazole gave a drastic decrease in COX-1 inhibitory activity, whereas the introduction of an electron-donating group (EDG) on the N-aryl pyrazole allowed recovery of COX-1 inhibitory activity and selectivity. The EDG-equipped 5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (17) selectively inhibits COX-1 activity (IC(50) =3.4 μM; 28% COX-2 inhibition at 50 μM), in contrast to its inactive analogue, 3-(furan-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole, which does not bear the methoxy EDG. Molecular docking studies of compound 17 into the binding site of COX-1 shed light on its binding mode. |
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Keywords: | COX‐1 inhibitors isothiazoles isoxazoles molecular modeling pyrazoles |
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