Exploring unsymmetrical dyads as efficient inhibitors against the insect β-N-acetyl-d-hexosaminidase OfHex2

The GH20 β-N-acetyl-d-hexosaminidase OfHex2 from the insect Ostrinia furnacalis (Guenée) is a target potential for eco-friendly pesticide development. Although carbohydrate-based inhibitors against β-N-acetyl-d-hexosaminidases are widely studied, highly efficient, non-carbohydrate inhibitors are more attractive due to low cost and readily synthetic manner. Based on molecular modeling analysis of the catalytic domain of OfHex2, a series of novel naphthalimide-scaffold conjugated with a small aromatic moiety by an alkylamine spacer linker were designed and evaluated as efficiently competitive inhibitors against OfHex2. The most potent one containing naphthalimide and phenyl groups spanning by an N-alkylamine linker has a Ki value of 0.37 μM, which is 6 fold lower than that of M-31850, the most potent non-carbohydrate inhibitor ever reported. The straightforward synthetic manners as well as the presumed binding model in this paper could be advantageous for further structural optimization for developing inhibitors against GH20 β-N-acetyl-d-hexosaminidases.