Borsari Chiara, Santarem Nuno, Macedo Sara, Jiménez-Antón María Dolores, Torrado Juan J, Olías-Molero Ana Isabel, Corral María J, Tait Annalisa, Ferrari Stefania, Costantino Luca, Luciani Rosaria, Ponterini Glauco, Gul Sheraz, Kuzikov Maria, Ellinger Bernhard, Behrens Birte, Reinshagen Jeanette, Alunda José María, Cordeiro-da-Silva Anabela, Costi Maria Paola
University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
IBMC and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4150-180 Porto, Portugal.
ACS Med Chem Lett. 2019 Jan 29;10(4):528-533. doi: 10.1021/acsmedchemlett.8b00565. eCollection 2019 Apr 11.
Chemical modulation of the flavonol 2-(benzo[d][1,3]dioxol-5-yl)-chromen-4-one (), a promising anti-Trypanosomatid agent previously identified, was evaluated through a phenotypic screening approach. Herein, we have performed structure-activity relationship studies around hit compound . The pivaloyl derivative () showed significant anti- activity (EC = 1.1 μM) together with a selectivity index higher than 92. The early ADME-tox properties (cytotoxicity, mitochondrial toxicity, cytochrome P450 and ERG inhibition) were determined for compound and its derivatives, and these led to the identification of some liabilities. The 1,3-benzodioxole moiety in the presented compounds confers better in vivo pharmacokinetic properties than those of classical flavonols. Further studies using different delivery systems could lead to an increase of compound blood levels.
通过表型筛选方法评估了黄酮醇2-(苯并[d][1,3]二氧杂环戊烯-5-基)-色原酮（）的化学修饰，该黄酮醇是先前鉴定出的一种有前景的抗锥虫病药物。在此，我们围绕命中化合物进行了构效关系研究。新戊酰基衍生物（）显示出显著的抗活性（EC = 1.1 μM），同时选择性指数高于92。测定了化合物及其衍生物的早期药物代谢动力学及毒性性质（细胞毒性、线粒体毒性、细胞色素P450和ERG抑制），这些结果导致发现了一些缺陷。所呈现化合物中的1,3-苯并二氧杂环戊烯部分赋予了比经典黄酮醇更好的体内药代动力学性质。使用不同递送系统的进一步研究可能会提高化合物的血药浓度。
