N-alkylated 5,5-diphenylhydantoin Derivatives: Synthesis, X-ray, Spectroscopic Characterization, Hirshfeld Surface Analysis, DFT, Molecular Docking, Molecular Dynamics Simulations, and Cholesterol Oxidase Inhibitory Estimation

Nine N-alkylated phenytoin derivatives (5-13) have been synthesized and characterized using spectroscopic tools with the structures of 4-6 confirmed by X-ray crystallography. The starting material, phenytoin 2, was obtained by a base-catalyzed condensation from benzyl and urea. Its alkylation with benzyl chloride yields 3 and 4. Subsequently, the alkylation of 3 with various alkyl halides under solid-liquid phase transfer catalysis (PTC) led to the formation of 5-13. The intercontacts in 4-6 crystals are identified by analyzing their corresponding Hirshfeld surfaces and fingerprint plots, and the HS analysis reveals that the most intercontacts involved H…H interactions. DFT calculations relatively well reproduce X-ray geometrical parameters in IEF-PCM at the B3LYP/6-3111++G(d,p) level of theory. The calculated electronic and molecular properties demonstrate that the N-alkylation of 5-6 may have slight effects on the calculated, and that reactivity is relatively similar. The inhibitory potency of 4-6 towards cholesterol oxidase (ChOx) is estimated by investigating their binding affinity into the binding site of binding cholesterol oxidase. The compound 4 with N-benzyl moiety displays higher binding affinity than 5 and 6 with N-methyl and N-ethyl moieties. Additionally, the stability of 4 in the binding site ChOx was evaluated and an 80 ns MD simulation was conducted. MD analysis shows that the 4-ChOx complex remained stable throughout the simulation, showing minimal conformational changes, which confirms the stability of 4 in the ChOx binding site.