Design, computational studies, Hirshfeld surface and In-Silico approach of novel pyrazoles and pyrazolines derivatives as promising antidiabetic agents

Novel pyrazole 3a-d, g and pyrazolines derivatives 3e-f were synthesized through nitrile imine-mediated tetrazolene cycloaddition (NITEC) reaction and the reasonable mechanism of the NITEC reaction was discussed using Density Functional Theory (DFT) at B3LYP/6-311+G(d,p) basis set in the gas phase. Additionally, the geometry optimization of the reactants and the products was studied. The calculations of transition-state (TS) and intrinsic reaction coordinate (IRC) analyses were performed at the same level of theory. Fukui functions, electrostatic potential surfaces, HOMO-LUMO, global and local reactivities were computed and discussed in the manuscript. Similarly, Hirshfeld surface analysis (HAS) was used to indicate the intramolecular interactions. Moreover, the band structures were additional evaluated on the hole crystal lattice of both compounds 3a and 3c by partial density of state (PDS) and total density of state (TDOS) utilizing CASTEP software with the Generalized Gradient Approximation (GGA) correlational function and ultra-soft pseudo potential (PBE). The obtained results showed that pyrazole derivatives 3a and 3c had indirect and direct band gaps with a magnitude of 2.452 eV and 3.339 eV respectively. Additionally, the molecular docking of the pyrazole and pyrazolines derivatives were deliberate against different proteins to investigate the efficacy against selected drug targets of antidiabetic disease. Molecular docking was conducted for the pyrazole and pyrazoline derivatives against human lysosomal acid α-glucosidase (HLGAA) proteins with PDB IDs: 5NN5, 5NN6, and 5NN8. The docking results revealed that the selected pyrazole and pyrazoline derivatives exhibited significant binding affinities, ranging from –7.0 to –10.2 kcal/mol. Among them, compounds 3d and 3g displayed the strongest binding to all the target proteins, indicating their potential as promising antidiabetic agents due to their remarkably low binding energies.