Instituto de Química Rosario (IQUIR-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina.
Queen Mary University of London, Mile End Road, London, E1 4NS, UK.
Eur J Med Chem. 2023 Jun 5;254:115378. doi: 10.1016/j.ejmech.2023.115378. Epub 2023 Apr 13.
A series of thirty 1,2,3-triazolylsterols, inspired by azasterols with proven antiparasitic activity, were prepared by a stereocontrolled synthesis. Ten of these compounds constitute chimeras/hybrids of 22,26-azasterol (AZA) and 1,2,3-triazolyl azasterols. The entire library was assayed against the kinetoplastid parasites Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, the causatives agents for visceral leishmaniasis, Chagas disease, and sleeping sickness, respectively. Most of the compounds were active at submicromolar/nanomolar concentrations with high selectivity index, when compared to their cytotoxicity against mammalian cells. Analysis of in silico physicochemical properties were conducted to rationalize the activities against the neglected tropical disease pathogens. The analogs with selective activity against L. donovani (E4, IC 0.78 μM), T brucei (E1, IC 0.12 μM) and T. cruzi (B1- IC 0.33 μM), and the analogs with broad-spectrum antiparasitic activities against the three kinetoplastid parasites (B1 and B3), may be promising leads for further development as selective or broad-spectrum antiparasitic drugs.
受具有已证实抗寄生虫活性的氮杂甾醇的启发，我们通过立体控制合成制备了一系列三十个 1,2,3-三唑基甾醇。其中十种化合物是 22,26-氮杂甾醇（AZA）和 1,2,3-三唑基氮杂甾醇的嵌合体/杂种。整个化合物库针对引起内脏利什曼病、恰加斯病和昏睡病的克氏锥虫、锥虫和利什曼原虫进行了测试。与对哺乳动物细胞的细胞毒性相比，大多数化合物在亚微摩尔/纳摩尔浓度下具有高选择性指数的活性。对化合物进行了计算物理化学性质分析，以合理阐明其对被忽视的热带病病原体的活性。对 L. donovani（E4，IC 0.78 μM）、T. brucei（E1，IC 0.12 μM）和 T. cruzi（B1-IC 0.33 μM）具有选择性活性的类似物，以及对三种锥虫具有广谱抗寄生虫活性的类似物（B1 和 B3），可能是进一步开发作为选择性或广谱抗寄生虫药物的有前途的先导化合物。
