Premium
Asymmetric synthesis of tetrahydroquinoline‐type ecdysone agonists and QSAR for their binding affinity against Aedes albopictus ecdysone receptors
Author(s) -
Yokoi Taiyo,
Nakagawa Yoshiaki,
Miyagawa Hisashi
Publication year - 2019
Publication title -
pest management science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.296
H-Index - 125
eISSN - 1526-4998
pISSN - 1526-498X
DOI - 10.1002/ps.5160
Subject(s) - enantiopure drug , quantitative structure–activity relationship , ecdysone , ecdysone receptor , stereochemistry , chemistry , ligand (biochemistry) , receptor , combinatorial chemistry , enantioselective synthesis , biochemistry , nuclear receptor , hormone , transcription factor , catalysis , gene
BACKGROUND Tetrahydroquinolines (THQs) are a class of non‐steroidal ecdysone agonists that specifically bind to mosquito ecdysone receptors (EcR). The THQ scaffold contains two chiral centers at the C‐2 and C‐4 positions, resulting in four stereoisomers. We have previously shown that the (2 R ,4 S )‐isomers are the most biologically active; however, the lack of a practical synthetic method for these isomers has hampered further structure–activity studies. RESULTS In this study, a chiral phosphoric acid‐catalyzed Povarov reaction was employed to develop a facile asymmetric synthesis of THQs with a (2 R ,4 S )‐configuration, which allowed the preparation of a 40‐compound library of enantiopure THQs. Evaluation of their binding affinity against Aedes albopictus EcR, followed by quantitative structure–activity relationship (QSAR) analyses, uncovered the physicochemical properties of THQs that are important for the ligand–receptor interaction. The most potent THQ derivative was twofold more active than the molting hormone, 20‐hydroxyecdysone. CONCLUSION The QSAR results provide valuable information for the rational design of novel mosquito‐specific ecdysone agonists. © 2018 Society of Chemical Industry