Synthesis, crystal structure, spectroscopic, antidiabetic, antioxidant and computational investigations of Ethyl 5-hydroxy-1-isonicotinoyl-3-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate

Abstract In this work, a novel pyrazole derivative, ethyl 5-hydroxy-1-isonicotinoyl-3-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate (EIMPC) has been synthesized by condensation of ethyl 2,4-dioxopentanoate with isoniazid. Its molecular structure was characterized by FT-IR, 1H-NMR, 13C-NMR and ESI-MS spectroscopies and by single crystal X-ray diffraction (XRD). The experimental structure shows the presence of both enantiomeric forms and of a most stable C2 conformer while the optimized theoretical structures in gas phase and aqueous solution by functional hybrid B3LYP/6-311++G** level of theory evidence two stable C1 and C2 conformers. Both differ in the position of side chains containing the carboxylate groups. Higher repulsions between the most electronegative O atoms of side chains together with the higher volume and low dipole moment value probably justify why C1 cannot exist in the solid phase. Hydrations of acceptors and donors groups of C2 by water molecules could explain the shifting of bands assigned to those groups toward lower wavenumbers and, also, its higher solvation energy. Frontier orbitals studies support the higher reactivity of C2 in both media, as compared with C1. Comparisons between theoretical and experimental IR and NMR spectra show good correlations among them. 1H and 13C NMR chemical shifts predicted for both forms of (EIMPC) in aqueous solution suggest that C1 could also be present in this medium, as suggested by NBO and AIM calculations. 3D Hirshfeld surface and 2D fingerprint plot are carried to define the contribution of non-covalent interactions in EIMPC crystal. EIMPC was also evaluated in vitro for their α-glucosidase and α-amylase inhibition, and antioxidant activities. Thus, molecular docking analyses of the title compound were performed within the active site of α-glucosidase (PDB ID: 4XP0 ), α-amylase (PDB ID: 2QPU ), oxidase (PDB ID: 6I95 ) to analyse the binding conformation and interactions responsible for their activities.