N2-substituted triazoles as trypanothione reductase inhibitors: in silico evaluation, synthesis, and anti-leishmanial activity.

Leishmaniasis remains a significant global health challenge, driven by limited therapeutic options and rising drug resistance, underscoring the need for novel, selective anti-leishmanial agents. Trypanothione reductase (TR), a key enzyme involved in the redox homeostasis of Leishmania parasites, represents an attractive and selective molecular target for anti-leishmanial drug discovery. In the present study, a series of N2-substituted 1,2,3-triazole derivatives (TZ1-TZ40) was rationally designed using a target-based drug design strategy. All compounds were subjected to molecular docking against Leishmania TR to evaluate binding affinity and key enzyme-ligand interactions, followed by in silico ADME prediction to assess drug-likeness and pharmacokinetic suitability. Based on favourable docking scores and acceptable ADME profiles, seven compounds (TZ1-TZ7) were selected for chemical synthesis. The synthesized compounds were screened for anti-leishmanial potential against promastigote and amastigote forms. Among them, compound TZ1 exhibited the most promising activity, with IC₅₀ values of 2.9 ± 0.3 µM against amastigotes and 3.9 ± 0.4 µM against promastigotes, supported by stable docking interactions and suitable ADME characteristics. However, its potential as a novel anti-leishmanial lead compound needs to be further investigated through trypanothione reductase enzymatic assay and in vivo antileishmanial assay.