Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay.
Future Med Chem. 2013 Oct;5(15):1719-32. doi: 10.4155/fmc.13.160.
In this paper, we report the solid-phase synthesis of 33 novel 1,2,5-tri-substituted benzimidazole derivatives and their in vitro activity on cruzipain and Trypanosoma cruzi epimastigotes.
Seven compounds were potent inhibitors of T. cruzi growth with IC50 values in the range 6-16 µM. Applying structure-activity relationships and principal component analysis strategies we were able to determine ring substituent effects and physicochemical properties that are important for the antichagasic activity of these novel derivatives, as well as get an insight into their possible mechanisms of action. Molecular docking studies revealed the binding orientation of the ligands in the active site of cruzipain providing new guidelines for the further design of better inhibitors.
Compound 2a constitute a promising hit compound for novel anti-T. cruzi agents showing that the benzimidazole scaffold may represent an interesting therapeutic alternative for the treatment of Chagas disease.
本文报道了 33 种新型 1,2,5-三取代苯并咪唑衍生物的固相合成及其对克氏锥虫 cruzipain 和 Trypanosoma cruzi 无鞭毛体的体外活性。
有 7 种化合物对 T. cruzi 的生长具有很强的抑制作用，IC50 值在 6-16 μM 范围内。通过应用构效关系和主成分分析策略，我们能够确定环取代基效应和对这些新型衍生物抗恰加斯病活性很重要的理化性质，以及深入了解它们可能的作用机制。分子对接研究揭示了配体在 cruzipain 活性部位的结合取向，为进一步设计更好的抑制剂提供了新的指导。
化合物 2a 是一种有前途的新型抗 T. cruzi 药物的命中化合物，表明苯并咪唑支架可能是治疗恰加斯病的一种有趣的治疗选择。
