Synthesis and spectroscopic study of three new oxadiazole derivatives with detailed computational evaluation of their reactivity and pharmaceutical potential

Abstract

© 2018 Elsevier B.V. Local reactivity properties and potential for application in new pharmaceutical compounds have been addressed for the three newly synthetized oxadiazole derivatives (2-(5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (ORTHONITRO), 2-(5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (METANITRO) and 2-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (PARANITRO), by application of computational molecular modeling. Within the framework of density functional theory (DFT) this study encompassed calculations of molecular electrostatic potential (MEP), average local ionization energies (ALIE) and bond dissociation energies for hydrogen abstraction (H-BDE). MD simulations have been used in order to assess the influence of water and to identify the atoms of these molecules with preference towards the interaction with water molecules. Molecular docking procedure has been applied in order to check the binding activity of these derivatives against the Glucan endo-1.6-beta-glucosidase inhibitor, Acrocylindropepsin inhibitor and Chymosin inhibitor proteins. The pharmaceutical potential of these derivatives has been assessed by the calculations of the well-established drug likeness parameters. A strong out-of-plane CH mode of the phenyl rings are observed at 769 cm −1 for ORTHONITRO, 768 cm −1 for METANITRO and at 848 cm −1 for PARANITRO in the IR spectrum as expected for substituted benzenes. The VCD signals, corresponding to C[dbnd]N and NO 2 modes of the title compounds are good markers for assigning of absolute configuration. In the title compounds, in ORTHONITRO, the oxadiazole ring is tilted from the phenyl and pyrazine ring while for METANITRO and PARANITRO, there is a planar orientation. The first hyperpolariazabilities of ORTHONITRO, METANITRO and PARANITRO are respectively, 34.83, 54.50 and 174.05 times that of urea. For all the compounds, HOMO is delocalized over the pyrazine and oxadiazole rings, while LUMO is delocalized over whole molecule, except pyrazine ring of ORTHONITRO, over phenyl ring and NO 2 group of METANITRO and in the entire molecule of PARANITRO. The title compounds are docked with the proteins, Glucan endo-1.6-beta-glucosidase inhibitor, Acrocylindropepsin inhibitor and Chymosin inhibitor and METANITRO exhibits more inhibitory activity against the receptors than the other ligands. The results obtained from anti-TB activity are more promising as the compounds were found to be more potent than reference standard, ORTHONITRO (MIC = 1.6 μg/ml), METANITRO (MIC = 0.8 μg/ml), PARANITRO (MIC = 1.6 μg/ml), streptomycin (MIC = 6.2 μg/ml) and pyrazinamide (MIC = 3.1 μg/ml).