Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin

Koushi Hidaka, Tooru Kimura, Adam J. Ruben, Tsuyoshi Uemura, Mami Kamiya, Aiko Kiso, Tetsuya Okamoto, Yumi Tsuchiya, Yoshio Hayashi, Ernesto Freire, Yoshiaki Kiso

Research output: Contribution to journalArticlepeer-review

Abstract

Plasmepsin (Plm) is a potential target for new antimalarial drugs, but most reported Plm inhibitors have relatively low antimalarial activities. We synthesized a series of dipeptide-type HIV protease inhibitors, which contain an allophenylnorstatine-dimethylthioproline scaffold to exhibit potent inhibitory activities against Plm II. Their activities against Plasmodium falciparum in the infected erythrocyte assay were largely different from those against the target enzyme. To improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity. These results suggest that auxiliary substituents on a specific basic group contribute to deliver the inhibitors to the target Plm.

Original languageEnglish (US)
Pages (from-to)10049-10060
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number23
DOIs
StatePublished - Dec 1 2008

Keywords

  • Allophenylnorstatine
  • Antimalarial drug
  • Aspartic protease
  • Hydoxymethylcarbonyl
  • Peptidomimetics
  • Plasmepsin inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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