Liu Haicheng, Futamura Yushi, Wu Honghai, Ishiyama Aki, Zhang Taotao, Shi Tao, Zheng Qunxiong, Iwatsuki Masato, Ōmura Satoshi, Zou Hongbin, Osada Hiroyuki
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Med Chem. 2021;17(10):1207-1218. doi: 10.2174/1573406416666200817160708.
Malaria is one of the most devastating parasitic diseases, yet the discovery of antimalarial agents remains profoundly challenging. Very few new antimalarials have been developed in the past 50 years, while the emergence of drug-resistance continues to appear.
This study focuses on the discovery, design, synthesis, and antimalarial evaluation of 3- cinnamamido-N-substituted benzamides.
In this study, a screening of our compound library was carried out against the multidrugsensitive Plasmodium falciparum 3D7 strain. Derivatives of the hit were designed, synthesized and tested against P. falciparum 3D7 and the in vivo antimalarial activity of the most active compounds was evaluated using the method of Peters' 4-day suppressive test.
The retrieved hit compound 1 containing a 3-cinnamamido-N-substituted benzamide skeleton showed moderate antimalarial activity (IC = 1.20 μM) for the first time. A series of derivatives were then synthesized through a simple four-step workflow, and half of them exhibited slightly better antimalarial effect than the precursor 1 during the subsequent in vitro assays. Additionally, compounds 11, 23, 30 and 31 displayed potent activity with IC values of approximately 0.1 μM, and weak cytotoxicity against mammalian cells. However, in vivo antimalarial activity is not effective, which might be ascribed to the poor solubility of these compounds.
In this study, the phenotypic screen of our compound library resulted in the first report of a 3-cinnamamide framework with antimalarial activity and 40 derivatives were then designed and synthesized. Subsequent structure-activity studies showed that compounds 11, 23, 30 and 31 exhibited the most potent and selective activity against the P. falciparum 3D7 strain with IC50 values around 0.1 μM. Our work herein sets another example of phenotypic screen-based drug discovery, leading to potentially promising candidates of novel antimalarial agents once given further optimization.
疟疾是最具破坏性的寄生虫病之一，然而抗疟药物的发现仍然极具挑战性。在过去50年里，很少有新的抗疟药物被研发出来，而耐药性却不断出现。
本研究聚焦于3-肉桂酰胺基-N-取代苯甲酰胺的发现、设计、合成及抗疟活性评价。
本研究针对多药敏感的恶性疟原虫3D7株对我们的化合物库进行了筛选。对筛选出的活性化合物进行衍生物设计、合成，并针对恶性疟原虫3D7进行测试，使用彼得斯4天抑制试验方法评估最具活性化合物的体内抗疟活性。
筛选出的命中化合物1含有3-肉桂酰胺基-N-取代苯甲酰胺骨架，首次显示出中等抗疟活性（IC = 1.20 μM）。然后通过简单的四步流程合成了一系列衍生物，其中一半在随后的体外试验中表现出比前体1稍好的抗疟效果。此外，化合物11、23、30和31表现出强效活性，IC值约为0.1 μM，对哺乳动物细胞的细胞毒性较弱。然而，其体内抗疟活性无效，这可能归因于这些化合物的溶解性较差。
在本研究中，对我们的化合物库进行表型筛选首次报道了具有抗疟活性的3-肉桂酰胺骨架，并设计合成了40种衍生物。随后的构效关系研究表明，化合物11、23、30和31对恶性疟原虫3D7株表现出最有效和选择性的活性，IC50值约为0.1 μM。我们的工作为基于表型筛选的药物发现树立了另一个范例，一旦进一步优化，有望成为新型抗疟药物的潜在候选物。
