Journal
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
Volume 71, Issue 30, Pages 11341-11349Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jafc.3c02096
Keywords
antifungal lead; oxazoline; scaffold hopping; isoquinoline-3-hydrazide; electron transfer chain
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A novel antifungal scaffold, isoquinoline-3-hydrazides, was identified through a bioassay-guided scaffold subtraction. The compound LW3 showed a broad-spectrum antifungal activity and no cross-resistance to commonly used fungicides. This finding highlights the practical potential of isoquinoline hydrazides as a novel model in fungicide innovation.
Thediscovery of novel and easily available leads provides a convincingsolution to agrochemical innovation. A bioassay-guided scaffold subtractionof the previous Chem-Bio Model isoquinoline-3-oxazoline MIQOX was conducted for identifying the easily available isoquinoline-3-hydrazideas a novel antifungal scaffold. The special and practical potentialof this model was demonstrated by a phenotypic antifungal bioassay,molecular docking, and cross-resistance evaluation. A panel of antifungalleads (LW2, LW3, and LW11)was acquired, showing much better antifungal performance than thepositive controls. Specifically, compound LW3 exhibiteda broad antifungal spectrum holding EC50 values as lowas 0.54, 0.09, 1.52, and 2.65 mg/L against B. cinerea, R. solani, S. sclerotiorum , and F. graminearum, respectively.It demonstrated a curative efficacy better than that of boscalid incontrolling the plant disease caused by B. cinerea. The candidate LW3 did not show cross-resistance tothe extensively used succinate dehydrogenase inhibitor (SDHI) fungicidesand can efficiently inhibit resistant B. cinerea strains. The molecular docking of compound LW3 is quitedifferent from that of the positive controls boscalid and fluopyram.This progress highlights the practicality of isoquinoline hydrazideas a novel model in fungicide innovation.
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