1,3,4-oxadiazole derivatives: synthesis, characterization, antimicrobial potential, and computational studies

Abstract

We report the synthesis and biological assessment of 1,3,4-oxadiazole substituted 24 derivatives as novel, potential antibacterial agents. The structures of the newly synthesized derivatives were established by the combined practice of UV, IR, (1)H NMR, (13)C NMR, and mass spectrometry. Further these synthesized derivatives were subjected to antibacterial activity against all the selected microbial strains in comparison with amoxicillin and cefixime. The antibacterial activity of synthesized derivatives was correlated with their physicochemical and structural properties by QSAR analysis using computer assisted multiple regression analysis and four sound predictive models were generated with good R(2), R(adj)(2), and Fischer statistic. The derivatives with potent antibacterial activity were subjected to molecular docking studies to investigate the interactions between the active derivatives and amino acid residues existing in the active site of peptide deformylase to assess their antibacterial potential as peptide deformylase inhibitor.

Figure 1

Synthetic scheme of 1-(4-methoxy-phenyl)-3-[5-(substituted phenyl)-1,3,4-oxadiazol-2-yl]propan-1-one (6a–h).

Figure 2

Synthetic scheme of [2-(5-substituted-phenyl-[1,3,4]oxadiazol-2-yl)-phenyl]phenyl-methanone (13a–h).

Figure 3

Minimum inhibitory concentrations (MIC) of synthesized 1,3,4-oxadiazole derivatives and standard drugs against gram negative bacterial strains.

Figure 4

Minimum inhibitory concentrations (MIC) of synthesized 1,3,4-oxadiazole derivatives and standard drugs against gram positive bacterial strains.

Figure 5

Plot of calculated pMIC₅₀ values against observed pMIC₅₀ for QSAR model for (a) Escherichia coli (b), Pseudomonas aeruginosa (c), Staphylococcus aureus, and (d) Staphylococcus epidermidis.

Figure 6

Binding modes of 6e and 6f (6e, 6f as docking view and 6 e′, 6 f′ as interaction view) with peptide deformylase, where blue/green lines and red lines represent hydrogen bonding and favourable steric interactions, respectively.

Figure 7

Binding modes of 8e, 8f and 8h (8e, 8f and 8h as docking views; 8 e′, 8 f′, and 8 h′ as interaction views) with peptide deformylase, where blue/green lines and red lines represent hydrogen bonding and favourable steric interactions, respectively.

Figure 8

Binding modes of 13b, 13c, 13e and 13g (13b, 13c, 13e and 13g as docking views; 13 b′, 13 c′, 13 e′ and 13 g′ as interaction views) with peptide deformylase, where blue/green lines and red lines represent hydrogen bonding and favourable steric interactions, respectively.

Figure 9

Binding modes of amoxicillin and cefixime (amoxicillin and cefixime as docking views; amoxicillin' and cefixime' as interaction views) with peptide deformylase, where blue/green lines and red lines represent hydrogen bonding and favourable steric interactions, respectively.