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Isoxazole‐Based‐Scaffold Inhibitors Targeting Cyclooxygenases (COXs)
Author(s) -
Perrone Maria Grazia,
Vitale Paola,
Panella Andrea,
Ferorelli Savina,
Contino Marialessandra,
Lavecchia Antonio,
Scilimati Antonio
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500439
Subject(s) - chemistry , isoxazole , selectivity , efflux , quinazoline , cyclooxygenase , stereochemistry , docking (animal) , enzyme , biochemistry , catalysis , medicine , nursing
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‐3 H ‐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‐(1 H )‐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.