Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
Future Med Chem. 2013 Sep;5(13):1573-91. doi: 10.4155/fmc.13.121.
Despite intense efforts, there has not been a truly new antimalarial, possessing a novel mechanism of action, registered for over 10 years. By virtue of a novel mode of action, it is hoped that the global challenge of multidrug-resistant parasites can be overcome, as well as developing drugs that possess prophylaxis and/or transmission-blocking properties, towards an elimination agenda. Many target-based and whole-cell screening drug development programs have been undertaken in recent years and here an overview of specific projects that have focused on targeting the parasite's mitochondrial electron transport chain is presented. Medicinal chemistry activity has largely focused on inhibitors of the parasite cytochrome bc1 Complex (Complex III) including acridinediones, pyridones and quinolone aryl esters, as well as inhibitors of dihydroorotate dehydrogenase that includes triazolopyrimidines and benzimidazoles. Common barriers to progress and opportunities for novel chemistry and potential additional electron transport chain targets are discussed in the context of the target candidate profiles for uncomplicated malaria.
尽管付出了巨大努力，但已经有 10 多年没有真正的新型抗疟药物，具有新的作用机制，注册了。希望通过一种新的作用模式，可以克服全球多药耐药寄生虫的挑战，并开发具有预防和/或阻断传播特性的药物，以实现消除目标。近年来，已经开展了许多基于靶点和全细胞筛选的药物开发项目，在这里介绍了专注于靶向寄生虫线粒体电子传递链的特定项目的概述。药物化学活性主要集中在寄生虫细胞色素 bc1 复合物（复合物 III）的抑制剂上，包括吖啶二酮、吡啶酮和喹啉芳基酯，以及二氢乳清酸脱氢酶的抑制剂，包括三唑并嘧啶和苯并咪唑。在无并发症疟疾的靶标候选物特征的背景下，讨论了进展的常见障碍和新型化学物质以及潜在的其他电子传递链靶标的机会。
