Jietacins, azoxy antibiotics with potent nematocidal activity: Design, synthesis, and biological evaluation against parasitic nematodes

Akihiro Sugawara, Masahiko Kubo, Tomoyasu Hirose, Kyoichi Yahagi, Noriaki Tsunoda, Yoshihiko Noguchi, Takuji Nakashima, Yoko Takahashi, Claudia Welz, Dennis Mueller, Christina Mertens, Johannes Koebberling, Satoshi Ōmura, Toshiaki Sunazuka

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Jietacins, an azoxy antibiotic class of chemicals, were isolated from the culture broth of Streptomyces sp. KP-197. They have a unique structural motif, including a vinyl azoxy group and a long acyclic aliphatic chain, which is usually branched but non-branched in the case of jietacin C. During a drug discovery program, we found that jietacins display potent anthelmintic activity against parasitic nematodes and that jietacin A has a moderate or low acute toxicity (LD50 > 300 mg/kg) and no mutagenic potential in a mini Ames screen. This suggests that jietacins have potential for drug discovery research. In order to create a novel anthelmintic agent, we performed design, synthesis, and biological evaluation of jietacin derivatives against parasitic nematodes. Of these derivatives, we found that a fully synthesized simplified derivative exhibited better anthelmintic activity against three parasitic nematodes than natural jietacins. In addition, it had a better efficacy in vivo through oral administration against a mouse nematode. This indicated that the azoxy motif could prove useful as a template for anthelmintic discovery, possibly creating a class of anthelmintic with novel skeletons, a potential new mode of action, and providing further insight for rational drug design.

Original languageEnglish
Pages (from-to)524-538
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Volume145
DOIs
Publication statusPublished - 2018 Feb 10
Externally publishedYes

Keywords

  • Anthelmintic
  • Jietacin
  • Late-stage diversification
  • Natural product
  • Nematocidal
  • Vinyl azoxy

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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