Synthesis, Characterization, Molecular Docking and Study biological Activity of some New Heterocyclic Derivatives from a Sulfa Drug

Abstract

A series of novel heterocyclic derivatives were synthesized starting from sulfadiazine via Schiff base intermediates, followed by cyclization to afford five-membered heterocyclic rings including imidazolidine, thiazolidine, and tetrazole derivatives. The synthesized compounds were obtained in good to excellent yields ranging from 74.5% to 97.5%. The structures of the synthesized compounds were confirmed using FT-IR, ¹H NMR, and ¹³C NMR spectroscopy. The disappearance of the azomethine (C=N) stretching band in FT-IR spectra and the absence of the corresponding proton signal in ¹H NMR confirmed the successful cyclization of Schiff bases into the desired heterocyclic systems. Molecular docking studies against dihydropteroate synthase (DHPS) from Escherichia coli (PDB ID: 3SRW) revealed that compound H1 exhibited the lowest binding energy (−8.40 kcal/mol), indicating strong binding affinity within the active site. Interaction analysis showed hydrogen bonding along with van der Waals and hydrophobic (alkyl and π-alkyl) interactions. Compound Z3 also showed favorable binding energy (−7.68 kcal/mol) with key interactions involving amino acid residues such as SER, GLN, TRP, and LEU. Biological evaluation demonstrated that the synthesized compounds exhibited varying antibacterial activity against both Gram-negative (Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria. The inhibition zones ranged from 10 to 28 mm, with compound H4 showing the highest activity (28 mm) compared to Pseudomonas aeruginosa, while compounds Z3, Z4, H3, and H4 exhibited significant activity against Staphylococcus aureus at higher concentration (500 mg/mL). In contrast, compounds Z1 and Z showed no detectable activity. Overall, the results indicate that structural modification of sulfadiazine through heterocyclic ring formation significantly enhances antibacterial activity and binding affinity, suggesting their potential as promising antimicrobial agents.