The cysteine protease falcipain-2 (FP-2) of Plasmodium falciparum is a principal cysteine protease and an essential hemoglobinase of erythrocytic P. falciparum trophozoites, making it become an attractive target enzyme for developing anti-malarial drugs. In this study, a series of novel small molecule FP-2 inhibitors have been designed and synthesized based on compound 1, which was identified by using structure-based virtual screening in conjunction with an enzyme inhibition assay. All compounds showed high inhibitory effect against FP-2 with IC50s of 1.46-11.38 μM, and the inhibitory activity of compound 2a was ~2 times greater than that of prototype compound 1. The preliminary SARs are summarized and should be helpful for future inhibitor design, and the novel scaffold presented here, with its potent inhibitory activity against FP-2, also has potential application in discovery of new anti-malarial drugs.

中文翻译：

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2-(3,4-Dihydro-4-Oxothieno[2,3-d]pyrimidin-2-ylthio) Acetamides 作为一类新的 Falcipain-2 抑制剂。3. 设计、合成和生物学评价

恶性疟原虫的半胱氨酸蛋白酶 falcipain-2 (FP-2) 是主要的半胱氨酸蛋白酶和红细胞恶性疟原虫滋养体的必需血红蛋白酶，使其成为开发抗疟疾药物的有吸引力的靶标酶。本研究以化合物1为基础，设计合成了一系列新型小分子FP-2抑制剂，该化合物是通过基于结构的虚拟筛选结合酶抑制试验鉴定的。所有化合物均显示出对 FP-2 的高抑制作用，IC50 为 1.46-11.38 μM，化合物 2a 的抑制活性是原型化合物 1 的约 2 倍。总结了初步的 SAR，应该有助于未来的抑制剂设计，以及这里介绍的新型支架，其对 FP-2 具有强效抑制活性，