Efficient Antibacterial/Antifungal Activities: Synthesis, Molecular Docking, Molecular Dynamics, Pharmacokinetic, and Binding Free Energy of Galactopyranoside Derivatives

Abstract

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.

Bioassay-Guided Alkaloids Isolation from Camellia sinensis and Colchicum luteum: In Silico and In Vitro Evaluations for Protease Inhibition

“…These may be utilized to detect physicochemical connections at the molecular level. Furthermore, the molecular electrostatic potentials along with other findings can be used to judge the chemical approachability of a new therapeutic agent to any electrophilic as well as nucleophilic attacks [ 39 ]. The red color shown on the surface of the molecule is due to the high electron density, and here any electrophilic moiety can be attached.…”

Design, Synthesis, In Silico and POM Studies for the Identification of the Pharmacophore Sites of Benzylidene Derivatives

“…These rules are defined as follows: 160 ≤ MW ≤ 480, −0.4 ≤ WLogP ≤ 5.6, 40 ≤ MR ≤ 130 and 20 ≤ atoms ≤ 70. The TPSA value is an indicator of the substance ease of use by the body [ 42 ]. Molecules with a TPSA greater than 140 Å 2 are believed to have a low capacity for penetrating cell membranes, while those with TPSA ≤ 60 Å 2 are easily absorbed [ 56 ] ( Figure S12 ).…”

“…Density functional theory (DFT) calculations were performed to study the derivatives’ electronic behaviors and geometrical structures. The chemical reactivity indicators, such as HOMO, LUMO and gap energies were also evaluated [ 41 , 42 ]. Molecular docking studies performed on pathogenic fungal and bacterial proteins have helped to obtain more information about the biological applications of synthesized molecules [ 43 , 44 ].…”

Antimicrobial Activity and Molecular Docking Studies of the Biotransformation of Diterpene Acanthoic Acid Using the Fungus Xylaria sp.

“…To obtain a better understanding of the mechanism by which S1 exhibited superior inhibition against E. coli , in silico enzymatic evaluation assays were developed using molecular docking studies. This molecular docking technique was highly useful in determining the binding affinity of drug molecules to the biological target [ 41 ]. In this case, the docking simulations evaluated the binding patterns of diterpenoids at the active sites of proteins 6G9S (PBP2), 4DUH (GyrB), 4HZ0 (Topo IV), and 4A7G (SOD1).…”