Department of Medicinal Chemistry, School of Pharmacy, University of Athens , 15771 Athens, Greece.
J Med Chem. 2014 Mar 27;57(6):2568-81. doi: 10.1021/jm401842e. Epub 2014 Mar 13.
Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis.
由于动脉粥样硬化是一个涉及一系列病理事件的炎症过程，如血脂异常、氧化应激和凝血机制，我们特此报告了通过设计将抗氧化、抗炎和角鲨烯合酶（SQS）抑制/降血脂活性结合在简单分子中的新型化合物的合成和评价。两种不同药效团的偶联得到了化合物 1-12，与母体先导结构（即降血脂的 2-羟基-2-芳基-（苯并）恶嗪（或噻嗪）和抗氧化剂吩噻嗪）相比，其生物特性得到了显著改善。大多数衍生物强烈抑制体外微粒体脂质和 LDL 过氧化，表现出强大的自由基清除活性。它们还在急性和高脂肪诱导的高脂血症动物模型中显著抑制 SQS 活性并显示出显著的抗血脂异常活性。最后，一些化合物在体外显示出抗炎活性，抑制环氧化酶（COX-1/2）活性。新化合物的多模式特性，特别是它们的抗氧化/SQS/COX 抑制活性的结合，使它们成为进一步评估抗动脉粥样硬化的有前途的先导化合物。
