新型烟碱酸衍生物的合成与生物评价，作为针对 COX-2 酶的潜在抗炎药物。
Synthesis and biological evaluation of new nicotinate derivatives as potential anti-inflammatory agents targeting COX-2 enzyme.
机构信息
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 33 Kasr El-Aini Street, Cairo 11562, Egypt.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 33 Kasr El-Aini Street, Cairo 11562, Egypt.
出版信息
Bioorg Chem. 2021 Feb;107:104610. doi: 10.1016/j.bioorg.2020.104610. Epub 2021 Jan 5.
Two novel series derived from nicotinic acid were synthesized and evaluated for their inhibitory activity against cyclooxygenases COX-1 and COX-2, and their selectivity indices were determined. Celecoxib, diclofenac and indomethacin were used as reference drugs. All compounds showed highly potent COX-2 inhibitory activity and higher selectivity towards COX-2 inhibition compared to indomethacin. In addition, these compounds except 3a showed clear preferential COX-2 over COX-1 inhibition compared to diclofenac. Compounds 3b, 3e, 4c and 4f showed COX-2 inhibitory activity equipotent to celecoxib. Compounds 4c and 4f demonstrated selectivity indices 1.8-1.9 fold higher than celecoxib. These two most potent and COX-2 selective compounds were further tested in vivo for anti-inflammatory activity by means of carrageenan induced rat paw edema method. Ulcerogenic activity with histopathological studies were performed. The results showed no ulceration, which implies their safe gastric profile. Compound 4f exhibited the most potent in vivo anti-inflammatory activity comparable to all reference drugs. Further, compounds 4c and 4f were investigated for their influence on certain inflammatory cytokines TNF-α and IL-1β in addition to PEG2. The findings revealed that these candidates could be identified as promising potent anti-inflammatory agents. Molecular docking of 4c and 4f in the COX-2 active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of celecoxib, explaining their remarkable COX-2 inhibitory activity.
合成了两个新型烟碱酸系列化合物，并对其抑制环氧化酶 COX-1 和 COX-2 的活性进行了评价，确定了它们的选择性指数。塞来昔布、双氯芬酸和吲哚美辛被用作参考药物。所有化合物对 COX-2 均表现出很强的抑制活性，与吲哚美辛相比，对 COX-2 的抑制具有更高的选择性。此外，与双氯芬酸相比，这些化合物除 3a 外，对 COX-2 的抑制均表现出明显的选择性。化合物 3b、3e、4c 和 4f 的 COX-2 抑制活性与塞来昔布相当。化合物 4c 和 4f 的选择性指数比塞来昔布高 1.8-1.9 倍。这两个最有效和最具 COX-2 选择性的化合物进一步通过角叉菜胶诱导的大鼠足肿胀法进行了体内抗炎活性测试。进行了组织病理学研究以检测溃疡形成活性。结果表明，这些化合物没有溃疡，这意味着它们具有安全的胃内特性。化合物 4f 表现出最有效的体内抗炎活性，与所有参考药物相当。此外，还研究了化合物 4c 和 4f 对某些炎症细胞因子 TNF-α 和 IL-1β 以及 PEG2 的影响。研究结果表明，这些候选物可被鉴定为有前途的强效抗炎剂。对 4c 和 4f 在 COX-2 活性部位的分子对接进行了研究，以合理化它们的 COX-2 抑制效力。结果与生物学发现一致，因为它们与塞来昔布相比表现出更有利的相互作用，解释了它们显著的 COX-2 抑制活性。
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