Mallari Jeremy P, Guiguemde Wendyam A, Guy R Kiplin
Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, CA 94143-2280, USA.
Bioorg Med Chem Lett. 2009 Jul 1;19(13):3546-9. doi: 10.1016/j.bmcl.2009.04.142. Epub 2009 May 5.
Malaria is a devastating illness caused by multiple species of the Plasmodium genus. The parasite's falcipain proteases have been extensively studied as potential drug targets. Here we report the testing of two established cysteine protease inhibitor scaffolds against both chloroquine sensitive and chloroquine resistant parasites. A subset of purine derived nitriles killed the parasite with moderate potency, and these inhibitors do not seem to exert their antiproliferative effects as cysteine protease inhibitors. Compound potency was determined to be similar against both parasite strains, indicating a low probability of cross resistance with chloroquine. These compounds represent a novel antimalarial scaffold, and a potential starting point for the development new inhibitors.
疟疾是一种由疟原虫属的多个物种引起的毁灭性疾病。该寄生虫的法氏蛋白酶已被广泛研究作为潜在的药物靶点。在此，我们报告了两种已确立的半胱氨酸蛋白酶抑制剂支架对氯喹敏感和氯喹耐药寄生虫的测试情况。一部分嘌呤衍生的腈类化合物以中等效力杀死了寄生虫，并且这些抑制剂似乎并非作为半胱氨酸蛋白酶抑制剂发挥其抗增殖作用。已确定化合物对两种寄生虫菌株的效力相似，这表明与氯喹产生交叉耐药的可能性较低。这些化合物代表了一种新型抗疟支架，也是开发新抑制剂的一个潜在起点。
