Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo 11777, Egypt.
Bioorg Chem. 2021 Oct;115:105253. doi: 10.1016/j.bioorg.2021.105253. Epub 2021 Aug 8.
Responding to the great demand of developing potent NSAIDs with an enhanced safety profile and reasonable selectivity, in the present study novel 4-fluorobenzamide derivatives were synthesized and screened for their anti-inflammatory and analgesic activities using carrageenan-induced rat paw edema method and acetic acid-induced abdominal writhing in mice, respectively. All the new target compounds except the carbamothioylhydrazine series (5a-d), and the 4-fluorophenyl thiadiazolo derivative 6b showed promising anti-inflammatory activity ranged between 53.43 and 92.36% inhibition of edema (at 3 h) compared to the reference standard indomethacin (65.64%). All the newly synthesized compounds showed potent analgesic activity ranged between 71 and 100 % writhing protection compared to indomethacin (74.06%). Moreover, the most active compounds; the ester hybrids 2a,b, the thioureido quinazolinones 4b,c, and the thiadiazole congener 6a, showed promising gastric tolerability with ulcer index ranged between 0 and 6.60 compared to indomethacin (12.13). The thioureido quinazolinone derivatives 4b,c showed the most potent anti-inflammatory and analgesic activities with a remarkable gastric tolerability compared to the other derivatives. The 4-chlorophenyl derivative 4b is considered the most promising analogue showing 92.36% inhibition of edema, 100% writhing protection in analgesia testing, and a COX-2 selectivity index of 5.75 which was better than that of indomethacin and celecoxib standards (selectivity index = 0.27 and 4.55; respectively). Moreover, it showed an ulcer index equals zero with gastric acidity and mucin levels comparable to that of the control group indicating its minor effect on gastric cell physiology and its high tolerability. Molecular docking studies predicted the binding pattern of the newly synthesized compounds in COX-1 and COX-2 enzymes confirming the ability of the most active candidates to satisfy the structural features required for binding and rationalized their selectivity based on their docking binding patterns and scores. Furthermore, the newly synthesized 4-fluorobenzamide derivatives possess promising predicted pharmacokinetic properties indicated by calculating their key physicochemical parameters and absorption percentages.
为满足开发具有增强安全性和合理选择性的强效非甾体抗炎药的巨大需求，本研究合成了新型 4-氟苯甲酰胺衍生物，并分别采用角叉菜胶诱导的大鼠足肿胀法和醋酸诱导的小鼠扭体法对其抗炎和镇痛活性进行了筛选。所有新的目标化合物（除了碳酰肼系列（5a-d）和 4-氟苯基噻二唑衍生物 6b）均表现出有希望的抗炎活性，在 3 小时时的水肿抑制率在 53.43%至 92.36%之间，与参比标准吲哚美辛（65.64%）相比。所有新合成的化合物均表现出强效的镇痛活性，扭体保护率在 71%至 100%之间，与吲哚美辛（74.06%）相比。此外，最活跃的化合物；酯类杂种 2a,b、硫脲基喹唑啉酮 4b,c 和噻二唑同系物 6a，与吲哚美辛（12.13）相比，溃疡指数在 0 到 6.60 之间，具有良好的胃耐受性。硫脲基喹唑啉酮衍生物 4b,c 与其他衍生物相比，表现出最强的抗炎和镇痛活性，且具有良好的胃耐受性。与其他衍生物相比，4-氯苯基衍生物 4b 被认为是最有前途的类似物，其水肿抑制率为 92.36%，镇痛试验中扭体保护率为 100%，COX-2 选择性指数为 5.75，优于吲哚美辛和塞来昔布标准（选择性指数分别为 0.27 和 4.55）。此外，它的溃疡指数为零，胃酸度和粘蛋白水平与对照组相当，表明其对胃细胞生理的影响较小，耐受性较高。分子对接研究预测了新合成化合物在 COX-1 和 COX-2 酶中的结合模式，证实了最活跃的候选物满足结合所需的结构特征的能力，并根据它们的对接结合模式和评分合理化了它们的选择性。此外，新合成的 4-氟苯甲酰胺衍生物具有有希望的预测药代动力学特性，这是通过计算它们的关键物理化学参数和吸收百分比得出的。
