Cutaneous leishmaniasis is a neglected tropical disease caused by a protozoan parasite that produces lesions of the skin and mucous membranes. Standard treatment involves intravenous pentavalent antimonials which are highly toxic drugs and incidents of relapse are increasing, forcing the use of more expensive agents including amphotericin B, isethionate pentamidine, paromomycin or miltefosine. These second-line drugs also exhibit high toxicity and many are accompanied by the emergence of drug resistance. It is clear that the existing therapies for leishmaniasis are inadequate, and new cost-effective drugs are needed. A series of zinc(II)-dipicolylamine complexes (ZnDPA) were prepared and found to exhibit selective toxicity against <i>Leishmania major</i> axenic promastigotes, with 50% effective concentration values in the range of 12.7 to 0.3 µM. Confocal microscopy of the a fluorescent ZnDPA (mSeek) probe revealed a strong distribution through the cytoplasm. One of the ZnDPA complexes was tested for activity against cutaneous leishmaniasis in a mouse footpad infection model. Lesion progression was monitored by imaging the red fluorescence emission of mCherry-<i>L. major</i> amastigotes. The parasite burden was 70% less in the cohort treated with five foot-pad injections of ZnDPA (0.1 mg/kg) compared to saline-treated animals (Fig. 1A). As shown in Fig. 1B, antimonial treated footpads (also five foot-pad injections) displayed cutaneous necrosis and scabbing, whereas, footpads treated with ZnDPA exhibited no apparent cutaneous reaction. These results demonstrate that ZnDPA coordination complexes are a promising new class of potent antileishmanial agents with potential for clinical translation.

Zinc(II)-dipicolylamine coordination complexes are strongly active against cutaneous leishmaniasis

253rd National Meeting (2017)

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