The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957.

Abstract

New antimalarial therapeutics are needed to ensure that malaria cases continue to be driven down, as both emerging parasite resistance to frontline chemotherapies and mosquito resistance to current insecticides threaten control programmes. Plasmodium, the apicomplexan parasite responsible for malaria, causes disease pathology through repeated cycles of invasion and replication within host erythrocytes (the asexual cycle). Antimalarial drugs primarily target this cycle, seeking to reduce parasite burden within the host as fast as possible and to supress recrudescence for as long as possible. Intense phenotypic drug screening efforts have identified a number of promising new antimalarial molecules. Particularly important is the identification of compounds with new modes of action within the parasite to combat existing drug resistance and suitable for formulation of efficacious combination therapies. Here we detail the antimalarial properties of DDD01034957-a novel antimalarial molecule which is fast-acting and potent against drug resistant strains in vitro, shows activity in vivo, and possesses a resistance mechanism linked to the membrane transporter PfABCI3. These data support further medicinal chemistry lead-optimization of DDD01034957 as a novel antimalarial chemical class and provide new insights to further reduce in vivo metabolic clearance.

• Authors: Celia Miguel-Blanco, James M Murithi, Ernest Diez Benavente, Fiona Angrisano, Katarzyna A Sala, Donelly A van Schalkwyk, Manu Vanaerschot, Frank Schwach, Matthew J Fuchter, Oliver Billker, Colin J Sutherland, Susana G Campino, Taane G Clark, Andrew M Blagborough, David A Fidock, Esperanza Herreros, Francisco Javier Gamo, Jake Baum, Michael J Delves
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 1888 (01 21 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 33479319 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials

Topics

• Animals
• Antimalarials (chemistry, pharmacology)
• Drug Resistance (drug effects)
• Erythrocytes (parasitology)
• Host-Parasite Interactions (drug effects)
• Humans
• Inhibitory Concentration 50
• Malaria (drug therapy, parasitology)
• Mice
• Molecular Structure
• Plasmodium (drug effects, parasitology)
• Plasmodium berghei (drug effects, parasitology)
• Plasmodium falciparum (drug effects, physiology)
• Species Specificity