Potent Antimalarial Activity of Two Arenes Linked with Triamine Designed to Have Multiple Interactions with Heme

Yosuke Sakata, Kosuke Yabunaka, Yuko Kobayashi, Hirohisa Omiya, Naoki Umezawa, Hye Sook Kim, Yusuke Wataya, Yoshimi Tomita, Yosuke Hisamatsu, Nobuki Kato, Hirokazu Yagi, Tadashi Satoh, Koichi Kato, Haruto Ishikawa, Tsunehiko Higuchi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Based on the idea that compounds designed to exhibit high affinity for heme would block hemozoin formation, a critical heme-detoxification process for malarial parasites, we synthesized a series of compounds with two π-conjugated moieties at terminal amino groups of triamine. These compounds exhibited moderate to high antimalarial activities in vitro toward both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. In a P. berghei-infected mouse model, 3a and 12a showed potent antimalarial activities compared to artesunate, as well as a prolonged duration of antimalarial effect. We found a good correlation between protective activity against hemin degradation and antimalarial activity. Compounds 8b and 3a strongly inhibited hemozoin formation catalyzed by heme detoxification protein.

Original languageEnglish
Pages (from-to)980-985
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume9
Issue number10
DOIs
Publication statusPublished - Oct 11 2018

Keywords

  • Antimalarial
  • heme
  • heme detoxification protein
  • hemozoin
  • molecular recognition

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Sakata, Y., Yabunaka, K., Kobayashi, Y., Omiya, H., Umezawa, N., Kim, H. S., Wataya, Y., Tomita, Y., Hisamatsu, Y., Kato, N., Yagi, H., Satoh, T., Kato, K., Ishikawa, H., & Higuchi, T. (2018). Potent Antimalarial Activity of Two Arenes Linked with Triamine Designed to Have Multiple Interactions with Heme. ACS Medicinal Chemistry Letters, 9(10), 980-985. https://doi.org/10.1021/acsmedchemlett.8b00222