Metal-Free Catalytic Synthesis of <i>N</i>-Allylaminocyclohex-2-enone via α-Regioselective Substitution of Morita–Baylis–Hillman Adducts: Characterization, Biological Activities, In Silico ADMET, and Molecular Docking Studies

In the pursuit of novel, safe, and biologically active compounds, we report the synthesis of a new series of <i>N</i>-allylaminocyclohex-2-enones <b>3</b>(<b>a-r</b>) via the α-regioselective substitution of Morita-Baylis-Hillman (<b>MBH</b>) adducts. A highly efficient and α-regioselective <i>N</i>-nucleophilic substitution strategy was developed utilizing both primary and secondary cyclic MBH adducts with various aromatic amines. The desired allylated amine derivatives were obtained in good to excellent yields (50-92%) under mild reaction conditions, and their structures were confirmed by spectroscopic analysis. Several compounds exhibited significant free radical scavenging activity, as determined by the <b>DPPH</b> assay. Notably, compounds <b>3a</b>, <b>3b</b>, <b>3c</b>, <b>3d</b>, and <b>3i</b> demonstrated potent antioxidant activity, with IC₅₀ values of 8.06 ± 0.340, 5.13 ± 0.275, 1.91 ± 0.081, 4.31 ± 0.374, and 5.63 ± 0.188 μg/mL, respectively. Antimicrobial screening revealed that most compounds displayed moderate antibacterial and antifungal activities. Compounds <b>3a</b> and <b>3b</b> were particularly active against <i>Salmonella enteritidis</i> (MIC = 31.25 μg/mL), while compound <b>3f</b> showed the highest antifungal efficacy against <i>Aspergillus fumigatus</i> (MIC = 62.5 μg/mL). Density functional theory (<b>DFT</b>) calculations, along with molecular docking studies, provided insights into the biological relevance of these derivatives. Compound <b>3a</b> exhibited a favorable binding affinity (docking score: -5.778 kcal·mol^-1) toward the active site of dihydropteroate synthase (<b>DHPS</b>), engaging in key hydrogen bonding and hydrophobic interactions. In silico <b>ADMET</b> and Ames toxicity analyses indicated promising pharmacokinetic and safety profiles for the majority of the compounds. Except for compound <b>3g</b>, all derivatives were predicted to be nontoxic with respect to tumorigenicity and reproductive toxicity.