Second-Generation Enamine-Type Schiff Bases as 2-Amino Acid-Derived Antifungals against Fusarium oxysporum: Microwave-Assisted Synthesis, In Vitro Activity, 3D-QSAR, and In Vivo Effect

In this manuscript, the synthesis of enamine-type Schiff bases 1-48 derived from the amino acids L-Ala, L-Tyr, and L-Phe was carried out. Their in vitro activity and in vivo protective effect against Fusarium oxysporum were also evaluated through mycelial growth inhibition and disease severity reduction under greenhouse conditions. The in vitro activity of test compounds 1-48 showed half-maximal inhibitory concentrations (IC50) at different levels below the 40 mM range. Deep analysis of the IC50 variations indicated that the size of the substituent on the acetylacetone derivatives and the electronic character on the cyclohexane-3-one fragment influenced the antifungal effect. 3D-QSAR models based on atoms (atom-based approach) were built to establish the structure-activity relationship of the test Schiff bases, showing a good correlation and predictive consistency (R-2 > 0.70 and Q(2) > 0.60). The respective contour analysis also provided information about the structural requirements for potentiating their antifungal activity. In particular, the amino acid-related fragment and the alkyl ester residue can favor hydrophobic interactions. In contrast, the nitrogen atoms and enamine substituent are favorable regions as H-donating and electron-withdrawing moieties. The most active compounds (40 and 41) protected cape gooseberry plants against F. oxysporum infection (disease severity index < 2), involving adequate physiological parameters (stomatal conductance > 150 mmol/m(2)s) after 45 days of inoculation. These promising results will allow the design of novel Schiff base-inspired antifungals using 2-amino acids as precursors.

Automated summary

The synthesis of 48 enamine-type Schiff bases derived from three amino acids was carried out, and their antifungal activity and protective effect against Fusarium oxysporum were evaluated. The results showed that the size of the substituent on the acetylacetone derivatives and the electronic character on the cyclohexane-3-one fragment influenced the antifungal effect. The structure-activity relationship of the compounds was established using atom-based 3D-QSAR models, which provided information about the structural requirements for enhancing their antifungal activity.