Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, 71524, Assiut, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, King Abdulaziz University, 21589, Saudi Arabia; Pharmaceutical Organic Chemistry Department Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
Eur J Med Chem. 2019 Jun 1;171:372-382. doi: 10.1016/j.ejmech.2019.03.042. Epub 2019 Mar 20.
Two new series of 1,2-benzisothiazol-3(2H)-one-1,1-dioxide derivatives containing either five membered heterocyclic rings or aryl hydrazones were synthesized and evaluated for their in vitro COX-1/COX-2 inhibitory activity. In vivo anti-inflammatory evaluation revealed that benzenesulfonamides bearing pyrazole moiety 19, 20 and its cyclized form 23 exhibited the highest anti-inflammatory activity with comparable potency to celecoxib. Furthermore, the ulcerogenic activity evaluation showed that compounds 19, 20 and 23 exerted the minimal ulcer index in comparison to indomethacin as a reference drug. Docking studies of the most selective COX-2 derivatives were also carried out against COX-2 active site. Benzenesulfonamide derivatives 19 and 20 displayed higher predicted binding affinities inside the COX-2 active site. Molecular modelling simulation and drug likeness studies showed good agreement with the obtained biological evaluation.
合成了两个新的 1,2-苯并异噻唑-3(2H)-酮-1,1-二氧化物衍生物系列，其中包含五员杂环或芳基腙。评估了它们在体外 COX-1/COX-2 抑制活性。体内抗炎评价表明，含有吡唑部分的苯磺酰胺 19、20 及其环化形式 23 具有最高的抗炎活性，与塞来昔布相当。此外，溃疡形成活性评价表明，与作为参考药物的吲哚美辛相比，化合物 19、20 和 23 的溃疡指数最小。对最具选择性的 COX-2 衍生物的对接研究也针对 COX-2 活性部位进行了。苯磺酰胺衍生物 19 和 20 在 COX-2 活性部位内显示出更高的预测结合亲和力。分子建模模拟和药物相似性研究与获得的生物学评价结果非常吻合。
