QHeteM - Laboratório de Química Heterocíclica e Medicinal, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14040-903, Brazil.
European Institute for Molecular Imaging (EIMI), Westphalian Wilhelms-University Münster, 48149, Münster, Germany.
ChemistryOpen. 2021 Sep;10(9):922-927. doi: 10.1002/open.202100180.
This study identified the isoindolone ring as a scaffold for novel agents against Trypanosoma brucei rhodesiense and explored the structure-activity relationships of various aromatic ring substitutions. The compounds were evaluated in an integrated in vitro screen. Eight compounds exhibited selective activity against T. b. rhodesiense (IC <2.2 μm) with no detectable side activity against T. cruzi and Leishmania infantum. Compound 20 showed low nanomolar potency against T. b. rhodesiense (IC =40 nm) and no toxicity against MRC-5 and PMM cell lines and may be regarded as a new lead template for agents against T. b. rhodesiense. The isoindolone-based compounds have the potential to progress into lead optimization in view of their highly selective in vitro potency, absence of cytotoxicity and acceptable metabolic stability. However, the solubility of the compounds represents a limiting factor that should be addressed to improve the physicochemical properties that are required to proceed further in the development of in vivo-active derivatives.
这项研究确定异吲哚啉环是一种新型抗布氏冈比亚锥虫药物的支架，并探讨了各种芳环取代基的结构-活性关系。这些化合物在综合体外筛选中进行了评估。有 8 种化合物对 T. b. rhodesiense 具有选择性活性（IC <2.2 μm），对 T. cruzi 和 L. infantum 没有可检测到的副作用。化合物 20 对 T. b. rhodesiense 具有低纳摩尔效力（IC =40 nm），对 MRC-5 和 PMM 细胞系没有毒性，可被视为针对 T. b. rhodesiense 的新型先导模板。鉴于其高度选择性的体外效力、无细胞毒性和可接受的代谢稳定性，基于异吲哚啉的化合物具有进入先导优化的潜力。然而，化合物的溶解度是一个限制因素，应加以解决，以改善进一步开发体内活性衍生物所需的物理化学性质。
