Piperine and its derivatives as a therapeutic alternative against leishmaniasis: A comprehensive review.

Leishmaniasis remains a major global health problem, especially in tropical and subtropical regions, where current treatments are limited by toxicity, cost, and drug resistance. The disease affects more than 98 endemic countries, causing approximately 1.3 million new cases and 30,000 deaths each year. Despite occasional advances, its global burden remains substantial and demands sustained attention. Piperine, a bioactive alkaloid from Piper species, shows promising antileishmanial effects, but its clinical use is limited by poor solubility and bioavailability. This review evaluates the potential of piperine and its derivatives as therapeutic agents against leishmaniasis, focusing on their mechanisms of action, effectiveness in experimental models, and drug delivery advancements. A systematic literature review gathered in vitro, in vivo, and in silico studies on piperine alone or combined with standard therapies. Findings show that piperine disrupts parasite mitochondria, induces cell cycle arrest, and modulates immune responses. Structural modifications, such as tetrahydropyridine and piperidine derivatives, improve potency, while novel delivery systems (as nanoparticles, liposomes, lipid nanospheres) enhance bioavailability and treatment outcomes. Piperine also exhibits synergistic effects with meglumine antimoniate and amphotericin B, potentially reducing toxicity and increasing effectiveness. In summary, piperine and its derivatives are promising candidates for leishmaniasis therapy. However, further studies, especially clinical trials, are necessary to confirm these benefits and enable clinical translation.