Laboratório de Catálise e Síntese de Substâncias Bioativas, Universidade Federal do Rio de Janeiro Campus Macaé Professor Aloísio Teixeira, Estrada do Imburo s/n - Ajuda de Baixo, Macaé, RJ CEP 27979-000, Brazil.
Departamento de Sintese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos - FIOCRUZ, Rio de Janeiro, RJ 21041-250, Brazil.
Bioorg Med Chem. 2019 Sep 1;27(17):3853-3859. doi: 10.1016/j.bmc.2019.07.022. Epub 2019 Jul 11.
Searching for new substances with antileishmanial activity, we synthesized and evaluated a series of α,α-difluorohydrazide and α,α-difluoramides against Leishmania amazonensis arginase (LaArg). Four α,α-difluorohydrazide derivatives showed activity against LaArg with K in the range of 1.3-26 μM. The study of the kinetics of LaArg inhibition showed that these substances might act via different inhibitory mechanisms or even by a combination of these. The compounds were tested against L. amazonensis promastigotes and the best result was obtained to the compound 4 (EC of 12.7 ± 0.3 μM). In addition, in order to obtain further insight into the binding mode of such compounds, molecular docking studies were performed to obtain additional validation of experimental results. Considering these results, it is possible to conclude that α,α-difluorohydrazide derivatives are a promising scaffold in the development of new substances against the etiological agent of leishmaniasis by targeting LaArg.
为了寻找具有抗利什曼原虫活性的新物质，我们合成并评估了一系列α,α-二氟腙和α,α-二氟酰胺类化合物对利什曼原虫精氨酸酶（LaArg）的抑制作用。四种α,α-二氟腙衍生物对 LaArg 的抑制活性 K 值在 1.3-26μM 之间。对 LaArg 抑制动力学的研究表明，这些物质可能通过不同的抑制机制发挥作用，甚至可能是这些机制的组合。对化合物进行了对抗利什曼原虫前鞭毛体的测试，化合物 4 的效果最好（EC 为 12.7±0.3μM）。此外，为了进一步深入了解此类化合物的结合模式，进行了分子对接研究，以获得实验结果的进一步验证。考虑到这些结果，可以得出结论，α,α-二氟腙衍生物是针对利什曼病病原体的新型物质的有前途的骨架，通过靶向 LaArg 发挥作用。
