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

• Published in: Scientific reports Vol. 11; no. 1; pp. 1888 - 9
• Main Authors: Miguel-Blanco, Celia, Murithi, James M., Benavente, Ernest Diez, Angrisano, Fiona, Sala, Katarzyna A., van Schalkwyk, Donelly A., Vanaerschot, Manu, Schwach, Frank, Fuchter, Matthew J., Billker, Oliver, Sutherland, Colin J., Campino, Susana G., Clark, Taane G., Blagborough, Andrew M., Fidock, David A., Herreros, Esperanza, Gamo, Francisco Javier, Baum, Jake, Delves, Michael J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/309/2144; 692/699/255/1629; Animals; Antimalarial agents; Antimalarials - chemistry; Antimalarials - pharmacology; Aquatic insects; Drug resistance; Drug Resistance - drug effects; Drug screening; Erythrocytes; Erythrocytes - parasitology; Host-Parasite Interactions - drug effects; Humanities and Social Sciences; Humans; Inhibitory Concentration 50; Insecticides; Malaria; Malaria - drug therapy; Malaria - parasitology; Mice; Molecular Structure; multidisciplinary; Parasite resistance; Parasites; Plasmodium - drug effects; Plasmodium - parasitology; Plasmodium berghei - drug effects; Plasmodium berghei - parasitology; Plasmodium falciparum - drug effects; Plasmodium falciparum - physiology; Science; Science (multidisciplinary); Species Specificity; Vector-borne diseases
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-81343-z

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 Pf ABCI3 . 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.