Design, Synthesis, and Molecular Modeling Study of Substituted 1, 3, 4-Thiadiazoles as Antibacterial Agents

ABSTRACTThe present study reports the design, synthesis, and molecular modeling of substituted 1,3,4-thiadiazoles as potential antibacterial agents. The heterocyclic 1,3,4-thiadiazole nucleus was selected for its well-documented pharmacological versatility. A series of novel derivatives were synthesized, employing microwave-assisted synthesis to reduce reaction time and improve yields. Structural characterization was performed using IR, ^1H-NMR, ^13C-NMR, and mass spectrometry, confirming the expected functionalities, including thiadiazole core signals and characteristic substituent peaks. Molecular docking studies were conducted to predict the binding affinity of the synthesized compounds toward bacterial target proteins, with compounds 5(a) and 5(d) showing the highest docking scores and favorable interaction profiles. In vitro antibacterial evaluation using the disc diffusion method demonstrated significant activity against both Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) strains, with MIC values ranging between 15–38 μg/mL. Ciprofloxacin served as the reference drug. The results indicate that the presence of a 4-substituted phenyl group linked via thioster/amide to the thiadiazole ring enhances antibacterial activity. This study suggests that the synthesized molecules have promising antibacterial potential, supported by both computational and experimental findings. Further investigations into their mechanism of action and potential structural optimizations are warranted to develop more potent derivatives. Keywords: 1,3,4-Thiadiazole, Antibacterial agents, Molecular docking, Heterocyclic compounds, Microwave-assisted synthesis