Design, Synthesis, Antimicrobial, and Antiviral Evaluation of Novel Hydantoin Derivatives: Insights from Molecular Docking Studies

Intermediate 2 was synthesized by stirring hydantoin derivative 1 with carbon disulfide in dry DMF at room temperature, using potassium hydroxide as a catalyst. Alkylation with chloroacetic acid produced the monoalkyl derivative, which was treated with HCl to yield compound 5. Heating compound 5 with ethanolic sodium ethoxide under reflux conditions cyclized it to form 1,3-dithiolane compound 6. Alternatively, 2 was reacted with ethyl bromoacetate under acidic conditions to form 6 through compound 4. Intermediate 2 was then cycloalkylated with dibromoethane to form derivative 3. Mannich bases 7a-d and 8a-d were synthesized by reacting compounds 3 and 6 with formaldehyde and secondary amines. Compound 1 reacted with p-chlorobenzaldehyde in ethanol, catalyzed by triethylamine, to form compound 9, which was then refluxed with hydrazine hydrate to form compound 10. Mannich bases 12a-d were synthesized by reacting compound 10 with formaldehyde and secondary amines. Diazotization of 2-aminothiazole followed by coupling with compound 1 yielded compound 13a, and Mannich bases 14a-d were obtained by reacting compound 13a with formaldehyde and secondary amines. The synthesized compounds were characterized and evaluated biologically for antimicrobial and antiviral activity. Compounds 7a, 8a, 12a, and 14a showed the highest antimicrobial activity. Compounds 8a, 12a, 7a, and 12b exhibited significant antiviral activity, with 8a showing 84% inhibition at 0.25 µM. A molecular docking study revealed binding affinities for compounds 7a, 8a, 12a, and 14a against the PDB: 1U1Z protein, highlighting their potential antibacterial effectiveness.