Braga Saulo Fehelberg Pinto, Martins Luan Carvalho, da Silva Elany Barbosa, Sales Júnior Policarpo Ademar, Murta Silvane Maria Fonseca, Romanha Alvaro José, Soh Wai Tuck, Brandstetter Hans, Ferreira Rafaela Salgado, de Oliveira Renata Barbosa
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Bioorg Med Chem. 2017 Mar 15;25(6):1889-1900. doi: 10.1016/j.bmc.2017.02.009. Epub 2017 Feb 9.
Analogues of 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]indol-4-amine 1, a known cruzain inhibitor, were synthesized using a molecular simplification strategy. Five series of analogues were obtained: indole, pyrimidine, quinoline, aniline and pyrrole derivatives. The activity of the compounds was evaluated against the enzymes cruzain and rhodesain as well as against Trypanosoma cruzi amastigote and trypomastigote forms. The 4-aminoquinoline derivatives showed promising activity against both enzymes, with IC values ranging from 15 to 125µM. These derivatives were selective inhibitors for the parasitic proteases, being unable to inhibit mammalian cathepsins B and S. The most active compound against cruzain (compound 5a; IC=15µM) is considerably more synthetically accessible than 1, while retaining its ligand efficiency. As observed for the original lead, compound 5a was shown to be a competitive enzyme inhibitor. In addition, it was also active against T. cruzi (IC=67.7µM). Interestingly, the pyrimidine derivative 4b, although inactive in enzymatic assays, was highly active against T. cruzi (IC=3.1µM) with remarkable selectivity index (SI=128) compared to uninfected fibroblasts. Both 5a and 4b exhibit drug-like physicochemical properties and are predicted to have a favorable ADME profile, therefore having great potential as candidates for lead optimization in the search for new drugs to treat Chagas disease.
已知的克氏锥虫蛋白酶抑制剂8-氯-N-(3-吗啉丙基)-5H-嘧啶并[5,4-b]吲哚-4-胺1的类似物，采用分子简化策略进行合成。获得了五个系列的类似物：吲哚、嘧啶、喹啉、苯胺和吡咯衍生物。对这些化合物针对克氏锥虫蛋白酶和罗德西亚锥虫蛋白酶以及克氏锥虫无鞭毛体和锥鞭毛体形式的活性进行了评估。4-氨基喹啉衍生物对这两种酶均显示出有前景的活性，IC值范围为15至125μM。这些衍生物是寄生蛋白酶的选择性抑制剂，无法抑制哺乳动物组织蛋白酶B和S。对克氏锥虫蛋白酶活性最高的化合物（化合物5a；IC = 15μM）比化合物1在合成上更易获得，同时保留了其配体效率。如对原始先导化合物所观察到的，化合物5a被证明是一种竞争性酶抑制剂。此外，它对克氏锥虫也有活性（IC = 67.7μM）。有趣的是，嘧啶衍生物4b尽管在酶促试验中无活性，但对克氏锥虫具有高活性（IC = 3.1μM），与未感染的成纤维细胞相比具有显著的选择性指数（SI = 128）。5a和4b均具有类药物的物理化学性质，预计具有良好的药代动力学性质，因此作为在寻找治疗恰加斯病新药的先导优化候选物具有巨大潜力。
