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ACS Med Chem Lett. 2013 Dec 6;5(1):89-93. doi: 10.1021/ml400412x. eCollection 2014 Jan 9.

Evaluation of aminohydantoins as a novel class of antimalarial agents.

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Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
Howard Hughes Medical Institute, Washington University School of Medicine , Departments of Molecular Microbiology and Medicine, Saint Louis, Missouri 63110, United States.


Given the threat of drug resistance, there is an acute need for new classes of antimalarial agents that act via a unique mechanism of action relative to currently used drugs. We have identified a set of druglike compounds within the Tres Cantos Anti-Malarial Set (TCAMS) which likely act via inhibition of a Plasmodium aspartic protease. Structure-activity relationship analysis and optimization of these aminohydantoins demonstrate that these compounds are potent nanomolar inhibitors of the Plasmodium aspartic proteases PM-II and PM-IV and likely one or more other Plasmodium aspartic proteases. Incorporation of a bulky group, such as a cyclohexyl group, on the aminohydantion N-3 position gives enhanced antimalarial potency while reducing inhibition of human aspartic proteases such as BACE. We have identified compound 8p (CWHM-117) as a promising lead for optimization as an antimalarial drug with a low molecular weight, modest lipophilicity, oral bioavailability, and in vivo antimalarial activity in mice.


Malaria; aminohydantoin; antimalarial; aspartic protease inhibitors; medicinal chemistry

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