Galactopyranoside derivatives as potential antimicrobial agents: Synthesis, biological evaluation, molecular docking with MurF and ALS3, molecular dynamics simulations and ADMET analysis

ABSTRACT Carbohydrate derivatives play a pivotal role in pharmaceutical chemistry as valuable scaffolds for the development of bioactive compounds. A unique series of p -tolyl-β-D-galactopyranoside derivatives was prepared via direct acylation of methyl β-D-galactopyranoside ( 1 , MβDG), followed by the conversion into tri-substituted derivatives using various acyl halides in excellent yields. The structures and conformations of the synthesized derivatives were characterized by FTIR, 1 H-NMR, and 13 C-NMR spectroscopy. Derivatives 7 and 9 showed moderate antibacterial activity, with MICs of 0.25–16.0 μg/mL and MBCs of 8.0–128.0 μg/mL against Salmonella typhi and Klebsiella pneumoniae , respectively. Among these derivatives, compound 7 strongly inhibited the mycelial growth of both Aspergillus niger (82.50%) and Candida albicans (75.92%). Compound 6 showed antibiofilm activity against Escherichia coli , and compounds 8 (IC 50 = 3735.85 μg/mL) and 9 (IC 50 = 7485.27 μg/mL) had anticancer activity against Ehrlich ascites carcinoma (EAC) cells. Compounds 4 (73.43%) and 7 (71.54%) presented the highest anti-inflammatory activity. The antioxidant activity was displayed by compounds 8 (36.0%) and 2 (33.0%). Molecular docking is executed to describe the binding affinities and interactions between the MβDG derivatives and the enzyme (MurF) and ALS3 protein. The binding affinities of derivatives 8 and 9 toward MurF were −9.2 and −9.0 kcal/mol, respectively, while those of derivatives 6 and 8 toward ALS3 were −9.3 and −9.1 kcal/mol, respectively. The improved derivatives strongly interact with different protein residues. The docked complexes underwent MD simulations to assess their stability. Structure–activity relationship (SAR) analysis revealed that the incorporation of {3-Cl.C 6 H 4 .CO-} > {2-Cl.C 6 H 4 . CO-} > {3,5-(NO 2 ) 2 C 6 H 3 CO-} substituents on the galactose moiety or galactopyranoside skeleton moiety progressively enhanced the antimicrobial activity. The extrapolation of ADMET and its medicinal attributes showed substantial outcomes because of favorable kinetic properties. These MβDG derivatives may serve as moderate inhibitors against various microorganisms and as prospective drug candidates for future development.