Discovery of new quinoline-based antimalaria agents with nanomolar potency towards multi-drug-resistant forms
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.