Multitarget Ligands in the Search for Novel Lead Candidates against Trypanosoma and Leishmania

Parasitic diseases caused by strains of Trypanosoma and Leishmania are still an unsolved public health problem causing morbidity and mortality among the poorest populations of the world. Drugs available to combat these diseases are inadequate. They have variable efficacy, serious toxic side effects, require long courses of administration, and are often expensive. Furthermore, several are becoming ineffective due to an ever-increasing parasite resistance. A significant improvement in the treatment of African trypanosomiasis has been achieved by the recent multicentre trial showing the effectiveness of a combination treatment with oral nifurtimox and low-dose intravenous eflornithine.1 This combination therapy represents a major advance in terms of making the treatment safer, cheaper, and easier to administer. It has therefore been placed on WHO's essential drugs list. As an alternative to combinations and as a means to overcome most NTD drug discovery challenges, we propose a multitarget drug design strategy.2 A multi-target-directed ligand (MTDL) is a single chemical entity that recognizes different targets inside the parasite pathways. Thus, such a ligand would be highly effective for treating the diseases. Moreover, the simultaneous development of resistance by the multiple targets is more improbable. Furthermore, with respect to combinations, the therapeutic regimen would be simplified with positive consequences for patient adherence and caregiver compliance. On these premises, we have designed and developed two series of innovative MTDLs against Trypanosoma and Leishmania, reported herein.