Loiseau P M, Rekik L, Madaule Y, Gayral P, Wolf J G
Faculté de Pharmacie, Université de Paris-Sud, France.
Arzneimittelforschung. 1993 Sep;43(9):1004-9.
Thirty-eight new spiroarsoranes were synthesized after structure-activity relationship studies from the first series. These compounds were predicted to cross more easily the membrane of protozoae or the cuticle of Nematodes and to reach their biological target with efficiency. The spiroarsoranes were evaluated for their antiparasitic properties, on helminths and protozoa models in regard of their parent arsonic acids. The following parasite models were used: Entamoeba histolytica and Trichomonas vaginalis in vitro; Molinema dessetae infective larvae in vitro, adults and microfilariae in vivo; Nippostrongylus brasiliensis infective larvae in vitro. The results obtained on these models indicated that the "spiranization" of arsonic acids produced new compounds with a biological activity 10-fold superior to those of arsonic acids. Nevertheless, each parasite had its own sensitivity to spiroarsoranes. Moreover, in vivo results showed that the lipophilicity of the molecules should be optimal to avoid high toxicity in host such as arsenical encephalopathy.
在对第一系列化合物进行构效关系研究后，合成了38种新的螺砷杂环烷。预计这些化合物更容易穿过原生动物的膜或线虫的角质层，并高效地到达其生物靶点。针对其母体砷酸，对螺砷杂环烷在蠕虫和原生动物模型上的抗寄生虫特性进行了评估。使用了以下寄生虫模型：体外培养的溶组织内阿米巴和阴道毛滴虫；体外培养的德氏莫尼线虫感染性幼虫、体内的成虫和微丝蚴；体外培养的巴西日圆线虫感染性幼虫。在这些模型上获得的结果表明，砷酸的“螺环化”产生了生物活性比砷酸高10倍的新化合物。然而，每种寄生虫对螺砷杂环烷都有其自身的敏感性。此外，体内实验结果表明，分子的亲脂性应该是最佳的，以避免在宿主中产生高毒性，如砷性脑病。
