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.
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.