Design and synthesis of oxathiapiprolin derivatives containing acetal fragments as potent fungicide candidates.

BACKGROUND

Oxysterol-binding proteins (OSBPs) serve as critical regulators throughout the oomycete life cycle. Oxathiapiprolin (OXA), a potent OSBP-targeting fungicide, represents the first commercially developed piperidine-thiazole-isooxazoline (PTI) product. Despite extensive structural modification focused on OXA, very few analogs with improved fungicidal activity have been identified to date.

RESULTS

In this study, a series of OXA derivatives were designed and synthesized by introducing a flexible acetal fragment into OXA. The compounds B3 and B5 respectively exhibited excellent 77.78% and 94.44% control efficiency against cucumber downy mildew (CDM) at 0.02 mg/L concentration. The field trials showed that compounds B3 and B5 took on higher control efficiency than OXA at the same concentration. The result of environmental toxicological risk assessment indicated that compounds B3 and B5 have lower toxicity to aquatic lives than OXA. Computational chemistry indicated that the binding mode of compound B3 with Phytophthora capsici OSBP (PcOSBP) is similar to that of OXA, and kept the main binding interaction with OSBPs.

CONCLUSION

Our findings suggested that a strategy focused on increasing molecular flexibility could be advantageous for optimizing OSBP inhibitors. The chemical structure of compound B3 may serve as a promising new starting point for the development of further OSBP inhibitors. © 2026 Society of Chemical Industry.