Author(s): Lopes, Andre ; Santarem, Nuno ; Cordeiro-da-Silva, Anabela ; Carvalho, M. Alice
Date: 2022
Persistent ID: https://hdl.handle.net/1822/81236
Origin: RepositóriUM - Universidade do Minho
Subject(s): novel class of antitrypanosomal agents; novel class of antileishmanial agents; pyrimido[5,4-d]pyrimidine derivatives; fused pyrimidine derivatives
Sleeping sickness and leishmaniasis are neglected tropical diseases that threaten millions of people. The currently available therapies present several limitations, including high toxicity, lack of efficacy, and emerging drug resistance, prompting a search for novel therapeutic agents. In this work, we designed, synthesized, and in vitro evaluated the activity of new pyrimido[5,4-d]pyrimidines against Trypanosoma brucei and Leishmania infantum (promastigote and amastigote forms). The cytotoxicity of the compounds against the THP1 cell line was also assessed. Most tested compounds presented low micromolar activity against T. brucei with IC50 values in the range between 0.9 and 13.4 mu M, and one compound also showed activity against L. infantum (IC50 = 3.13 mu M). Several molecules presented a selectivity index higher than 10. The most active compound against booth parasites is derivative 4c, with IC50 = 0.94 mu M (SI > 107) against T. brucei and IC50 = 3.13 mu M (SI > 32) against L. infantum. This data enabled the identification of a new promising molecular scaffold for developing a novel class of antitrypanosomal and antileishmanial agents.
