Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt; Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah 21418, Saudi Arabia.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
Bioorg Chem. 2018 Apr;77:568-578. doi: 10.1016/j.bioorg.2018.02.018. Epub 2018 Feb 16.
Twelve new compounds of 1,3,4-trisubstituted-pyrazole derivatives possessing two cyclooxygenase-2 (COX-2) pharmacophoric moieties (SOMe or/and SONH) 11a-c, 12a-c, 13a-c and 14a-c were designed and synthesized to be evaluated for their COX inhibition, anti-inflammatory activity, ulcerogenic liability. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. The bisaminosulphonyl derivatives (14a-c) were the most COX-2 selective compounds (S.I. = 9.87, 9.50 and 9.22 respectively) and showed good anti-inflammatory potency (ED = 15.06, 42.51 and 50.43 μmol/kg respectively) in comparison with celecoxib (COX-2 S.I. = 8.61, ED = 82.2 μmol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexes = 2.72-3.72) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.93). In addition, to explain the preferential (COX-2) inhibitory and selectivity, the designed compounds were subjected to molecular docking studies. It was found that compound 14c with the highest COX-2 activity and selectivity exhibited a binding pattern and interactions similar to that of celecoxib with formation of more hydrogen-bond features.
设计并合成了 12 种新型 1,3,4-三取代吡唑衍生物化合物，它们具有两个环氧化酶-2（COX-2）药效团（SOMe 和/或 SONH）11a-c、12a-c、13a-c 和 14a-c，以评估它们的 COX 抑制、抗炎活性和溃疡形成倾向。所有化合物对 COX-2 同工酶具有更高的选择性，并表现出良好的体内抗炎活性。双氨磺酰基衍生物（14a-c）是最具 COX-2 选择性的化合物（S.I.分别为 9.87、9.50 和 9.22），并且与塞来昔布（COX-2 S.I.分别为 8.61、ED 分别为 82.2 μmol/kg）相比，具有良好的抗炎效力（ED 分别为 15.06、42.51 和 50.43 μmol/kg）。此外，化合物 14a-c 的溃疡形成倾向（溃疡指数分别为 2.72-3.72）低于布洛芬（溃疡指数为 20.25），与塞来昔布相当（溃疡指数为 2.93）。此外，为了解释优先（COX-2）抑制和选择性，对设计的化合物进行了分子对接研究。结果发现，具有最高 COX-2 活性和选择性的化合物 14c 表现出与塞来昔布相似的结合模式和相互作用，形成了更多的氢键特征。
