Structural requirement and stereospecificity of tetrahydroquinolines as potent ecdysone agonists

Seiya Kitamura, Toshiyuki Harada, Hajime Hiramatsu, Ryo Shimizu, Hisashi Miyagawa, Yoshiaki Nakagawa

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Tetrahydroquinoline (THQ)-type compounds are a class of potential larvicides against mosquitoes. The structure-activity relationships (SAR) of these compounds were previously investigated (Smith et al., Bioorg. Med. Chem. Lett. 2003, 13, 1943-1946), and one of cis-forms (with respect to the configurations of 2-methyl and 4-anilino substitutions on the THQ basic structure) was stereoselectively synthesized. However, the absolute configurations of C2 and C4 were not determined. In this study, four THQ-type compounds with cis configurations were synthesized, and two were submitted for X-ray crystal structure analysis. This analysis demonstrated that two enantiomers are packed into the crystal form. We synthesized the cis-form of the fluorinated THQ compound, according to the published method, and the enantiomers were separated via chiral HPLC. The absolute configurations of the enantiomers were determined by X-ray crystallography. Each of the enantiomers was tested for activity against mosquito larvae in vivo and competitive binding to the ecdysone receptor in vitro. Compared to the (2S,4R) enantiomer, the (2R,4S) enantiomer showed 55 times higher activity in the mosquito larvicidal assay, and 36 times higher activity in the competitive receptor binding assay.

Original languageEnglish (US)
Pages (from-to)1715-1718
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number7
DOIs
StatePublished - Apr 1 2014
Externally publishedYes

Keywords

  • Ecdysone
  • Larvicide
  • Mosquito
  • Stereospecificity
  • Tetrahydroquinoline

ASJC Scopus subject areas

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

Fingerprint

Dive into the research topics of 'Structural requirement and stereospecificity of tetrahydroquinolines as potent ecdysone agonists'. Together they form a unique fingerprint.

Cite this