SAR Study of 4,8-Disubstituted Pyrimido[5,4-<i>d</i>]pyrimidines Exhibiting Antitrypanosomal and Antileishmanial Activity
A set of new derivatives of 4,8-disubstituted pyrimido[5,4-<i>d</i>]pyrimidines were efficiently synthesized and <i>in vitro</i> evaluated against <i>Trypanosoma brucei</i> and <i>Leishmania infantum</i> promastigotes and intramacrophage amastigotes. The <i>in vitro</i> cytotoxicity was determined using the THP-1 cell line, and early <i>in vitro</i> ADME-Tox was carried out using <i>in vitro</i> assays for cytotoxicity (A549 and HEK293 cell lines) and CYP3A4 and hERG cardiotoxicity liabilities. All the new compounds were active against <i>T. brucei</i> (0.11 μM ≤ IC<sub>50</sub> ≤ 8.72 μM; 1 ≤ selectivity index (SI) ≤ 877), but only eight were active against <i>L. infantum</i> promastigotes (0.20 μM ≤ IC<sub>50</sub> ≤ 14.88 μM; 1 ≤ SI < 502) with three also active against <i>L. infantum</i> intramacrophage amastigotes (3.00 μM ≤ IC<sub>50</sub> ≤ 8.51 μM). Compounds <b>4a</b>, <b>4c</b>, and <b>4n</b> were identified as the hit compounds to further develop as antitrypanosomal and antileishmanial agents.
Authors
- Nuno Santarém (ORCID: https://orcid.org/0000-0003-4973-9933)
- Oliver Keminer (ORCID: https://orcid.org/0000-0003-1473-469X)
- Sheraz Gul (ORCID: https://orcid.org/0000-0003-2543-1643)
- M. Alice Carvalho (ORCID: https://orcid.org/0000-0002-8666-0362)
- André Lopes (ORCID: https://orcid.org/0000-0001-6821-8936)
- A M Pagliaro
- Anabela Cordeiro‐da‐Silva (ORCID: https://orcid.org/0000-0003-2392-6087)
- Sofia Teixeira (ORCID: https://orcid.org/0000-0002-4086-0975)
- Alessandro Greco (ORCID: https://orcid.org/0000-0001-5017-6694)
Institutions
- University of Pisa (IT)
- Universidade do Porto (PT)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT)
- Instituto de Biologia Molecular e Celular
- University of Minho (PT)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-08-22
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00277
- Citations
- 2
- Primary Topic
- Research on Leishmaniasis Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.09
Funders
- European Cooperation in Science and Technology
- Universidade do Porto
- Università di Pisa
- Universidade do Minho
- Fundação para a Ciência e a Tecnologia
- Erasmus+
- European Social Fund