Repurposing Drugs and Phytochemicals in Leishmaniasis Therapy: Emerging Strategies and Translational Potential

ABSTRACT

Leishmaniasis, a vector‐borne disease caused by protozoan parasites of the genus Leishmania , is a significant global challenge, particularly in resource‐constrained areas. The treatment of leishmaniasis has remained stagnant for over 70 years since the discovery of pentavalent antimonials (SbV), with no novel antileishmanial drugs developed during this period, reflecting limited engagement from academia and the pharmaceutical industry. Numerous FDA‐approved and investigational pharmaceuticals, initially designed for cancer, fungal, viral, or inflammatory disorders, have encouraging antileishmanial efficacy. The recent clinical landscape highlights that all three new treatments—amphotericin‐B, paromomycin, and miltefosine—are repurposed drugs rather than novel compounds. The current antileishmanial drug pipeline is notably sparse, with LXE 408 as the only candidate progressing to phase II clinical trials. Only two emerging candidates (DNDI‐6174 and ChAd63‐KH vaccine) are ready for preclinical/clinical studies. This scenario underscores an urgent need for drug repurposing strategies to accelerate the availability of effective therapies. Concurrently, phytotherapy offers promising adjunctive or alternative options due to the bioactive potential of plant‐derived compounds, as demonstrated by varying antileishmanial activities against different Leishmania species. Integrating drug repurposing with phytotherapeutic approaches could address the gaps in treatment options and combat species‐specific drug susceptibilities, thereby enhancing therapeutic outcomes in leishmaniasis management.