Rational Design of Novel Piperine Derivatives Bearing an N -Sulfonylpiperazine Moiety as Selectively Potent Of ChtII Inhibitors

OfChtII, an indispensable enzyme whose expression precedes other chitinases in the chitin metabolic system of Ostrinia furnacalis, becomes a promising target for green pest control. In this work, a series of novel piperine derivatives bearing an N-sulfonylpiperazine moiety were rationally designed and synthesized based on the binding cavity characteristics of OfChtII. Among them, compound I–H15 (Ki = 0.88 μM) exhibited superior inhibitory potency against OfChtII over piperine (Ki = 50.06 μM). In vivo bioassays demonstrated that I–H15 displayed high insecticidal efficacy and prominent growth-inhibitory effects on O. furnacalis at 500 μg/mL. Molecular mechanism demonstrated that I–H15 deeply occupies the previously unexploited subsite −2 of OfChtII and forms critical interactions through hydrogen bonding, π–π stacking, and π–cation with key residues Trp1951 and Phe1889 in OfChtII, as shown by molecular simulations. This study validates a subsite-targeted optimization strategy by discovering novel piperine derivatives and offers a promising lead for developing eco-friendly Chitinase inhibitors against O. furnacalis.