Chemotherapy of Leishmaniasis: Past, Present and Future

Leishmaniasis is a parasitic disease caused by hemoflagellate, Leishmania spp. The parasite is transmitted through the bites of an infected female phlebotomine sandfly. Leishmaniasis is prevalent throughout the world and in at least 88 countries. For its treatment, nearly 25 compounds are reported to have anti-leishmanial effects but not all are in use. Pentavalent antimony compounds had remained mainstay for nearly 75 years. However, emergence of resistance to this drug, led to the use of other compounds such as -Amphotericin B, Pentamidine, Paromomycin, Allopurinol etc. Amphotericin B, an antifungal macrolide polyene is characterized by the hydrophilic polyhydroxyl and hydrophobic polyene faces on it long axis which acts on membrane sterols resulting in parasite cell lysis. Presently, it is the only drug with highest cure rate. Other anti-fungals like ketoconazole, fluconazole and terbinafine are found less effective. Recently, anticancer alkylphosphocholines have been found to be the most effective oral compounds. These act as membrane synthetic ether-lipid analogues, and consist of alkyl chains in the lipid portions. Most promising of these are miltefosine (hexadecylphosphocholine), Edelfosine (ET-18-OCH3) and Ilmofosine (BM 41.440). However, the recent focus has been on identifying newer therapeutic targets in the parasite such as DNA topoisomerases. The present review describes the current understanding of different drugs against leishmaniasis, their chemistry, mode of action and the mechanism of resistance in the parasite. Future perspectives in the area of new anti-leishmanial drug targets are also enumerated. However, due to the vastness of the topic main emphasis is given on visceral leishmaniasis.

Keywords: Leishmaniasis, kala-azar, Antileishmanial drugs, chemotherapy, drug resistance, antimonials, miltefosine and natural products.