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

This study was designed to address the critical challenge of widespread insecticidal resistance in agricultural pests by exploring novel botanical synergists as alternatives to piperonyl butoxide (PBO), a primary insecticide synergist in today’s market but facing growing safety concerns due to adverse mammalian effects. Our study focused on dillapiol, a natural botanical compound with synergistic efficacy comparable to PBO. We synthesized six novel dillapiol analogs and evaluated their ability to enhance the potency of pyrethrum against the Colorado potato beetle (CPB). Several analogs significantly boosted pyrethrum’s insecticidal activity, especially when the compounds were consumed by insects rather than topically applied. Mechanistic investigations confirmed that, like PBO, several new compounds effectively inhibited key Phase I detoxification enzymes. These enzymes perform the primary transformation of molecules through oxidation–reduction to create water-soluble compounds. Notably, several new analogs demonstrated higher inhibitory activity of the analogs compared to PBO in the enzyme inhibition assays. Some even demonstrated a unique capacity to reduce Phase II detoxification enzyme activity, which facilitates the conjugation of molecules into water-soluble forms, a process typically unaffected by PBO in in vivo assays. One compound, in particular, exhibited a significant reduction in enzymatic activity across both phases. Our data suggest that these new dillapiol-based compounds represent a promising new class of synergists. Their enhanced efficacy and novel modes of action could enhance the management of resistant pest populations, improve integrated pest management (IPM) strategies and contribute to more sustainable agricultural practices.