Design, synthesis and biological evaluation of novel epigenetic modulators for parasitic diseases

Current therapies for human parasite infections rely on a few drugs, most of which have severe side effects, and their usefulness is being seriously threatened by the drug resistance problem. Globally, this is pushing anti-parasitic drug discovery research towards new agents endowed with novel mechanisms of action. Epigenetic processes and the histone modifying enzymes perform vital functions in parasite growth and survival and are validated therapeutic targets. A wealth of current literature indicates that by the use of the so called “drug repurposing” approach, small molecule epigenetic modulators, which were originally developed to treat other human disease conditions, are being investigated for treatment of parasitic diseases, including P. falciparum and S. mansoni infections. The current project focuses on the development and synthesis of novel epigenetic modulators as potential antimalarial and antischistosomal agents. The first part of the project deals with the target-based drugs approach using a small library of HDAC inhibitors to identify potential antimalarial agents. Antiplasmodial activity revealed that MC1742, a uracil-based hydroxamide HDAC inhibitor, as a potent compound with an IC50 value of 4 nM and 6 nM against Pf3D7 sensitive and W2 multidrug resistant strains, respectively. Another project deals with development and synthesis of smSirt2 inhibitors, where several compounds showed modest activity against S. mansoni and good selectivity over hSirt2 that could be potentially used as hits/leads for further medicinal chemistry optimization. Finally, as far as the LSD1 inhibitors as potential antischistosomal agents is considered, preliminary data indicated that most of the tested compounds were relatively toxic to the juvenile stage of schistosomula and to a lesser extent to adult worms. Among these tested compounds, MC3935 was found to be extremely toxic to both schistosomula and adults. Taking into account the preliminary effects of these compounds, it has been demonstrated, as expected, that histone demethylase inhibitors are essential and attractive targets for development of new antimalarial and antischistosomal agents.