Abstract：
As part of our continuous research for the discovery of bioactive compounds against Trypanosoma cruzi and Leishmania infantum, the alkaloid (6aS)-dicentrine (1) was oxidized to afford (6aS,6S)- (2) and (6aS,6R)- (3) dicentrine-N-oxides. Evaluation of the cytotoxicity against NCTC cells indicated that 2 and 3 are non-toxic (CC50>200 μM) whereas 1 demonstrated CC50 of 52.0 μM. Concerning T. cruzi activity against amastigotes, derivatives 2 and 3 exhibited EC50 values of 9.9 μM (SI>20.2) and 27.5 μM (SI>7.3), respectively, but 1 is inactive (EC50>100 μM). Otherwise, when tested against L. infantum amastigotes, 1 and 3 exhibited EC50 values of 10.3 μM (SI=5.0) and 12.7 μM (SI>15.7), respectively, being 2 inactive (EC50>100 μM). Comparing the effects of positive controls benznidazol (EC50=6.5 μM and SI>30.7) and miltefosine (EC50=10.2 μM and SI=15.2), it was observed a selective antiparasitic activity to diastereomers 2 and 3 against T. cruzi and L. infantum. Considering stereochemical aspects, it was suggested that the configuration of the new stereocenter formed after oxidation of 1 played an important role in the bioactivity against amastigotes of both tested parasites.
摘要：
作为我们针对克氏锥虫和婴儿利什曼原虫发现生物活性化合物的持续研究的一部分，将生物碱(6aS)-双中心(1)氧化得到(6aS，6S)-(2)和(6aS，6R)-(3)双中心-N-氧化物。对NCTC细胞的细胞毒性的评估表明2和3是无毒的(CC50>200μM),而1显示52.0μM的CC50。关于T.Cruzi反对amastigotes的活动，衍生物2和3表现出9.9μM(SI>20.7)和27.5μM(SI>7.3)的EC50值，分别,但1是无效的（EC50>100μM）。否则,当测试婴儿羊毛虫时，1和3的EC50值为10.3μM(SI=5.0)和12.7μM(SI>15.7)，分别,为2失活(EC50>100μM)。比较阳性对照苯并咪唑（EC50=6.5μM和SI>30.7）和米替福辛（EC50=10.2μM和SI=15.0）的效果，观察到非对映异构体2和3对T.cruzi和L.infantum的选择性抗寄生虫活性。考虑到立体化学方面，有人认为，1氧化后形成的新立体中心的构型在两种测试寄生虫的抗amastigotes的生物活性中起着重要作用。
