Discovery of Biphenyl-Sulfonamides as Novel β--Acetyl-d-Hexosaminidase Inhibitors via Structure-Based Virtual Screening.

Novel insecticidal targets are always in demand due to the development of resistance. Hex1, a β--acetyl-d-hexosaminidase identified in (Asian corn borer), is involved in insect chitin catabolism and has proven an ideal target for insecticide development. In this study, structure-based virtual screening, structure simplification, and biological evaluation are used to show that compounds with a biphenyl-sulfonamide skeleton have great potential as Hex1 inhibitors. Specifically, compounds , , and have values of 4.30, 3.72, and 4.56 μM, respectively, and thus, they are more potent than some reported nonglycosyl-based inhibitors such as phlegmacin B ( = 26 μM), berberine ( = 12 μM), ( = 11.2 μM), and ( = 28.9 μM). Furthermore, inhibitory kinetic assessments reveal that the target compounds are competitive inhibitors with respect substrate, and based on toxicity predictions, most of them have potent drug properties. The obtained results indicate that the biphenyl-sulfonamide skeleton characterized by simple chemical structure, synthetic tractability, potent activity, and low toxicity has potential for further development in pest management targeting Hex1.