Chalcogen and <i>Para</i> ‐Substituent Effects on the Electronic, Optical, and Biological Properties of Diaryl Urea Derivatives: A DFT, TD‐DFT, and Molecular Docking Study

ABSTRACT This study presents a comprehensive investigation of the structural, electronic, optical, and nonlinear optical (NLO) properties of unsymmetrical N,N ′‐diaryl‐ N,N ′‐dialkyl derivatives of urea, thiourea, and selenourea, using density functional theory (DFT) and time‐dependent DFT (TD‐DFT) methods. The influence of chalcogen substitution (O, S, Se) and para ‐substituents (–NH 2 , –CH 3 , –Cl, –NO 2 ) was systematically analyzed. Conformational studies reveal a consistent thermodynamic preference for the endo isomers, driven by reduced steric repulsion and favorable π–π stacking, with rotational barriers calculated between 15 and 30 kcal mol − 1 . Electronic structure analysis indicates that urea and thiourea derivatives possess donor–donor–acceptor (DDA) character, while selenoureas adopt donor–acceptor–acceptor (DAA) configurations. HOMO–LUMO energy gaps range from 6.0–8.0 eV, decreasing notably with electron‐withdrawing substituents, particularly –NO 2 . TD‐DFT calculations show dominant π–π* transitions in ureas, while thiourea and selenourea analogs exhibit additional n–π* transitions. First‐order hyperpolarizabilities are significantly enhanced by both the chalcogen atom and para ‐substituents, with NO 2 ‐substituted derivatives exhibiting the strongest NLO responses. Molecular docking against CDK2 kinase and SARS‐CoV‐2 main protease reveals that thiourea and selenourea derivatives bind more strongly than parent urea structures. SwissADME predictions indicate favorable pharmacokinetics, drug‐likeness, and gastrointestinal absorption, especially for halogenated and nitro derivatives, although some nitro compounds flagged potential toxicity. The combined structural and functional analysis highlights how chalcogen identity and para ‐substitution can be effectively employed to tailor the multifunctional properties of these derivatives for therapeutic, NLO, and optoelectronic applications.