Methyl β-D-galactopyranoside esters as potential inhibitors for SARS-CoV-2 protease enzyme: synthesis, antimicrobial, PASS, molecular docking, molecular dynamics simulations and quantum computations

Abstract

Carbohydrate esters are significant in medicinal chemistry because of their efficacy for the synthesis of biologically active drugs. In the present study, methyl β-D-galactopyranoside (MGP) was treated with various acyl halides to produce 6- O -acyl MGP esters by direct acylation method with an excellent yield. To obtain newer products for antimicrobial assessment studies, the 6- O -MGP esters were further modified into 2,3,4-tri- O -acyl MGP esters containing a wide variety of functionalities in a single molecular framework. The chemical structures of the newly synthesized compounds were elucidated by analyzing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial testing against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) revealed that these MGP estes have promising antifungal functionality compared to their antibacterial activities. The antimicrobial tests demonstrated that the compounds 3 and 10 were the most potent against Bacillus subtilis and Escherichia coli strains, with the minimum inhibitory concentration (MIC) values ranging from 0.352 ± 0.02 to 0.703 ± 0.01 mg/ml and minimum bactericidal concentration (MBC) values ranging from 0.704 ± 0.02 to 1.408 ± 0.04 mg/ml. Density functional theory (DFT) at the B3LYP/3-21G level of theory was employed to enumerate, frontier orbital energy, enthalpy, free energy, electronic energy, MEP, dipole moment which evaluated the effect of certain groups (aliphatic and aromatic) on drug properties. They discovered that all esters were more thermodynamically stable than the parent molecule. Molecular docking is performed using AutoDock Vina to determine the binding affinities and interactions between the MGP esters and the SARS-CoV-2 main protease. The modified esters strongly interact with the prime Cys145, His41, MET165, GLY143, THR26, and ASN142 residues. The MGP esters’ shape and ability to form multiple electrostatic and hydrogen bonds with the active site match other minor-groove binders’ binding modes. The molecular dynamics simulation validates the molecular docking results. The pharmacokinetic characterization of the optimized inhibitor demonstrates that these MGP esters appear to be safer inhibitors and a combination of in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction and drug-likeness had promising results due to their improved kinetic properties. Structure activity relationships (SAR) study including in vitro and silico results revealed that the acyl chain, palmitoyl (C16) and 4-chlorobenzoyl (4.ClC 6 H 4 CO-) in combination with sugar were found the most potential activates against human and fungal pathogens. After all, our comprehensive computational and statistical analysis shows that these selected MGP esters can be used as potential inhibitors against the SA...

Synthesis, antimicrobial, PASS, SAR, molecular docking, molecular dynamics and pharmacokinetic studies of designed benzylidene derivatives

“…A sixteen-proton multiplet at δ 1.29 {CH 3 (CH 2 ) 8 (CH 2 ) 2 CO-} and three-proton multiplet at δ 0.90 {CH 3 (CH 2 ) 10 CO-} were also seen. These ndings rationalized the appearance of a lauroyl group in the position 2 as depicted by the deshielding of the C-2 proton from its common value (~ 4.00) [29] in the initial diol (2) to δ 4.83 (as dd, J = 3.7 Hz, and 9.7 Hz). The 13 13 C-NMR and mass spectrum led us to con rm the structure of compound (3) as methyl 4,6-O-benzylidine-2-O-lauroyl-α-D-glucopyranoside (Table 1).…”

Deciphering the effects of co-culturing on the metabolite profiles of Ligilactobacillus reuteri ZJ625 and Limosilactobacillus salivarius ZJ614 using untargeted metabolomics

“…The growth of the strains on MDM (MLR, MLS, and MLSLR) also revealed the upregulation in the expression of methyl-galactoside, a beta-Dgalactopyranoside (a monosaccharide derivative) with a methyl substituent at the anomeric position. Methylgalactoside was recently reported to possess potential antimicrobial activities against Bacillus subtilis, Escherichia coli, and in-silico ability to inhibit SAR-CoV-2 by binding proteases 39 . Another study by Amin et al 40 revealed that acylation of beta-D-galactopyranoside with different acyl halides resulted in methyl esters with antifungal, antibacterial and anticancer activities.…”

“…The potential probiotic strains in this study can produce beta-D-galactopyranoside, especially in MDM, which supports their potential for use in precision probiotic therapy if properly harnessed. Additionally, methyl-galactoside was involved in cell-to-cell binding and co-aggregation 39 .…”

Physicochemical, ADMET, and Molecular Dynamics Simulations against Bacillus subtilis HmoB for Antibacterial Potentiality of Methyl 𝜶-D-glucopyranoside Derivatives

“…They are the source of the metabolic energy supply and are also useful for the fine-tuning of cell-cell interactions and other crucial processes (Varki 1993;Seeberger and Werz 2007). It was found from the literature survey that a large number of biologically active compounds also possess aromatic, heteroaromatic, and acyl substituents (Amin et al 2021(Amin et al , 2022Lepenies et al 2010;Rana et al 2020;Bulbul et al 2021a, b;Arifuzzaman et al 2018;Maowa et al 2021a;Alam et al 2021a). The benzene, substituted benzene, and also nitrogen, sulfur, and halogen-containing substituents are known to enhance the biological activity of the parent compound (Rana et al 2021;Farhana et al 2021a;Devi et al 2019;Alam et al 2021b).…”