Second-generation N,N′-disubstituted aliphatic diamines: discovery of potent hits for multi-species leishmaniasis treatment

Kinetoplastid diseases remain a major global health challenge, highlighting the need for new antiparasitic chemotypes. N,N′ -disubstituted aliphatic diamines have emerged as a promising scaffold against trypanosomatid parasites. Building on our previous studies, we expanded the structure–activity relationship (SAR) of this chemotype through the synthesis of fifty-two analogues obtained by one-pot reductive amination of aliphatic diamine linkers with structurally diverse aromatic and heteroaromatic aldehydes. The compounds were first evaluated against the extracellular stages of Trypanosoma cruzi , Trypanosoma brucei , and Leishmania donovani . Several derivatives displayed pIC 50 values above 6.0 and Vero-cell selectivity index above 10. Based on these results, nine hits were further evaluated against the promastigote and amastigote stages of L. amazonensis , L. braziliensis , and L. infantum, responsible for cutaneous and visceral leishmaniasis. Among them, compounds 12a, 12m, and 8e showed potent activity against intracellular amastigotes with selectivity indices above 10, highlighting this scaffold as a promising starting point for antileishmanial drug discovery.