Acylated glucopyranosides: FTIR, NMR, FMO, MEP, molecular docking, dynamics simulation, ADMET and antimicrobial activity against bacterial and fungal pathogens

Carbohydrates, among the most abundant and widespread biomolecules in nature, play indispensable roles in diverse biological functions and represent a treasure trove of untapped potential for pharmaceutical applications. From this perspective, the present study was designed to explore and evaluate the synthesis and spectral characterization of methyl α-D-glucopyranoside derivatives 2-6 with different aliphatic groups through comprehensive in vitro antimicrobial screening, physicochemical analysis, molecular docking and molecular dynamics analysis, and pharmacokinetic prediction. The unimolar one-step propionylation of methyl α-D-glucopyranoside under controlled conditions furnished 6-O-propionyl derivative 2 and the development of glucoopyranoside-based potential antimicrobial derivatives, which were further converted into four newer 2,3,4-tri-O-glucopyranoside derivatives (3-6) in reasonably good yields. The chemical structures of the newly synthesized analogs were ascertained by analyzing their physicochemical, elemental, FTIR, and NMR spectroscopic data. In vitro antimicrobial tests against five bacteria and two fungi indicated the promising antibacterial functionality of these synthesized analogs compared with their antifungal activity. Structure-activity relationship (SAR) analysis indicated that adding lauroyl> stearoyl > palmitoyl groups to the ribose moiety increased the potency against bacterial and fungal strains. In support of this observation, molecular docking experiments were performed on the 3TI6 H1N1 receptor and the 6VMZ H5N1 receptor. Molecular interactions with solvents were investigated in terms of FMO, HOMO-LUMO, and MEP properties. In addition, a 100 ns molecular dynamics simulation process was performed to monitor the behavior of the complex structure formed by the receptor 6VMZ under in silico physiological conditions to examine its stability over time, which revealed a stable conformation and binding pattern in a stimulating environment of methyl α-D-glucopyranoside derivatives. Pharmacokinetic predictions were investigated to evaluate their absorption, distribution, metabolism and toxic properties, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico.