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

Author:
Yokoi, Taiyo, Nakagawa, Yoshiaki, Miyagawa, Hisashi
Source:
Pest management science 2019 v.75 no.1 pp. 115-124
ISSN:
1526-498X
Subject:
Aedes albopictus, binding capacity, ecdysone agonists, ecdysone receptor, ecdysterone, enantiomers, pest management, physicochemical properties, quantitative structure-activity relationships
Abstract:
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 (2R,4S)‐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 (2R,4S)‐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
Agid:
6255060