Design and synthesis of thiazolylhydrazone derivatives as inhibitors of chitinolytic N-acetyl-beta-D-hexosaminidase

N-acetyl-beta-D-hexosaminidase (Hex) is potential target for pesticide design. Here, a series of thiazolylhydrazone derivatives were designed, synthesized and evaluated as competitive inhibitors of OfHex1, a Hex from the agricultural pest Ostrinia furnacalis. The derivative 3k, with a (benzyloxy) methyl group at the N3 atom, demonstrated greater potency with a K-i of 10.2 mu M. Molecular docking analysis indicated that the (benzyloxy) methyl group of 3k was bound to a previously unexplored pocket formed by Loop478-496. Then further optimization around naphthalene ring led to find the more potency substituent phenyl. The derivative 7, with phenoxyethyl group at R-1 and a phenyl group at R-2, demonstrated an augmented potency with a K-i of 2.1 mu M. Molecular docking analysis indicated that 7 was bound to the active pocket of OfHex1 more favorably than 3k. This work suggests a novel scaffold for developing specific Hex inhibitors.