Bioactivity-Guided Subtraction of MIQOX for Easily Available Isoquinoline Hydrazides as Novel Antifungal Candidates

Abstract

The discovery of novel and easily available leads provides a convincing solution to agrochemical innovation. A bioassay-guided scaffold subtraction of the previous "Chem-Bio Model" isoquinoline-3-oxazoline <b>MIQOX</b> was conducted for identifying the easily available isoquinoline-3-hydrazide as a novel antifungal scaffold. The special and practical potential of this model was demonstrated by a phenotypic antifungal bioassay, molecular docking, and cross-resistance evaluation. A panel of antifungal leads (<b>LW2</b>, <b>LW3</b>, and <b>LW11</b>) was acquired, showing much better antifungal performance than the positive controls. Specifically, compound <b>LW3</b> exhibited a broad antifungal spectrum holding EC₅₀ values as low as 0.54, 0.09, 1.52, and 2.65 mg/L against <i>B. cinerea</i>, <i>R. solani</i>, <i>S. sclerotiorum</i> , and <i>F. graminearum</i>, respectively. It demonstrated a curative efficacy better than that of boscalid in controlling the plant disease caused by <i>B. cinerea</i>. The candidate <b>LW3</b> did not show cross-resistance to the extensively used succinate dehydrogenase inhibitor (SDHI) fungicides and can efficiently inhibit resistant <i>B. cinerea</i> strains. The molecular docking of compound <b>LW3</b> is quite different from that of the positive controls boscalid and fluopyram. This progress highlights the practicality of isoquinoline hydrazide as a novel model in fungicide innovation.