Isoxazole‐Based‐Scaffold Inhibitors Targeting Cyclooxygenases (COXs) |
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Authors: | Dr Maria Grazia Perrone Dr Paola Vitale Dr Andrea Panella Prof Savina Ferorelli Dr Marialessandra Contino Prof Antonio Lavecchia Prof Antonio Scilimati |
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Affiliation: | 1. Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari “A. Moro”, Bari, Italy;2. Dipartimento di Farmacia, “Drug Discovery” Laboratory, Università di Napoli “Federico II”, Italy |
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Abstract: | A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G 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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Keywords: | molecular docking decomposition analysis cyclooxygenase isoxazoles P-glycoprotein |
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