2. Academic Validation
  3. SAR Study of 4,8-Disubstituted Pyrimido[5,4- d]pyrimidines Exhibiting Antitrypanosomal and Antileishmanial Activity

SAR Study of 4,8-Disubstituted Pyrimido[5,4- d]pyrimidines Exhibiting Antitrypanosomal and Antileishmanial Activity

  • ACS Med Chem Lett. 2024 Aug 22;15(9):1541-1548. doi: 10.1021/acsmedchemlett.4c00277.
André Lopes 1 2 3,  Sofia Teixeira 1,  Nuno Santarém 2 3,  Alessandro Greco 4 5 6,  Angela Pagliaro 4 5 6,  Oliver Keminer 5 6,  Sheraz Gul 5 6,  Anabela Cordeiro-da-Silva 2 3,  Maria Alice Carvalho 1
Affiliations

Affiliations

  • 1 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.
  • 2 Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute for Molecular and Cell Biology, University of Porto, Porto 4150-180, Portugal.
  • 3 Departamento de Ciências Biológicas, Faculdade de Farmácia da Universidade do Porto (FFUP), Porto 4050-313, Portugal.
  • 4 Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy.
  • 5 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Hamburg 22525, Germany.
  • 6 Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Hamburg 22525, Germany.
PMID: 39291018 DOI: 10.1021/acsmedchemlett.4c00277
Abstract

A set of new derivatives of 4,8-disubstituted pyrimido[5,4-d]pyrimidines were efficiently synthesized and in vitro evaluated against Trypanosoma brucei and Leishmania infantum promastigotes and intramacrophage amastigotes. The in vitro cytotoxicity was determined using the THP-1 cell line, and early in vitro ADME-Tox was carried out using in vitro assays for cytotoxicity (A549 and HEK293 cell lines) and CYP3A4 and hERG cardiotoxicity liabilities. All the new compounds were active against T. brucei (0.11 μM ≤ IC50 ≤ 8.72 μM; 1 ≤ selectivity index (SI) ≤ 877), but only eight were active against L. infantum promastigotes (0.20 μM ≤ IC50 ≤ 14.88 μM; 1 ≤ SI < 502) with three also active against L. infantum intramacrophage amastigotes (3.00 μM ≤ IC50 ≤ 8.51 μM). Compounds 4a, 4c, and 4n were identified as the hit compounds to further develop as antitrypanosomal and antileishmanial agents.

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