| Summary: | In this manuscript, the synthesis of enamine-type Schiff bases <b>1–48</b> derived from the amino acids <i>L</i>-Ala, <i>L</i>-Tyr, and <i>L</i>-Phe was carried out. Their in vitro activity and in vivo protective effect against <i>Fusarium oxysporum</i> were also evaluated through mycelial growth inhibition and disease severity reduction under greenhouse conditions. The in vitro activity of test compounds <b>1–48</b> showed half-maximal inhibitory concentrations (IC<sub>50</sub>) at different levels below the 40 mM range. Deep analysis of the IC<sub>50</sub> 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<sup>2</sup> > 0.70 and Q<sup>2</sup> > 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 <i>H</i>-donating and electron-withdrawing moieties. The most active compounds (<b>40</b> and <b>41</b>) protected cape gooseberry plants against <i>F. oxysporum</i> infection (disease severity index < 2), involving adequate physiological parameters (stomatal conductance > 150 mmol/m<sup>2</sup>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.
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