Metal-Free Catalytic Synthesis of N‑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 N-allylaminocyclohex-2-enones 3(a-r) via the α-regioselective substitution of Morita-Baylis-Hillman (MBH) adducts. A highly efficient and α-regioselective N-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 DPPH assay. Notably, compounds 3a, 3b, 3c, 3d, and 3i 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 3a and 3b were particularly active against Salmonella enteritidis (MIC = 31.25 μg/mL), while compound 3f showed the highest antifungal efficacy against Aspergillus fumigatus (MIC = 62.5 μg/mL). Density functional theory (DFT) calculations, along with molecular docking studies, provided insights into the biological relevance of these derivatives. Compound 3a exhibited a favorable binding affinity (docking score: -5.778 kcal·mol-1) toward the active site of dihydropteroate synthase (DHPS), engaging in key hydrogen bonding and hydrophobic interactions. In silico ADMET and Ames toxicity analyses indicated promising pharmacokinetic and safety profiles for the majority of the compounds. Except for compound 3g, all derivatives were predicted to be nontoxic with respect to tumorigenicity and reproductive toxicity.