Department of Chemistry, University of Liverpool, Oxford Street, Liverpool L69 7ZD, UK.
Curr Opin Chem Biol. 2010 Aug;14(4):440-6. doi: 10.1016/j.cbpa.2010.05.005.
The cytochrome bc(1) complex is a key mitochondrial enzyme that catalyses transfer of electrons maintaining the membrane potential of mitochondria. Currently, atovaquone is the only drug in clinical use targeting the Plasmodium falciparum bc(1) complex. The rapid emergence of resistance to atovaquone resulted in a costly combination with proguanil (Malarone), limiting its widespread use in resource-poor disease-endemic areas. Cheaper alternatives that can overcome resistance are desperately required. Here we describe recent advances of bc(1)-targeted inhibitors that include hydroxynaphthoquinones (atovaquone analogues), pyridones (clodipol analogues), acridine related compounds (acridinediones and acridones) and quinolones. Significantly, many of these developmental compounds demonstrate little cross resistance with atovaquone-resistant parasite strains, and selected classes have excellent oral activity profiles in rodent models of malaria.
细胞色素 bc(1) 复合酶是一种关键的线粒体酶，它催化电子的转移，维持线粒体的膜电位。目前，阿托伐醌是唯一一种针对恶性疟原虫 bc(1) 复合物的临床应用药物。阿托伐醌的耐药性迅速出现，导致与普罗喹（Malarone）联合使用，限制了其在资源匮乏的疾病流行地区的广泛应用。急需更便宜的、能克服耐药性的替代品。在这里，我们描述了针对 bc(1) 的抑制剂的最新进展，包括羟基萘醌（阿托伐醌类似物）、吡啶酮（氯碘羟喹类似物）、吖啶相关化合物（吖啶二酮和吖啶酮）和喹诺酮类。重要的是，这些开发中的化合物中的许多与阿托伐醌耐药虫株的交叉耐药性很小，并且一些类别在疟疾的啮齿动物模型中具有极好的口服活性谱。
