Synthesis, antifungal evaluation, two-dimensional quantitative structure–activity relationship and molecular docking studies of isoxazole derivatives as potential fungicides

BACKGROUND: Sheath blight and bakanae disease, prominent among emerging rice ailments, exert a profound impact on rice productivity, causing severe impediments to crop yield. Excessive use of older fungicides may lead to the development of resistance in the pathogen. Indeed, a pressing and immediate need exists for novel, low-toxicity and highly selective fungicides that can effectively combat resistant fungal strains. RESULTS: A series of 20 isoxazole derivatives were synthesized using alkoxy/halo acetophenones and N,N-dimethylformamidedimethylacetal. These compounds were characterized by various spectroscopic techniques, namely ¹H nuclear magnetic resonance (NMR), ¹³C NMR and liquid chromatography–high-resolution mass spectrometry, and were evaluated for their fungicidal activity against Rhizoctonia solani and Fusarium fujikuroi. Compound 5n (5-(2-chlorophenyl) isoxazole) exhibited highest activity (effective dose for 50% inhibition [ED₅₀] = 4.43 μg mL⁻¹) against R. solani, while 5p (5-(2,4-dichloro-2-hydroxylphenyl) isoxazole) exhibited highest activity (ED₅₀ = 6.7 μg mL⁻¹) against F. fujikuroi. Two-dimensional quantitative structural–activity relationship (QSAR) analysis, particularly multiple linear regression (MLR) (Model 1), highlighted chi6chain and DistTopo as the key descriptors influencing fungicidal activity. Molecular docking studies revealed the potential of these isoxazole derivatives as novel fungicides targeting sterol 14α-demethylase enzyme, suggesting their importance as crucial intermediates for the development of novel and effective fungicides. CONCLUSION: All test compounds were effective in inhibiting both fungi, according to the QSAR model, with various descriptors, such as structural, molecular shape analysis, electronic and thermodynamic, playing an important role. Molecular docking studies confirmed that these compounds can potentially replace commercially available fungicides and help control fungal pathogens in rice crops effectively.