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

2 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

Fingerprint

Antimalarials
Heme
Detoxification
Chloroquine
Hemin
Plasmodium falciparum
Parasites
Degradation
Proteins
hemozoin

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Potent Antimalarial Activity of Two Arenes Linked with Triamine Designed to Have Multiple Interactions with Heme. / Sakata, Yosuke; Yabunaka, Kosuke; Kobayashi, Yuko; Omiya, Hirohisa; Umezawa, Naoki; Kim, Hye-Sook; Wataya, Yusuke; Tomita, Yoshimi; Hisamatsu, Yosuke; Kato, Nobuki; Yagi, Hirokazu; Satoh, Tadashi; Kato, Koichi; Ishikawa, Haruto; Higuchi, Tsunehiko.

In: ACS Medicinal Chemistry Letters, Vol. 9, No. 10, 11.10.2018, p. 980-985.

Research output: Contribution to journalArticle

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, vol. 9, no. 10, pp. 980-985. https://doi.org/10.1021/acsmedchemlett.8b00222
Sakata, Yosuke ; Yabunaka, Kosuke ; Kobayashi, Yuko ; Omiya, Hirohisa ; Umezawa, Naoki ; Kim, Hye-Sook ; Wataya, Yusuke ; Tomita, Yoshimi ; Hisamatsu, Yosuke ; Kato, Nobuki ; Yagi, Hirokazu ; Satoh, Tadashi ; Kato, Koichi ; Ishikawa, Haruto ; Higuchi, Tsunehiko. / Potent Antimalarial Activity of Two Arenes Linked with Triamine Designed to Have Multiple Interactions with Heme. In: ACS Medicinal Chemistry Letters. 2018 ; Vol. 9, No. 10. pp. 980-985.
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