Abstract
Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products.
Highlights
Malaria is widespread in tropical and subtropical regions, including parts of America, Asia and Africa
Most deaths from malaria are caused by Plasmodium falciparum, one of the five species of human infectious malaria parasites
Chemical libraries created by iterative synthesis around a few families of compounds are not always the best option when the objective is to identify non-previously exploited novel scaffolds
Summary
Malaria is widespread in tropical and subtropical regions, including parts of America, Asia and Africa. An estimated 3.2 billion people are at the risk of suffering malaria and from one-half to one million deaths were reported in 2014 In 2014, 97 countries and territories had ongoing malaria transmission. Most deaths from malaria are caused by Plasmodium falciparum, one of the five species of human infectious malaria parasites. The increasing resistance of P. falciparum to the available drugs [1] and new efforts to eradicate malaria all drive the need to develop new, effective and affordable antimalarial agents.
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