The structural diversity of secondary enamines provides an opportunity to examine how substituent variation affects molecular conformation, electronic characteristics, and physicochemical behavior. In this study, four N-cyclohexyl secondary enamine derivatives were investigated using density functional theory at the B3LYP/6-31G level, complemented by SwissADME predictions. The computational investigation encompassed conformational analysis, vibrational frequencies, frontier molecular orbitals, global reactivity descriptors, and Mulliken atomic charges. Among the four optimized structures considered for each derivative, the Chair-Z structure exhibited the lowest calculated Gibbs free energy for all four compounds.  Physicochemical properties, lipophilicity, aqueous solubility, pharmacokinetic profiles, and medicinal chemistry filters were also assessed. The derivatives showed molecular weights of 181.27-243.34 g/mol, topological polar surface areas of 29.10-38.33 Ų, and three to five rotatable bonds. Their consensus Log P values ranged from 2.35 to 3.26, indicating moderate lipophilicity. Compound 3 consistently exhibited the most favorable predicted aqueous solubility, whereas the phenyl-containing compound 2 showed the lowest solubility across the three prediction models. All compounds satisfied Lipinski’s rule of five and were computationally predicted to exhibit high gastrointestinal absorption and potential blood-brain barrier permeation, with no predicted P-glycoprotein substrate behavior. Compound 2 was distinguished by predicted inhibition of CYP1A2, CYP2C19, and CYP2D6. No PAINS alerts were detected, although a shared Michael-acceptor Brenk alert indicated a structural feature requiring further assessment. Mulliken analysis revealed a conserved polarization pattern within the enamine framework, with negatively charged nitrogen atoms and contrasting charges at the selected carbon sites. Overall, the study identifies substitution-dependent differences in predicted molecular behavior and provides a basis for experimental investigations of chemical reactivity, solubility, permeability, and metabolic interactions.