Malaria has been a military problem throughout history capable of causing epidemics that stop military operations. Particularly, malaria has had a greater impact on world history than any other infectious disease. Primarily, malaria is a disease of the blood. Plasmodium parasite causes malaria. Crucially, malaria transmits from person to person by a particular type of female Anopheles mosquito. Plasmodium falciparum is a unicellular protozoan parasite of humans. The deadliest species of Plasmodium cause malaria in humans. Therefore, given the persistent emergence of drug-resistant strains of Plasmodium falciparum, there is an ongoing need to find and identify new antimalarial agents.

In the study, Meyers MJ, et al described the evaluation of pyrrolidine carboxamides as a novel class of antimalarial compounds with the potential for optimization as drug candidates. Gratifyingly, antimalarial compounds are potent inhibitors of P. falciparum and have good pharmacokinetic properties and oral efficacy in a mouse model of malaria. Surprisingly, the absolute stereochemical preference for this acetamide series is opposite of that for the related carboxamide series.

Fortunately, this research leads to the discovery of CWHM-1552. Especially, CWHM-1552 is a potent inhibitor of P. falciparum growth in both the drug-sensitive 3D7 and resistant Dd2 strains with IC50s of 51 nM and 53 nM, respectively. Moreover, CWHM-1552 is nontoxic at 50 μM. Besides, CWHM-1552 is orally efficacious in a mouse model of malaria (ED90 of >10 mg/kg/day and ED99 of 30 mg/kg/day in a murine P. chabaudi model). In addition, CWHM-1552 has respectable half-lives and low clearance in mice. All in all, these results indicate that CWHM-1552 is an orally efficacious antimalarial agent.

Meyers MJ, et al. 4-Aryl Pyrrolidines as Novel Orally Efficacious Antimalarial Agents. Part 2: 2-Aryl-N-(4-arylpyrrolidin-3-yl)acetamides. ACS Med Chem Lett. 2019 May 28;10(6):966-971.