Navarro P, Sánchez-Moreno M, Marín C, García-España E, Ramírez-Macías I, Olmo F, Rosales M J, Gómez-Contreras F, Yunta M J R, Gutierrez-Sánchez R
Instituto de Química Médica, Centro de Química Orgánica M. Lora-Tamayo, CSIC,E-28006 Madrid,Spain.
Departamento de Parasitología, Facultad de Ciencias,Universidad de Granada,E-18071 Granada,Spain.
Parasitology. 2014 Jul;141(8):1031-43. doi: 10.1017/S0031182014000201. Epub 2014 Mar 17.
The in vitro leishmanicidal activity and cytotoxicity of pyrazole-containing macrocyclic polyamines 1-4 was assayed on Leishmania infantum and Leishmania braziliensis species. Compounds 1-4 were more active and less toxic than glucantime and both infection rates and ultrastructural alterations confirmed that 1 and 2 were highly leishmanicidal and induced extensive parasite cell damage. Modifications in the excretion products of parasites treated with 1-3 were also consistent with substantial cytoplasm alterations. Compound 2 was highlighted as a potent inhibitor of Fe-SOD in both species, whereas its effect on human CuZn-SOD was poor. Molecular modelling suggested that 2 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the enzyme`s antioxidant features.
测定了含吡唑的大环多胺1-4对婴儿利什曼原虫和巴西利什曼原虫的体外杀利什曼活性和细胞毒性。化合物1-4比葡聚糖胺更具活性且毒性更小，感染率和超微结构改变均证实1和2具有高度杀利什曼活性，并能引起广泛的寄生虫细胞损伤。用1-3处理的寄生虫排泄产物的变化也与大量细胞质改变一致。化合物2在两种物种中均被突出显示为铁超氧化物歧化酶（Fe-SOD）的有效抑制剂，而其对人铜锌超氧化物歧化酶（CuZn-SOD）的作用较弱。分子模拟表明，2可能由于与支持该酶抗氧化特性的氢键网络相互作用的空间优势增强能力而使Fe-SOD失活。
