Rapid and Systematic Exploration of Chemical Space Relevant to Artemisinins: Anti-malarial Activities of Skeletally Diversified Tetracyclic Peroxides and 6-Aza-artemisinins

Karunakar Reddy Bonepally, Norihito Takahashi, Naoya Matsuoka, Hikari Koi, Haruki Mizoguchi, Takahisa Hiruma, Kyohei Ochiai, Shun Suzuki, Yutaka Yamagishi, Hideaki Oikawa, Aki Ishiyama, Rei Hokari, Masato Iwatsuki, Kazuhiko Otoguro, Satoshi Mura, Nobutaka Kato, Hiroki Oguri

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

To achieve both structural changes and rapid synthesis of the tetracyclic scaffold relevant to artemisinins, we explored two kinds of de novo synthetic approaches that generate both skeletally diversified tetracyclic peroxides and 6-aza-artemisinins. The anti-malarial activities of the tetracyclic peroxides with distinct skeletal arrays, however, were moderate and far inferior to artemisinins. Given the privileged scaffold of artemisinins, we next envisioned element implantation at the C6 position with a nitrogen without the trimmings of substituents and functional groups. This molecular design allowed the deep-seated structural modification of the hitherto unexplored cyclohexane moiety (C-ring) while keeping the three-dimensional structure of artemisinins. Notably, this approach induced dramatic changes of retrosynthetic transforms that allow an expeditious catalytic asymmetric synthesis with generation of substitutional variations at three sites (N6, C9, and C3) of the 6-aza-artemisinins. These de novo synthetic approaches led to the lead discovery with substantial intensification of the in vivo activities, which undermine the prevailing notion that the C-ring of artemisinins appears to be merely a structural unit but to be a functional area as the anti-malarial pharmacophore. Furthermore, we unexpectedly found that racemic 6-aza-artemisinin (33) exerted exceedingly potent in vivo efficacies superior to the chiral one and the first-line drug, artesunate.

Original languageEnglish
Pages (from-to)9694-9712
Number of pages19
JournalJournal of Organic Chemistry
Volume85
Issue number15
DOIs
Publication statusPublished - Aug 7 2020
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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