Lopes André, Teixeira Sofia, Santarém Nuno, Greco Alessandro, Pagliaro Angela, Keminer Oliver, Gul Sheraz, Cordeiro-da-Silva Anabela, Carvalho Maria Alice
Centre of Chemistry of University of Minho (CQUM), Campus de Gualtar, Braga, Portugal and Departamento de Química, Escola de Ciências da Universidade do Minho, Braga 4710-057, Portugal.
Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute for Molecular and Cell Biology, University of Porto, Porto 4150-180, Portugal.
ACS Med Chem Lett. 2024 Aug 22;15(9):1541-1548. doi: 10.1021/acsmedchemlett.4c00277. eCollection 2024 Sep 12.
A set of new derivatives of 4,8-disubstituted pyrimido[5,4-]pyrimidines were efficiently synthesized and evaluated against and promastigotes and intramacrophage amastigotes. The cytotoxicity was determined using the THP-1 cell line, and early ADME-Tox was carried out using assays for cytotoxicity (A549 and HEK293 cell lines) and CYP3A4 and hERG cardiotoxicity liabilities. All the new compounds were active against (0.11 μM ≤ IC ≤ 8.72 μM; 1 ≤ selectivity index (SI) ≤ 877), but only eight were active against promastigotes (0.20 μM ≤ IC ≤ 14.88 μM; 1 ≤ SI < 502) with three also active against intramacrophage amastigotes (3.00 μM ≤ IC ≤ 8.51 μM). Compounds , , and were identified as the hit compounds to further develop as antitrypanosomal and antileishmanial agents.
高效合成了一组4,8-二取代嘧啶并[5,4 -]嘧啶的新衍生物，并对其抗前鞭毛体和巨噬细胞内无鞭毛体的活性进行了评估。使用THP - 1细胞系测定细胞毒性，并使用细胞毒性测定法（A549和HEK293细胞系）以及CYP3A4和hERG心脏毒性评估方法进行早期药物代谢动力学 - 毒性（ADME - Tox）研究。所有新化合物对（0.11 μM≤IC≤8.72 μM；1≤选择性指数（SI）≤877）均有活性，但只有八种对前鞭毛体有活性（0.20 μM≤IC≤14.88 μM；1≤SI < 502），其中三种对巨噬细胞内无鞭毛体也有活性（3.00 μM≤IC≤8.51 μM）。化合物、和被确定为有潜力进一步开发为抗锥虫和抗利什曼原虫药物的活性化合物。
