Evaluation of aminohydantoins as a novel class of antimalarial agents

Marvin J. Meyers, Micky D. Tortorella, Jing Xu, Limei Qin, Zhengxiang He, Xingfen Lang, Wentian Zeng, Wanwan Xu, Li Qin, Michael J. Prinsen, Francis M. Sverdrup, Christopher S. Eickhoff, David W. Griggs, Jonathan Oliva, Peter G. Ruminski, E. Jon Jacobsen, Mary A. Campbell, David C. Wood, Daniel E. Goldberg, Xiaorong LiuYongzhi Lu, Xin Lu, Zhengchao Tu, Xiaoyun Lu, Ke Ding, Xiaoping Chen

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish
Pages (from-to)89-93
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume5
Issue number1
DOIs
StatePublished - Jan 9 2014

Keywords

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

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