Today, malaria affects more than 200 million people worldwide. The most severe forms of the disease are all caused by P. falciparum, and mortality from severe malaria is highest in children aged six months to three years in endemic areas, according to the World Health Organisation.
Malaria research is going on for decades but is still considered a neglected tropical disease with rather low budgets and less interest; however, resistance to the well-established therapy options and climatic changes result in more and more malaria infections which urgently need modern and safe treatment options.
Screening on a large library of different molecules and drugs on various models of Plasmodium infection resulted in a nanomolar activity of the well-known non-nucleoside inhibitor of human DNA-methyltransferases (DNMTs) SGI-1027 without exhibiting toxicity in HepG2 liver cells.
Prompted by this unexpected finding, we screened our SGI-1027 analogues library to delineate first structure-activity relationships. Based on our promising preliminary results, we propose herein the design of clickable probes on our best molecules to start a target fishing process to unravel the underlying target of its potent antimalarial activity even in resistant and late-stage malaria infection models.
CAVEATS and PITFALLS
Malaria research is going on for decades but is still considered a neglected tropical disease with rather low budgets and less interest; however, resistance to the well-established therapy options and climatic changes result in more and more malaria infections which urgently need modern and safe treatment options.
Hence, there is a need to identify new potent and selective antimalarial agents either as a potential therapeutic agent or as a tool to understand better the various targets of a malaria infection, which is the aim in our project presented here: the development of a novel potent malaria agent with an eventual novel mechanism of action. Our main goal is to find new molecules highly active (and preferably also selective) against malaria but with the lowest side effects (i.e., affecting healthy cells) as possible. Therefore, we plan to do a toxicity screen in normal healthy cells, in addition to our disease models. Additionally, as our compounds derive from molecules originally designed as DNMT inhibitors, we aim to test our most active compound against this and other epigenetic targets.
Regarding the probe design, we need to consider that the probes might not possess a (sufficient) antimalarial activity anymore; thus, we might need to change the design and/or position of the probe warhead.
We can meet in our project some pitfalls with the planned organic synthesis: in this case, it will be necessary to change the chemical strategy by planning different steps and/or ways of synthesis and by starting from different starting materials.