通过协同抑制 COX-2/PGE2 轴和 DHPS 酶双重作用来治疗败血症的可生物降解磺胺类候选药物的合理设计。
Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme.
机构信息
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
出版信息
J Enzyme Inhib Med Chem. 2022 Dec;37(1):1737-1751. doi: 10.1080/14756366.2022.2086868.
A new series of co-drugs was designed based on hybridising the dihydropteroate synthase (DHPS) inhibitor sulphonamide scaffold with the COX-2 inhibitor salicylamide pharmacophore through biodegradable linkage to achieve compounds with synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme to enhance antibacterial activity for treatment of septicaemia. Compounds and demonstrated potent COX-2 inhibitory activity comparable to celecoxib. and exhibited ED lower than celecoxib in carrageenan-induced paw edoema test with % PGE2 inhibition higher than celecoxib. Furthermore, , and showed gastric safety profile like celecoxib. Moreover, antibacterial screening revealed that, showed activity against higher than sulfasalazine. While, revealed activity against higher than sulfasalazine and against comparable to sulfasalazine. Compound achieved the target goal as potent inhibitor of COX-2/PGE2 axis and broad-spectrum antibacterial activity against induced septicaemia in mice.
基于二氢叶酸合成酶（DHPS）抑制剂磺胺结构与 COX-2 抑制剂水杨酰胺药效团的杂合化，设计了一系列新的共药物。通过生物可降解键将它们连接起来，以获得具有协同双重抑制 COX-2/PGE2 轴和 DHPS 酶的化合物，从而增强抗菌活性，用于治疗败血症。化合物 和 表现出与塞来昔布相当的强效 COX-2 抑制活性。化合物 和 在角叉菜胶诱导的爪肿胀试验中，ED 低于塞来昔布，对 PGE2 的抑制率高于塞来昔布。此外， 、 和 与塞来昔布一样具有胃安全性。此外，抗菌筛选显示， 对 显示出比柳氮磺胺吡啶更高的活性。而 对 显示出比柳氮磺胺吡啶更高的活性，对 与柳氮磺胺吡啶相当。化合物 作为 COX-2/PGE2 轴的强效抑制剂和对诱导的败血症具有广谱抗菌活性，达到了目标。
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