In Silico designing of piperazine-sulfathiazole derivatives: A computational approach for novel anti-microbial agents

Background Antimicrobial Resistance (AMR) poses a significant threat to global public health, increasing mortality, morbidity, and economic burdens. Among the pathogens contributing to this crisis, Staphylococcus aureus , particularly Methicillin-Resistant S. aureus (MRSA) and Vancomycin-Resistant S. aureus (VRSA), stands out due to its ability to evade multiple antibiotic treatments. In response to this challenge, heterocyclic compounds such as Piperazine and Sulfathiazole have emerged as promising candidates. These compounds exhibit broad-spectrum antibacterial activities, which can potentially overcome the resistance mechanisms employed by MRSA and VRSA, offering a hopeful avenue for combating AMR effectively. Objective This study used Molecular Docking techniques to design and evaluate novel Piperazine-Sulfathiazole derivatives for their antibacterial potential against S. aureus . Methods Molecular Docking studies were performed using AutoDock Vina 4.2, targeting the bacterial receptor protein Dihydrofolate Reductase (DHFR) with PDB ID: 2W9H. Docking scores and binding interactions were analyzed to assess the affinity of the designed derivatives. Furthermore, drug-likeness was evaluated based on Lipinski’s Rule of Five and ADME (Absorption, Distribution, Metabolism, and Excretion) properties using the Swiss ADME web server, and toxicity has also been evaluated through the inhibition profile of the P450 enzyme. Results and conclusion Among the tested derivatives, A1, A10, A11, and A21 demonstrated superior binding affinities with docking scores exceeding the standard drug Ciprofloxacin (-9.5 kcal/mol). Particularly, A1 exhibited the strongest binding (-10.6 kcal/mol) through robust hydrogen bonding with key amino acid residues. ADME analysis confirmed favorable drug-like properties without Lipinski’s rule violations, indicating the potential of these derivatives as effective antibacterial agents.