Biological Targets in Leishmaniasis and the Identification of the Next: Generation of Antileishmanial Compounds

With increasing mortality and morbidity, leishmaniasis remains a global health burden. The lack of vaccines and limited drug options for treatment, each with low efficacy and severe toxicities, highlights the urgent need for new therapeutics. Our review of 260 articles (1981-2025) provides comprehensive insights, emphasizing the critical identification and characterization of viable biological targets in Leishmania for efficient drug development. We summarize the various strategies utilized in the drug design pipeline, detailing how these approaches have revealed key biological targets involved in parasite survival, virulence, and pathogenesis, and have identified promising inhibitors across metabolic and non-metabolic pathways. We report the biochemical reactions and inhibitory activities (IC₅₀) of these compounds against their respective targets. Additionally, we outline the synthetic strategies for key chemotypes and identify ongoing challenges and future directions in antileishmanial agent research. Importantly, our review evaluates multitarget inhibitors, highlighting their pros and cons and proposing actionable steps to leverage these molecules to overcome leishmaniasis.