Synthesis, antimicrobial evaluation, and molecular docking studies of Mannich base analogs derived from 2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione scaffold

A series of novel trans-3-substituted aminomethyl-5-(4-(4-chlorophenyl)cyclohexyl)-1,3,4-oxadiazole-2(3 H )-thiones was synthesized successfully from achiral trans-4-(4-chlorophenyl)cyclohexane-1-carboxylic acid. To investigate their potential binding interactions with proteins at the active site, molecular docking studies were conducted using CDOCKER module (Biovia Discovery Studio 2022) against Penicillin Binding Protein 2 of Escherichia coli (PDB: 6G9F) and Pseudomonas aeruginosa (PDB: 7KIS). The results of the docking studies indicate that the compounds exhibit limited binding efficacy. Molecular Dynamics simulations were carried out for Ceftazidime to predict the ligand binding status in the physiological environment. The antibacterial in-vitro inhibitory potential was evaluated against a panel of microorganisms consisting of two Gram-positive bacterial strains, Bacillus subtilis (ATCC6633) and Staphylococcus aureus (ATCC6538), as well as three Gram-negative bacterial strains, Pseudomonas aeruginosa (ATCC9027), Escherichia coli (ATCC8739), and Salmonella typhi (ATCC9207). The N-Mannich bases displayed promising antibacterial activity against both the Gram-positive microorganisms and demonstrated effective inhibition of Escherichia coli . However, their activity against Pseudomonas aeruginosa was moderate. The binding affinity to Penicillin Binding Proteins was evaluated by observing morphological changes in Escherichia coli rods under an optical microscope. The results revealed a notable decrease in cell count without observable morphological changes, indicating that the N-Mannich bases do not bind strongly to Penicillin Binding Proteins and likely operate through an alternative mechanism. The antifungal activity against Saccharomyces cerevisiae (ATCC9763) and Aspergillus niger (ATCC16404) was not observed. Graphical abstract