title: Evaluation of aminohydantoins as a novel class of antimalarial agents.
abstract: 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.
authors.affiliation: Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Meyers
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Micky D
authors.initials: MD
authors.lastname: Tortorella
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Qin
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Zhengxiang
authors.initials: Z
authors.lastname: He
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Xingfen
authors.initials: X
authors.lastname: Lang
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Wentian
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Wanwan
authors.initials: W
authors.lastname: Xu
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.affiliation: Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Prinsen
authors.affiliation: Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
authors.forename: Francis M
authors.initials: FM
authors.lastname: Sverdrup
authors.affiliation: Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Eickhoff
authors.affiliation: Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
authors.forename: David W
authors.initials: DW
authors.lastname: Griggs
authors.affiliation: Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Oliva
authors.affiliation: Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Ruminski
authors.affiliation: Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
authors.forename: E Jon
authors.initials: EJ
authors.lastname: Jacobsen
authors.affiliation: Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Campbell
authors.affiliation: Center for World Health and Medicine, Saint Louis University , Saint Louis, Missouri 63104, United States.
authors.forename: David C
authors.initials: DC
authors.lastname: Wood
authors.affiliation: Howard Hughes Medical Institute, Washington University School of Medicine , Departments of Molecular Microbiology and Medicine, Saint Louis, Missouri 63110, United States.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Goldberg
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: Guangzhou Institutes of Biomedicine and Health , Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
keywords: Malaria; aminohydantoin; antimalarial; aspartic protease inhibitors; medicinal chemistry