Gros Ludovic, Lorente Silvia Orenes, Jimenez Carmen Jimenez, Yardley Vanessa, Rattray Lauren, Wharton Hayley, Little Susan, Croft Simon L, Ruiz-Perez Luis M, Gonzalez-Pacanowska Dolores, Gilbert Ian H
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, UK.
J Med Chem. 2006 Oct 5;49(20):6094-103. doi: 10.1021/jm060290f.
In this article, the design and synthesis of some novel azasterols is described, followed by their evaluation against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum, the causative agents of human African trypanosomiasis, Chagas disease, leishmaniasis, and malaria, respectively. Some of the compounds showed anti-parasitic activity. In particular, a number of compounds appeared to very potently inhibit the growth of the blood stream form T. b. rhodesiense, with one compound giving an IC50 value of 12 nM. Clear structure activity relationships could be discerned. These compounds represent important leads for further optimization. Azasterols have previously been shown to inhibit sterol biosynthesis in T. cruzi and L. donovani by the inhibition of the enzyme sterol 24-methyltransferase. However, in this case, none of the compounds showed inhibition of the enzyme. Therefore, these compounds have an unknown mode of action.
本文描述了一些新型氮杂甾醇的设计与合成，随后对它们针对布氏罗得西亚锥虫、克氏锥虫、杜氏利什曼原虫和恶性疟原虫（分别是人类非洲锥虫病、恰加斯病、利什曼病和疟疾的病原体）进行了评估。一些化合物显示出抗寄生虫活性。特别是，许多化合物似乎能非常有效地抑制布氏罗得西亚锥虫血流型的生长，其中一种化合物的IC50值为12 nM。可以看出明确的构效关系。这些化合物是进一步优化的重要先导物。先前已表明氮杂甾醇通过抑制甾醇24-甲基转移酶来抑制克氏锥虫和杜氏利什曼原虫中的甾醇生物合成。然而，在这种情况下，没有一种化合物显示出对该酶的抑制作用。因此，这些化合物的作用模式未知。
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