Roberts Bracken F, Zheng Yongsheng, Cleaveleand Jacob, Lee Sukjun, Lee Eunyoung, Ayong Lawrence, Yuan Yu, Chakrabarti Debopam
Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
Department of Chemistry, University of Central Florida, Orlando, FL, USA.
Int J Parasitol Drugs Drug Resist. 2017 Apr;7(1):120-129. doi: 10.1016/j.ijpddr.2017.02.002. Epub 2017 Feb 21.
Drugs against malaria are losing their effectiveness because of emerging drug resistance. This underscores the need for novel therapeutic options for malaria with mechanism of actions distinct from current antimalarials. To identify novel pharmacophores against malaria we have screened compounds containing structural features of natural products that are pharmacologically relevant. This screening has identified a 4-nitro styrylquinoline (SQ) compound with submicromolar antiplasmodial activity and excellent selectivity. SQ exhibits a cellular action distinct from current antimalarials, acting early on malaria parasite's intraerythrocytic life cycle including merozoite invasion. The compound is a fast-acting parasitocidal agent and also exhibits curative property in the rodent malaria model when administered orally. In this report, we describe the synthesis, preliminary structure-function analysis, and the parasite developmental stage specific action of the SQ scaffold.
由于新出现的耐药性，抗疟疾药物正逐渐失去其有效性。这凸显了开发新型疟疾治疗方案的必要性，这些方案的作用机制应与现有抗疟药物不同。为了鉴定新型抗疟药效基团，我们筛选了含有具有药理学相关性的天然产物结构特征的化合物。此次筛选鉴定出一种具有亚微摩尔抗疟活性和优异选择性的4-硝基苯乙烯基喹啉（SQ）化合物。SQ表现出与现有抗疟药物不同的细胞作用，在疟原虫红细胞内生命周期早期发挥作用，包括裂殖子入侵。该化合物是一种速效杀寄生虫剂，口服给药时在啮齿动物疟疾模型中也具有治愈效果。在本报告中，我们描述了SQ支架的合成、初步结构-功能分析以及对寄生虫发育阶段的特异性作用。
