Synthesis, Molecular Docking Study, and Molecular Dynamics Simulation of New 1,3-Dimethyl-5-methylidenebarbituric Acid Derivatives Prepared by Cyclobutane Cleavage

Various organic derivatives of 1,3-dimethylbarbituric acid attract widespread interest as biologically active compounds, medicinal agents, and precursors in organic synthesis. The chemical reactivity of the cyclobutane moiety in 1,3-dimethyl-5-methylidenebarbituric acid dimer ( 2 ) was examined at room temperature toward various primary aliphatic amines (benzylamine, 4-methoxybenzylamine, and 3-fluorobenzylamine) and hydroxide ion, as well as in acidic medium. New compounds were prepared by ring-opening of the cyclobutane moiety via nucleophile attack on the exocyclic methylene group. The structures of the synthesized compounds were elucidated by employing 1 H and 13 C NMR (including DEPT) and mass spectrometric techniques. Molecular docking revealed a high binding affinity (–9.0 kcal/mol) of one of the obtained compounds ( 6 ). In addition, the molecular dynamics simulation and binding free energy calculation data confirmed that compound 6 is the most stable among the others.