New Series of Pentamidine-Based 1,2,3-Triazole-Diaryl-Hydrazones: Design, Synthesis, and Evaluation of Their Leishmanicidal Activity and Mechanism of Action Against Leishmania (L.) amazonensis

Abstract

Leishmaniasis is caused by over twenty Leishmania species worldwide. Current chemotherapy is limited to a few approved drugs, with high toxicity and significant side effects, and compromised efficacy due to parasite resistance. Pentamidine is an effective drug for Leishmaniasis; however, it is highly toxic. In this study, eleven new pentamidine-based 1,2,3-triazole-diarylhydrazole analogues PQM-250 to PQM-254, PQM-256 to PQM-259, PQM-261, and PQM-262 were evaluated for their leishmanicidal activity. The most promising compounds were further investigated for their potential mechanisms of action, particularly regarding their effects on bioenergetics and mitochondrial function. Compounds PQM-250, PQM-254, and PQM-261 exhibited marked activities against promastigote and amastigote forms of L. amazonensis, with low toxicity to macrophages. When evaluated together, the four compounds displayed distinct mitochondrial and redox responses. Pentamidine caused mitochondrial depolarization (10.90%), markedly reduced ATP production (-73%), and decreased H₂O₂ levels (-37.9%), a profile consistent with apoptosis induction. PQM-254 similarly promoted depolarization (10.44%) but differed by reducing H₂O₂ levels more substantially (-41.7%), while having no stimulatory effect on ATP. In contrast, PQM-261 induced mitochondrial hyperpolarization (+13.16%) accompanied by a notable increase in ATP production (+32%). Finally, PQM-250 did not markedly alter membrane potential but produced a moderate elevation in H₂O₂ levels (+18.9%), suggesting a distinct oxidative profile from the other analogues. These findings highlight the leishmanicidal potential of these three analogues, especially PQM-250, which targets vital parasite survival mechanisms, while exhibiting lower mammalian toxicity. The study provides valuable insights into the metabolic pathways affected by these compounds, offering a strong foundation for developing safer therapeutic strategies against leishmaniasis.