Inhibitory effects against Trypanosoma cruzi, Leishmania infantum and trypanothione reductase of N1,N4-bisbenzylbutane-1,4-diamines

Trypanosoma cruzi and Leishmania spp. are the protozoan parasites responsible for Chagas disease and leishmaniasis. The treatment of these neglected diseases relies on repurposed drugs and faces several challenges including high toxicity, and the emergence of resistant strain. Therefore, there is a constant demand for promising antiparasitic agents. The present work aimed to investigate seventeen prepared N¹,N⁴-bisbenzylbutane-1,4-diamines against recombinant T. cruzi and L. infantum as well as their inhibitory effects against the T. cruzi recombinant trypanothione reductase (TcTR). N¹,N⁴-bis(4-chlorobenzyl)butane-1,4-diamine showed significant trypanocidal activity with an IC₅₀ of 6.0 ± 0.9 μM with a selectivity index of 4.3. This compound was more active than the positive control, benznidazole (IC₅₀ of 14.6). It moderately inhibited TcTR with an IC₅₀ of 55.6 ± 18.6 μM. N¹,N⁴-bis(4-chlorobenzyl)butane-1,4-diamine also inhibited L. infantum with an IC₅₀ of 19.3 ± 1.2 μM (SI of 3.4). N¹,N⁴-bis((E)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine exhibited potent inhibitory effect against T. cruzi (2.4 ± 0.3 μM); However, it also turned out to be highly cytotoxic to the L929 fibroblast cell line. Its inhibitory effect against TcTR was also significant, with an IC₅₀ of 3.9 ± 1.9 μM. Alongside the two diamines, nine other synthesized derivatives displayed antitrypanosomal activity with IC₅₀ ranging from 8 to 150 μM. Concerning the leishmanicidal effects, all tested compounds were moderately active. Moreover, during in silico studies of the active compounds using TcTR (PDB ID 4NEW), N¹,N⁴-bis((E)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine emerged as the most promising candidate, displaying both strong binding affinity and significant biological activity.