Synthesis, DFT studies, and molecular docking of novel pyrazole semicarbazones targeting GPb, PPA-II, and DPP-4 enzymes

Abstract

Six new phenyl-1 H -pyrazole-carbaldehyde semicarbazone derivatives ( 1 – 6 ) have been synthesized and characterized by FT-IR, NMR ( 1 H and 13 C), and mass spectrometry. NMR analysis indicated that these compounds in DMSO-d 6 exhibit a cisE isomeric form. This evidence is supported by computational calculations performed for all compounds using DFT at the ωB97XD level with the 6-311 + + G(d, p) basis set in both gas and liquid (DMSO) phases, and these results are in agreement with the obtained spectroscopic data. Geometrical parameters, frontier molecular orbital (FMO) analysis and molecular electrostatic potential (MEP) mapping were also carried out at the same level of theory, taking into account the computed Gibbs free energy (ΔG). The MEP descriptors reveal that the oxygen atom of the carbonyl group (C = O) is susceptible to electrophilic attack, whereas the hydrogen atoms of the amide and hydrazone fragments are prone to nucleophilic attack. The calculated HOMO–LUMO gap energies (Eg) indicate that compound 3 (in the liquid phase) and compound 5 (in the gas phase) are the most reactive, while compound 1 is the most stable in both phases. Compounds 1 – 6 exhibited favourable ADMET profiles. In silico predictions revealed that compounds 3–5 with Pa values greater than 0.5, are potential candidates for antiprotozoal, antiviral, and type 2 antidiabetic activities. Furthermore, targeted molecular docking simulations of 3 and 5 against key enzymes involved in carbohydrate metabolism (GPb, PPA-II, and DPP-4) demonstrated favorable binding profiles, with compound 3 exhibiting competitive consensus energy distribution and active-site interaction stability. Therefore, further molecular dynamics simulations as well as in vitro and in vivo biological assessments are required to obtain a deeper understanding of the actual therapeutic potential of the studied compounds.