The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia; School of Medicine, Deakin University, Waurn Ponds, 3216, Australia.
Eur J Med Chem. 2021 Mar 15;214:113253. doi: 10.1016/j.ejmech.2021.113253. Epub 2021 Feb 4.
The emerging resistance to combination therapies comprised of artemisinin derivatives has driven a need to identify new antimalarials with novel mechanisms of action. Central to the survival and proliferation of the malaria parasite is the invasion of red blood cells by Plasmodium merozoites, providing an attractive target for novel therapeutics. A screen of the Medicines for Malaria Venture Pathogen Box employing transgenic P. falciparum parasites expressing the nanoluciferase bioluminescent reporter identified the phenylsulfonyl piperazine class as a specific inhibitor of erythrocyte invasion. Here, we describe the optimization and further characterization of the phenylsulfonyl piperazine class. During the optimization process we defined the functionality required for P. falciparum asexual stage activity and determined the alpha-carbonyl S-methyl isomer was important for antimalarial potency. The optimized compounds also possessed comparable activity against multidrug resistant strains of P. falciparum and displayed weak activity against sexual stage gametocytes. We determined that the optimized compounds blocked erythrocyte invasion consistent with the asexual activity observed and therefore the phenylsulfonyl piperazine analogues described could serve as useful tools for studying Plasmodium erythrocyte invasion.
抗疟药组合疗法中出现的耐药性促使人们需要寻找具有新型作用机制的新药。疟原虫的生存和增殖的核心是疟原虫裂殖子入侵红细胞，这为新型疗法提供了一个有吸引力的靶点。利用表达纳米荧光素酶生物发光报告基因的转基因恶性疟原虫筛选了医药艾滋病风险投资病原体盒，发现苯磺酰基哌嗪类是红细胞入侵的特异性抑制剂。在这里，我们描述了苯磺酰基哌嗪类的优化和进一步特征。在优化过程中，我们确定了苯磺酰基哌嗪类对恶性疟原虫无性生殖阶段活性的功能要求，并确定α-羰基 S-甲基异构体对抗疟活性很重要。优化后的化合物对耐多药恶性疟原虫株也具有相当的活性，对有性生殖阶段的配子体活性较弱。我们确定优化后的化合物能阻止红细胞入侵，与观察到的无性生殖活性一致，因此，所描述的苯磺酰基哌嗪类似物可用作研究疟原虫红细胞入侵的有用工具。
