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

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.