关键词: 顶体酶抑制剂, 活性腔, 胍基鸟嘌呤, 晶体结构, 抑制活性

Abstract: Acrosin, a trypsin-like endoprotease, present in the acrosome of spermatozoa, is a promising target for contraceptive agents. Based on the previous homology modeling and the analysis of the properties of the activity site of human acrosin, a series of 9-substituted-2-amino-6-guanidinopurines were designed and synthesized on a scaffold represented by KF950. The structrues of all the title compounds were comfirmed by ¹H NMR, MS, IR and elemental analysis. Intermediate 5m was determined by single crystal X-ray diffraction analysis. The inhibitory activities against acrosin of all target compounds were tested in vitro and all of them exhibited much more inhibitory activities against acrosin, respectively, with positive control, TLCK. Compound 6z exhibited similar inhibitory activities against KF950. The activity results indicate the following structure-activity relationship(SAR): (1) the introduction of disubstituded groups at aryl moiety caused better inhibitory activities than those of monosubstituded groups; (2) lower inhibitory activities were also observed for the compounds bearing electron-donating groups(6q—6w)comparing with the compounds bearing withdrawing electron groups(6b—6p); (3) long chain substituents at 9-position(6x—6z) can enhance the inhibitory activity signficantly.

Key words: Acrosin inhibitor, Activity site, Guanidinopurine, Crystal structure, Inhibitor activity