Department of Drug Discovery Chemistry, GlaxoSmithKline, Madrid, Spain.
J Med Chem. 2010 Aug 26;53(16):6129-52. doi: 10.1021/jm100556b.
Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2-cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. Introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.
疟原虫裂殖子蛋白 2（Falcipain-2）和裂殖子蛋白 3（Falcipain-3）属于木瓜蛋白酶家族半胱氨酸蛋白酶，负责水解宿主血红蛋白，为寄生虫蛋白合成提供氨基酸。不同的杂芳基腈衍生物被研究为潜在的裂殖子蛋白抑制剂，因此也是有潜力的抗寄生虫先导化合物，其中 5-取代-2-氰基嘧啶类化合物是最有效和最有前途的先导系列。通过对初始支架中存在的不同位置进行连续的先导优化，鉴定出对裂殖子蛋白 2 和 3 具有纳摩尔和亚纳摩尔级抑制活性的抑制剂，对培养寄生虫的活性在微摩尔范围内。在先导分子中引入可质子化的胺，可使活性提高多达 1000 倍，而对其他 SAR 趋势没有明显改变。优化后的化合物在皮摩尔至低纳摩尔范围内具有酶活性，在纳摩尔范围内具有抗寄生虫活性。
