Evaluation of Novel Dillapiol Analogs as Insect Detoxification Enzyme Inhibitors and Insecticide Synergists

Dillapiol is a naturally occurring methylenedioxyphenyl compound with insecticide-synergizing activity comparable to piperonyl butoxide (PBO). This study identified structurally related molecules with practical potential for managing insecticide-resistant insects. Six new dillapiol analogs, containing ester- or ether-linked side chains, were synthesized and evaluated as pyrethrum synergists against the Colorado potato beetle (CPB) Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae). Their activity was assessed through bioassays and by quantifying inhibition of Phase I and II detoxification enzymes in vitro and in vivo. All six compounds displayed higher synergistic activity by ingestion than by topical exposure, and each structural class included at least one compound with a synergism ratio greater than 20. In the resistant CPB strain (RS-CPB), two ester compounds inhibited P450 monooxygenase activity in vitro as effectively as PBO, while dillapiol and one ether analog reduced P450 activity in vivo. Notably, all six analogs reduced glutathione S-transferase (GST) activity; the most active was an ether analog with an in vitro IC₅₀ of 0.23 (±0.04) mM. Dillapiol also significantly reduced GST activity in vivo. These analogs demonstrated PBO-equivalent P450 inhibition combined with unique GST inhibition and show promise as alternative synergists for managing insecticide-resistant insects.