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.
Highlights
Malaria, caused by Plasmodium parasites, remains a global disease of devastating morbidity and mortality
To determine whether DDD01034957 has a unique mode of action or acts through an already recognised mechanism, its efficacy was tested in asexual growth assays against a range of selection-derived drug resistant P. falciparum parasites and their parental non-resistant lines (Table 1)
This result suggests that DDD01034957 has a distinct mode of resistance and is active against parasites harbouring resistance mutations linked to a loss of efficacy against many new antimalarials currently under clinical development
Summary
Malaria, caused by Plasmodium parasites, remains a global disease of devastating morbidity and mortality. P. falciparum asexual stages and male and female gametocytes were screened against a 70,000 compound diversity library identifying a number of new scaffolds for antimalarial drug development[3]. One such compound, DDD01034957 (Fig. 1), was identified to possess a chemical scaffold not represented in previous. We perform a detailed in vitro and in vivo characterisation of the antimalarial and pharmacokinetic properties of DDD01034957 using three different Plasmodium species, test for development of resistance in vitro and perform structure–function studies of analogues which share the same chemical scaffold
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
