Leishmaniasis is a neglected tropical disease caused by a protozoal parasite, which globally affects more than 1 million people every year. Unfortunately, most treatments still rely on toxic or parasite-resistant drugs and just a fraction of the scientific community is focused on the development of new treatments for this neglected disease. Our work aims to tackle Leishmaniasis in a new manner by developing several libraries of novel coupled molecules and then test their biological activity <i>in vitro</i> against Leishmania cells. Herein, we will describe one approach where we have combined a unit toxic to Leishmania with a mitochondria-targeting function.<br/>The inner membrane of the mitochondria has a negative electrochemical potential and can therefore be targeted by lipophilic positively charged compounds. Crucially, this membrane potential is subtly different in different species. Phosphonium salts are widely used to target mitochondria, and our strategy relies on the employment of triphenylphosphonium-based compounds to target the Leishmania mitochondria; moreover by functionalising the phenyl groups on the phosphorus it is possible to fine-tune its positive charge, allowing the compound to target the parasite cells instead of the host ones. We are currently investigating the optimal structure for the linker between the triazole and the phosphorus and the one between the triazole and the toxic group. We are confident that by finely tuning the structure of the phosphonium salt and the toxic moiety, we can create a valid alternative to the current antileishmanial agents.

Development of novel therapeutic approaches for the treatment of Leishmaniasis and related neglected tropical diseases

ACS Spring 2022

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