Probing 5-Nitroimidazole-Triazole Hybrids as Potential Anti-Kinetoplastid Agents: Synthesis and In Vitro Efficacy

Neglected tropical diseases caused by kinetoplastid parasites, including leishmaniasis, human African trypanosomiasis and Chagas disease, remain severely underserved by current chemotherapies, which are limited by toxicity, resistance and poor efficacy. Nitroheterocycles continue to be clinically relevant due to their redox activation within parasites, and the 1,2,3-triazole linker offers a modular approach by enabling systematic variation of substituents, thereby allowing controlled modulation of physicochemical and biological properties. Accordingly, this study investigated a new library of 5-nitroimidazole-1,2,3-triazole hybrids and evaluated substituent-dependent effects on their antiparasitic activity. A series of 5-nitroimidazole-1,2,3-triazole hybrids was synthesised via copper(I)-catalysed azide-alkyne cycloaddition and evaluated in vitro for their antileishmanial and antitrypanosomal activity, alongside cytotoxicity profiling. Most compounds exhibited low toxicity against mammalian cell lines. No antileishmanial hit was uncovered. In the trypanosome panel, 3j demonstrated selective micromolar inhibition against Trypanosoma congolense (IC₅₀ = 6.38 ± 1.03 µM, SI = 48); hence, it was identified as a trypanocidal hit.