The design and synthesis of a new series of 1,4-dihydroquinazolin-3(2H)-yl benzamide derivatives (4a-o) as anti-inflammatory and analgesic agents and COX-1/2 inhibitors are reported. The target compounds (4a-o) were synthesized using a two-step scheme, and their chemical structures were confirmed with 1H NMR, 13C NMR, and mass spectra and elemental analysis. Compounds 4b, 4d, 4h, 4l, 4n and 4o showed the best in vitro COX-2 inhibitory activity (IC50 0.04-0.07 μM), which was nearly the same as that of the reference drug celecoxib (IC50 0.049 μM), but had a lower selectivity index, as dictated in our target design. In the in vivo anti-inflammatory inhibition assay, compounds 4b, 4c, 4e, 4f, 4m and 4o showed better oedema inhibition percentages, ranging from 38.1% to 54.1%, than did diclofenac sodium (37.8%). An in vivo analgesic assay revealed that compounds 4b and 4n had a potential analgesic effect 4- to 21-fold more potent than that of indomethacin and diclofenac sodium. All the tested compounds showed an improved ulcerogenic index when compared to indomethacin. In the synthesized series, compound 4b showed the best biological activity in all the experiments. The docking study results agreed with the in vitro COX inhibition assay results. Moreover, the predicted in silico studies of all the compounds support their potential as drug candidates.

中文翻译：

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1,4-二氢喹唑啉-3（2H）-基苯甲酰胺衍生物具有改善胃部的消炎和镇痛作用：设计，合成，COX-1 / 2抑制活性和分子对接研究。

据报道设计和合成了一系列新的1,4-二氢喹唑啉-3（2H）-基苯甲酰胺衍生物（4a-o）作为抗炎和止痛药和COX-1 / 2抑制剂。使用两步方案合成目标化合物（4a-o），并通过1H NMR，13C NMR以及质谱和元素分析确定其化学结构。化合物4b，4d，4h，4l，4n和4o显示出最佳的体外COX-2抑制活性（IC50 0.04-0.07μM），与参考药物塞来昔布（IC50 0.049μM）几乎相同，但具有较低的选择性指数，这是我们目标设计所要求的。在体内抗炎抑制试验中，化合物4b，4c，4e，4f，4m和4o与双氯芬酸钠（37.8％）相比，显示出更好的水肿抑制百分比，范围为38.1％至54.1％。体内止痛分析显示，化合物4b和4n的潜在止痛作用比消炎痛和双氯芬酸钠的效力高4至21倍。与消炎痛相比，所有测试的化合物均显示出改善的促溃疡指数。在合成的系列中，化合物4b在所有实验中均显示出最佳的生物活性。对接研究结果与体外COX抑制测定结果一致。此外，所有化合物的计算机模拟研究都证明了它们作为候选药物的潜力。在所有实验中，化合物4b表现出最好的生物活性。对接研究结果与体外COX抑制测定结果一致。此外，所有化合物的计算机模拟研究都证明了它们作为候选药物的潜力。在所有实验中，化合物4b表现出最佳的生物活性。对接研究结果与体外COX抑制测定结果一致。此外，所有化合物的计算机模拟研究都证明了它们作为候选药物的潜力。