A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine6G or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, two moieties typical of efflux pump substrates and inhibitors, respectively. Among all the synthesized compounds, two new COX inhibitors with opposite selectivity were discovered: compound 8 [N-(9-(2-[(4-(2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetamido)butyl)carbamoyl]phenyl-6-(ethylamino)-2,7-dimethyl-3H-xanthen-3-ylidene)ethanaminium chloride] was found to be a selective COX-1 inhibitor, whereas 17 (2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]-1-[6,7-dimethoxy-3,4-dihydroisoquinolin-2-(1H)-yl]ethanone) was found to be a sub-micromolar selective COX-2 inhibitor. However, both were shown to interact with P-glycoprotein. Docking experiments helped to clarify the molecular aspects of the observed COX selectivity.

Isoxazole-Based-Scaffold Inhibitors Targeting Cyclooxygenases (COXs)

PERRONE, MARIA GRAZIA;VITALE, PAOLA;PANELLA, ANDREA;FERORELLI, Savina;CONTINO, MARIALESSANDRA;SCILIMATI, Antonio
2016-01-01

Abstract

A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine6G or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, two moieties typical of efflux pump substrates and inhibitors, respectively. Among all the synthesized compounds, two new COX inhibitors with opposite selectivity were discovered: compound 8 [N-(9-(2-[(4-(2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetamido)butyl)carbamoyl]phenyl-6-(ethylamino)-2,7-dimethyl-3H-xanthen-3-ylidene)ethanaminium chloride] was found to be a selective COX-1 inhibitor, whereas 17 (2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]-1-[6,7-dimethoxy-3,4-dihydroisoquinolin-2-(1H)-yl]ethanone) was found to be a sub-micromolar selective COX-2 inhibitor. However, both were shown to interact with P-glycoprotein. Docking experiments helped to clarify the molecular aspects of the observed COX selectivity.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/165280
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