Design and Discovery of Novel Chiral Antifungal Amides with 2‑(2-Oxazolinyl)aniline as a Promising Pharmacophore

Inspired by established succinate
dehydrogenase inhibitors (SDHIs), our continuing efforts toward the
discovery of chiral antifungal amides turned to the optimization of
their polar regions with 2-(2-oxazolinyl)­aniline as a known pharmacophore.
Scaffold hopping and bioactivity-guided convergent synthesis enabled
the identification of promising antifungal categories. Fine tuning
of the substituents and chirality furnished seven amides (1s, 1t, 2d, 2h, 2j, 3k, and 2l) as antifungal candidates,
with EC50 values lower than 5 mg/L. The first investigation
of chiral amides of acyclic acids as SDHIs was conducted, and compound 2d was selected as a promising candidate against Botrytis cinerea, with a preventative efficacy of
up to 93.9% at 50 mg/L, which is better than that of boscalid. The
different binding models between compounds with different configurations
were simulated for compound 2d and its diastereoisomers.
The benefits of synthetic accessibility and cost-effectiveness highlight
the practical potential for compound 2d as a good alternative
to known SDHI fungicides.