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Synthesis, Antimicrobial, Anticancer, PASS, Molecular Docking, Molecular Dynamic Simulations & Pharmacokinetic Predictions of Some Methyl β-D-Galactopyranoside Analogs.

ABSTRACT: A series of methyl β-D-galactopyranoside (MGP, 1) analogs were selectively acylated with cinnamoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to yield 6-O-substitution products, which was subsequently converted into 2,3,4-tri-O-acyl analogs with different acyl halides. Analysis of the physicochemical, elemental, and spectroscopic data of these analogs revealed their chemical structures. In vitro antimicrobial testing against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) showed promising antifungal functionality comparing to their antibacterial activities. Minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) tests were conducted for four compounds (4, 5, 6, and 9) based on their activity. MTT assay showed low antiproliferative activity of compound 9 against Ehrlich's ascites carcinoma (EAC) cells with an IC₅₀ value of 2961.06 µg/mL. Density functional theory (DFT) was used to calculate the thermodynamic and physicochemical properties whereas molecular docking identified potential inhibitors of the SARS-CoV-2 main protease (6Y84). A 150-ns molecular dynamics simulation study revealed the stable conformation and binding patterns in a stimulating environment. In-silico ADMET study suggested all the designed molecules to be non-carcinogenic, with low aquatic and non-aquatic toxicity. In summary, all these antimicrobial, anticancer and in silico studies revealed that newly synthesized MGP analogs possess promising antiviral activity, to serve as a therapeutic target for COVID-19.

SUBMITTER: Amin MR

PROVIDER: S-EPMC8621697 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.ClC6H4CO-) 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 SARS-CoV-2.

Project description:The chemistry and biochemistry of carbohydrate esters are essential parts of biochemical and medicinal research. A group of methyl β-d-galactopyranoside (β-MGP, 1) derivatives was acylated with 3-bromobenzoyl chloride and 4-bromobenzoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to obtain 6-O-substitution products, which were subsequently converted into 2,3,4-tri-O-acyl derivatives with different aliphatic and aromatic substituents. Spectroscopic and elemental data exploration of these derivatives confirmed their chemical structures. In vitro biological experiments against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) revealed ascending antifungal and antibacterial activities compared with their antiviral activities. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) experiments were performed for two derivatives, 3 and 9, based on their antibacterial activities. Most of these derivatives showed >780% inhibition of fungal mycelial growth. Density functional theory (DFT) was used to calculate the chemical descriptors and thermodynamic properties, whereas molecular docking was performed against antibacterial drug targets, including PDB: 4QDI, 5A5E, 7D27, 1ZJI, 3K8E, and 2MRW, and antifungal drug targets, such as PDB: 1EA1 and 1AI9, to identify potential drug candidates for microbial pathogens. A 100 ns molecular dynamics simulation study revealed stable conformation and binding patterns in a stimulating environment by their uniform RMSD, RMSF, SASA, H-bond, and RoG profiles. In silico pharmacokinetic and quantitative structure−activity relationship (QSAR) calculations (pIC50 values 3.67~8.15) suggested that all the designed β-MGP derivatives exhibited promising results due to their improved kinetic properties with low aquatic and non-aquatic toxicities. These biological, structure−activity relationship (SAR) [lauroyl-(CH3(CH2)10CO-) group was found to have potential], and in silico computational studies revealed that the newly synthesized MGP derivatives are potential antibacterial/antifungal candidates and can serve as therapeutic targets for human and plant pathogens.

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Synthesis, Antimicrobial, Anticancer, PASS, Molecular Docking, Molecular Dynamic Simulations & Pharmacokinetic Predictions of Some Methyl β-D-Galactopyranoside Analogs.

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