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One-Pot Synthesis of Chiral Succinate Dehydrogenase Inhibitors and Antifungal Activity Studies

Summary

Scientists developed a new method to create potent antifungal medications that can protect crops from destructive fungal diseases. By carefully controlling the molecular structure (chirality) of the compounds, they created drugs that are significantly more effective and potentially less toxic than existing treatments. Testing showed that the new compound called (S)-5f works 76 times better against gray mold fungus than its mirror-image counterpart, similar to how your left and right hands have the same shape but can’t be superimposed.

Background

Fungal diseases account for over 70% of crop diseases and pose serious threats to agricultural production. Succinate dehydrogenase inhibitors (SDHIs) are effective targeted fungicides, but the development of chiral variants represents an opportunity to reduce pesticide doses while improving efficacy. This work addresses the need for efficient synthetic methods to produce chiral SDHI fungicides.

Objective

To develop an efficient one-pot Rh-catalyzed asymmetric hydrogenation-condensation strategy for synthesizing chiral succinate dehydrogenase inhibitors and to evaluate their antifungal properties and mechanisms of action. The study aims to demonstrate the importance of stereochemistry in fungicide efficacy.

Results

The synthetic method achieved up to 1000 Ton scale with 94% yield and 99% enantiomeric excess. (S)-5f demonstrated superior antifungal activity against Botrytis cinerea (EC50 = 0.48 µM) compared to its R-enantiomer (EC50 = 36.7 µM) and commercial fungicide Boscalid. Molecular studies showed (S)-5f binds more effectively to succinate dehydrogenase and inhibits spore germination and hyphal growth more effectively than the R-enantiomer.

Conclusion

This work presents an efficient synthetic strategy for chiral SDHIs with broad-spectrum antifungal activity. Significant differences between enantiomers in both biological activity and toxicity underscore the importance of stereochemistry in fungicide development, potentially enabling reduced-dose applications of pesticides for improved environmental and food safety.
  • Published in:Advanced Science,
  • Study Type:Research Study,
  • Source: 10.1002/advs.202416250
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