Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 5, Issue 1, Pages 89-93Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml400412x
Keywords
Malaria; antimalarial; aminohydantoin; medicinal chemistry; aspartic protease inhibitors
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Funding
- Saint Louis University
- National Institute Of Allergy And Infectious Diseases of the National Institutes of Health [R01AI106498]
- Bureau of Science and Information Technology of Guangzhou Municipality [2009Z1-E841]
- Natural Science Foundation of China (NSFC)
- National Institutes of Health [AI047798]
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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.
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