Optimization of plasmepsin inhibitor by focusing on similar structural feature with chloroquine to avoid drug-resistant mechanism of Plasmodium falciparum

Takuya Miura, Koushi Hidaka, Yukiko Azai, Keisuke Kashimoto, Yuko Kawasaki, Shen En Chen, Renato Ferreira De Freitas, Ernesto Freire, Yoshiaki Kiso

Research output: Contribution to journalArticle

Abstract

The plasmepsins are specific aspartic proteases of the malaria parasite and a potential target for developing new antimalarial agents. Our previously reported peptidomimetic plasmepsin inhibitor with modified 2-aminoethylamino substituent, KNI-10740, was tested against chloroquine sensitive Plasmodium falciparum, D6, to be highly potent, however, the inhibitor exhibited about 5 times less activity against multi-drug resistant parasite (TM91C235). We hypothesized the potency reduction resulted from structural similarity between 2-aminoethylamino substituent of KNI-10740 and chloroquine. Then, we modified the moiety and finally identified compound 15d (KNI-10823), that could avoid drug-resistant mechanism of TM91C235 strain.

Original languageEnglish (US)
Pages (from-to)1698-1701
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number7
DOIs
StatePublished - Apr 1 2014

Keywords

  • Allophenylnorstatine
  • Antimalarial drug
  • Aspartic protease
  • Drug-resistance
  • Plasmepsin inhibitor

ASJC Scopus subject areas

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

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