Asymmetric synthesis of tetrahydroquinoline‐type ecdysone agonists and QSAR for their binding affinity against Aedes albopictus ecdysone receptors

Abstract

The QSAR results provide valuable information for the rational design of novel mosquito-specific ecdysone agonists. © 2018 Society of Chemical Industry.

Catalytic Asymmetric Aza‐Diels‐Alder Reaction: Pivotal Milestones and Recent Applications to Synthesis of Nitrogen‐Containing Heterocycles

“…A tetrahydroquinoline ring system is present in cinchona alkaloid derivatives [191,192] and numerous natural compounds such as martinellic acid and martinelline isolated from roots of the tropical plant Martinella iquitosensis , [193] galipeine and angustureine extracted from the Galipea officinalis tree, [194] and in a number of other pharmacology‐relevant molecules [195–203] . Because of the significance of this heterocyclic scaffold in drug discovery, development of efficient methodologies for the facile stereoselective synthesis of tetrahydroquinoline derivatives has remained in demand [9,204,205] .…”

Receptor-binding affinity and larvicidal activity of tetrahydroquinoline-type ecdysone agonists against <i>Aedes albopictus</i>

“…General Compounds 1-20 (Series I) were prepared in our previous work. 18) The other THQ derivatives (21-35, Series II) were newly synthesized according to the synthetic route shown in Scheme 1. In brief, compound 36 was prepared in 97% ee from 4-fluoroaniline, acetaldehyde, and benzyl vinylcarbamate in accordance to the procedure reported in the literature.…”

“…In brief, compound 36 was prepared in 97% ee from 4-fluoroaniline, acetaldehyde, and benzyl vinylcarbamate in accordance to the procedure reported in the literature. 18) The carboxybenzyl (Cbz) group of 36 was removed by catalytic hydrogenolysis, and the resulting diamine was selectively arylated via a Chan-Evans-Lam coupling reaction to give the common intermediate 37. Compounds 21, 24, 25 and 26 were synthesized via HATU-assisted condensation of 37 with carboxylic acids (Method A), and the other compounds were synthesized via acylation of 37 with acid chlorides (Method B).…”

“…17) More recently, we performed quantitative structureactivity relationship (QSAR) analyses of THQ analogs with the (2R,4S)-configuration and identified several physicochemical properties of THQs that are important for binding affinity. 18) However, only a few studies 14,17) have investigated the larvicidal activity of THQs, and the determinants of larvicidal activity still remain unclear.…”

“…In this study, we newly synthesized 15 THQ derivatives that have a heteroaryl group instead of the benzene ring of the benzoyl moiety and evaluated their binding affinity against A. albopictus EcRs. These newly synthesized compounds, together with 20 THQ analogs prepared in our previous study, 18) were tested for their larvicidal activity against A. albopictus. By performing multiple regression analyses, we found that the binding affinity and the molecular hydrophobicity are key determinants of the larvicidal activity of THQs.…”