de Oliveira Rezende Júnior Celso, Martinez Pablo David Grigol, Ferreira Rafael Augusto Alves, Koovits Paul John, Miranda Soares Bruna, Ferreira Leonardo L G, Michelan-Duarte Simone, Chelucci Rafael Consolin, Andricopulo Adriano D, Matheeussen An, Van Pelt Natascha, Caljon Guy, Maes Louis, Campbell Simon, Kratz Jadel M, Mowbray Charles E, Dias Luiz Carlos
Institute of Chemistry, University of Campinas (UNICAMP), Campinas, SP, 13083-861, Brazil.
Laboratory of Medicinal and Computational Chemistry, Physics Institute of São Carlos, University of São Paulo (USP), São Carlos, SP, 13563-120, Brazil.
Eur J Med Chem. 2023 Jan 15;246:114925. doi: 10.1016/j.ejmech.2022.114925. Epub 2022 Nov 15.
Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. Because current treatments present several limitations, including long duration, variable efficacy and serious side effects, there is an urgent need to explore new antitrypanosomal drugs. The present study describes the hit-to-lead optimization of a 2-aminobenzimidazole hit 1 identified through in vitro phenotypic screening of a chemical library against intracellular Trypanosoma cruzi amastigotes, which focused on optimizing potency, selectivity, microsomal stability and lipophilicity. Multiparametric Structure-Activity Relationships were investigated using a set of 277 derivatives. Although the physicochemical and biological properties of the initial hits were improved, a combination of low kinetic solubility and in vitro cytotoxicity against mammalian cells prevented progression of the best compounds to an efficacy study using a mouse model of Chagas disease.
恰加斯病是一种由克氏锥虫引起的被忽视的热带病。由于目前的治疗方法存在若干局限性，包括疗程长、疗效不一和严重的副作用，因此迫切需要探索新的抗锥虫药物。本研究描述了通过对化学文库针对细胞内克氏锥虫无鞭毛体进行体外表型筛选鉴定出的2-氨基苯并咪唑类先导化合物1的从苗头化合物到先导化合物的优化过程，该过程着重于优化活性、选择性、微粒体稳定性和亲脂性。使用一组277种衍生物研究了多参数构效关系。尽管初始苗头化合物的物理化学和生物学性质得到了改善，但低动力学溶解度和对哺乳动物细胞的体外细胞毒性的综合作用阻碍了最佳化合物进入使用恰加斯病小鼠模型的疗效研究。
