Synthesis, antimicrobial activity, molecular docking, molecular dynamics simulation, and ADMET properties of the mannopyranoside derivatives as antimicrobial agents

Abstract

Multiple diseases are treated with carbohydrate-based medicinal products worldwide. Direct regioselective acylation of methyl α-D-mannopyranoside (MDMP) derivatives 2-6 afforded from the 6-O-butyryl derivative. This isolated 6-O-derivative was converted to 2,3,4-tri-O-acyl derivatives, and the resulting compounds were analyzed using FTIR, 1H-NMR, 13C-NMR, and elemental analysis. The acylated derivatives showed moderate to good antimicrobial activity. Cytotoxicity assessment indicated that compound 2 had the lowest toxicity. A SAR study demonstrated that lauroyl and myristoyl acyl chains combined with mannopyranose were particularly effective against bacteria. In this context, molecular docking analysis demonstrated crucial interactions involved in assessing the binding affinity of ligands 1-6 for the active sites of Escherichia coli (4XO8) and Aspergillus flavus (1R51). A 100-ns molecular dynamics simulation showed that all the compounds were stable at the active site of protein 1R51. In silico ADMET prediction revealed greater drug similarity for MDMP derivatives. The results of this investigation may help create MDMP derivative-based multidrug-resistant antimicrobial agents. Highlights: Methyl α-D-mannopyranoside (MDMP) derivatives were designed, and synthesized, and their structures were ascertained via spectral analyses. MDMPs were assessed in vitro to identify potential antibacterial or antifungal potential antimicrobial candidate(s) against human and plant organisms. Molecular docking results revealed significant interactions between compounds 1-6 and the active sites of Escherichia coli (4XO8) and Aspergillus flavus (1R51). A 100 ns molecular dynamic simulation demonstrated that the docked ligand–receptor complex had better dynamic stability, as determined through the RMSD, RMSF, SASA, and Rg profiles. ADMET prediction revealed an improved drug-likeness profile for all MDMP derivatives.