Synthesis, Antimicrobial, Anti-Inflammatory, Antioxidant Activities, Molecular Docking, and Dynamic Simulations with Lanosterol 14α-Demethylase of Propionyl Glucopyranoside Derivatives

Objective: Carbohydrate derivatives have attracted significant attention due to their broad applications in various industrial and biomedical fields. Methods: In this study, selective propionylation of methyl α-D-glucopyranoside (MDGP, I) was carried out, leading to the synthesis of a series of 2,3,4-tri-O-acyl derivatives (III–VII) from the 6-O-glucopyranoside precursor. The structures of the MDGP derivatives were confirmed by physicochemical characterization, elemental analysis, and spectral data. In vitro antimicrobial assays, along with the Prediction of Activity Spectra for Substances (PASS), indicated promising antifungal activity of these derivatives, which was more pronounced than their antibacterial activity. Results and Discussion: The compounds also exhibited notable antioxidant activity in the DPPH free radical-scavenging assay, surpassing that of the standard antioxidant. Anti-inflammatory properties were evaluated using protein denaturation assays. Supporting these findings, molecular docking studies were performed with lanosterol 14α-demethylase (CYP51A1), revealing significant binding affinities and non-covalent interactions, thereby corroborating the experimental data. The compounds met drug-likeness criteria and demonstrated favorable pharmacokinetic profiles in silico. Notably, compounds (III) and (V) exhibited binding affinities of −10.2 and −10.6 kcal/mol, respectively. During 100 ns molecular dynamics (MD) simulations, the RMSD, RMSF, radius of gyration, and solvent-accessible surface area (SASA) values remained within acceptable ranges. These compounds also formed a greater number of hydrogen bonds. Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) analyses of the 3-3LD6 and 5-3LD6 complexes showed that van der Waals, electrostatic, polar solvation, and SASA energy contributions positively influenced the binding free energies. Conclusions: Structure–activity relationship (SAR) analysis, together with in vitro and in silico studies, suggests that MDGP derivatives possess enhanced therapeutic potential and represent promising candidates for the development of new antimicrobial agents.