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


Type
Article
Change log
Authors
Miguel-Blanco, Celia 
Murithi, James M 
Benavente, Ernest Diez 
Angrisano, Fiona 
Sala, Katarzyna A 
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.

Description
Keywords
Animals, Antimalarials, Drug Resistance, Erythrocytes, Host-Parasite Interactions, Humans, Inhibitory Concentration 50, Malaria, Mice, Molecular Structure, Plasmodium, Plasmodium berghei, Plasmodium falciparum, Species Specificity
Journal Title
Sci Rep
Conference Name
Journal ISSN
2045-2322
2045-2322
Volume Title
11
Publisher
Springer Science and Business Media LLC
Sponsorship
Royal Society (IEC\R3\193020)
Global Health Innovative Technology Fund (GHIT) (via Kanazawa University) (RFP-TRP-2019-002)
Royal Society (RGS\R1\201293)
Medical Research Council (MR/N00227X/1)