Krenitsky T A, Rideout J L, Koszalka G W, Inmon R B, Chao E Y, Elion G B, Latter V S, Williams R B
J Med Chem. 1982 Jan;25(1):32-5. doi: 10.1021/jm00343a007.
The finding that 6-(methylthio)-9-beta-D-ribofuranosyl-9H-purine (6) was more toxic to the avian coccidium, Eimeria tenella, than to embryonic chick liver host cells in vitro prompted the synthesis and testing of analogues of this compound. It was revealed that the beta-D-ribofuranosyl moiety was an important structural feature and that several types of 2-substituents in the purine ring decreased efficacy, as did 3-deaza and 8-aza ring modifications of 6. In contrast, the pyrazolo[3,4-d]pyrimidine analogue of 6 (24) was an order of magnitude more active. Moreover, this analogue was 24-fold less toxic to the host cells than was 6. A series of 4-(alkylthio)-1-beta-D-ribofuranosyl-1H-pyrazolo[3,4-d]pyrimidines was prepared from 4-mercapto-1-beta-D-ribofuranosyl-1H-pyrazolo[3,4-d]pyrimidine (23) and various alkyl halides. The most effective compound in this series in vivo, 4-(ethylthio)-1-beta-D-ribofuranosyl-1H-pyrazolo[3,4-d]pyrimidine (25), cleared chicks of the parasite at 50 ppm in the diet and was much less toxic than was 24.
6-(甲硫基)-9-β-D-呋喃核糖基-9H-嘌呤（6）在体外对禽球虫柔嫩艾美耳球虫的毒性比对胚胎鸡肝宿主细胞的毒性更大，这一发现促使人们合成并测试该化合物的类似物。结果表明，β-D-呋喃核糖基部分是一个重要的结构特征，嘌呤环上几种类型的2-取代基会降低药效，6的3-脱氮和8-氮杂环修饰也会如此。相比之下，6的吡唑并[3,4-d]嘧啶类似物（24）的活性高一个数量级。此外，该类似物对宿主细胞的毒性比6低24倍。由4-巯基-1-β-D-呋喃核糖基-1H-吡唑并[3,4-d]嘧啶（23）和各种卤代烷制备了一系列4-(烷硫基)-1-β-D-呋喃核糖基-1H-吡唑并[3,4-d]嘧啶。该系列中体内最有效的化合物4-(乙硫基)-1-β-D-呋喃核糖基-1H-吡唑并[3,4-d]嘧啶（25），在饲料中50 ppm时能清除雏鸡体内的寄生虫，且毒性比24小得多。
