Design, Synthesis and Molecular Docking of some Oxazolidinone Compounds


A series of oxazolidinone compounds have been obtained and characterized by physico-chemical methods and antimicrobial activity against Staphylococcus Aureus ATCC 6538. For the synthesized compounds have been performed calculations of characteristics and molecular properties, using Spartan 14 Software from Wavefunction, Inc. Irvine, CA. and molecular docking studies using CLC Drug Discovery Workbench 2.4 software, to identify and visualize the most likely interaction ligand (oxazolidinone derivatives) with the receptor protein.



Experimental part
Melting points were determined in opened capillary on Melting point apparatus OptiMelt and are uncorrected. Progress of the reaction was followed by TLG on Merck silica gel 60F 254 plates eluted with the solvent system: tetrahydrofuran:dioxan: ammoniac (60:20:30) (v:v:v). 1 Hand 13 C-NMR spectra were recorded in CDCl 3 , DMSO-d 6 and trifluoroacetic acid, on two instruments Varian, Varian Gemini 300 BB (operating at 300 MHz for proton and 75 MHz for carbon) and UNITY 400 Plus(operating at 400 MHz for proton and 100 MHz for carbon).Tetramerthylsilane as internal standard was the reference for the chemical shifts. All chemical shifts are given in the delta scale (ppm vs internal TMS). FT IR was recorded on an instrument Bruker Vertex 70 with diamond optic. UV-Vis was recorded on an instrument UV -Vis LAMBDA 12. Elemental analysis was Synthesis of 1-(2-fluoro-4-nitrophenyl)-3-methyl-piperidine A solution of 0.03 Mol (5 g) 3,4-difluoronitrobenzene in 50 mL methanol, was treated with 0.075 mol (7.15 g) 3methyl-piperidine, followed by stirring 5 h at 50 0 . The solution was cooled to room temperature and concentrated in vacuum. The residue was dissolved in 50 mL ethyl acetate and extracted with 2 x 50 mL water and 50 mL saturated sodium chloride solution followed by drying on sodium sulfate. The solution was concentrated in vacuum to afford an brown oil which was chromatographed over 200 g silica gel and eluting with toluene-ethyl acetate : 1:1 (v:v) to yield 6.43 g 1-(2-fluoro-4-nitrophenyl)-3-methyl-piperidine (oil, yield. 90%). 1   Synthesis of 3-fluoro-4-(3-methyl-piperidinyl)-aniline A solution of 0.03 Mol (7.12 g) 1-(2-fluoro-4-nitrophenyl)-3-methyl-piperidine in 100 mL acetone, was treated with 0.09 mol (5.7 g) ammonium formate (6.53 g) and 0.0712 g Pd/C followed by stirring 6 h at 50 0 . The solution was cooled to room temperature and was filtered. The filtrate was concentrated in vacuo. The residue was dissolved in 50 mL ethyl acetate and extracted with 2 x 50 mL water and 50 mL saturated sodium chloride solution followed by drying on sodium sulfate. The solution was concentrated in vacuum to afford an brown oil which was chromatographed over 200 g silica gel and eluting with toluene-ethyl acetate: 3:1 (v:v) to yield 5 g 3-fluoro-4-(3methyl-piperidinyl)-aniline (oil, yield. 80%). 1  To a mixture of 0.027 mol (5.32 g) 3-fluoro-4-(3-methylpiperidinyl)-aniline, 0.065 mol (5.4 g) sodium bicarbonate in 100 mL acetone and 50 mL water cooled at 5 0 C was added drop wise for 20-30 min., 0.033 mol (5.63 g) benzyl chloroformate, while maintaining the temperature between 5 and 10 0 C, and then allowed to stir at room temperature 4 h. The mixture was poured over 500 g ice and 100 mL of water. The mixture was filtered, and the solids were washed with water, and then dried to give 8. pharmacologically. All compounds exhibit moderate activity from Staphylococcus aureus, MIC > 64µg/mL.
Ligand preparation: The ligands have been prepared using SPARTAN'14 software package [10]. In this study, the DFT/B3LYP/6-31 G * level of basis set has been used for the computation of molecular structure, vibrational frequencies and energies of optimized structures ( fig. 2-5). In order to perform structure-activity relationship (SAR) studies, some electronic properties (  Compounds molecular properties Molecular Docking :The steps to go through to explore protein-ligand interaction using docking, are: setup the binding site in a Molecule Project, dock ligands imported to a Molecule Table, inspect the docking results.The docking studies have been carried out using CLC Drug Discovery Workbench Software. The score and hydrogen bonds formed with the amino acids from group interaction atoms are used to predict the binding modes, the binding affinities and the orientation of the docked compounds ( fig. 6) in the active site of the protein-receptor (table 2). It was realized molecular docking studies in order to to identify and visualize the most likely interaction, the binding affinities and the orientation of the docked ligands at the active site of Staphylococcus aureus ribosomal subunit (PDB ID: 4WFA) [11].

Docking method validation
The ensure that the ligand orientations and position obtained from the molecular docking studies are valid and reasonable potential binding modes of ligands, the docking methods and parameters used have been validated by redocking ( fig. 7).

Calculate molecular properties
Using the Calculate Molecular Properties tool it have been calculated commonly used properties of small molecules, such as Lipinski's rule of five [12]: number of hydrogen bond donors less than 5 (the total number of nitrogen-hydrogen and oxygen-hydrogen bonds), number of hydrogen bond acceptors less than 10 (the total number of nitrogen and oxygen atoms), the molecular weight less than 500 Daltons; Log P (octanol-water partition coefficient) less than 5. The calculation of the log P is based on the XLOGP3-AA method [13].The number of violations of the Lipinski rules gives an indication of how drug-like for a molecule is. In general, orally active drugs have fewer than two violations. These properties can be useful for identifying potential drug-like molecules, or for removing non drug-like molecules from a compound library before starting a large virtual screening experiment (table  3).

Conclusions
We have synthesized somme oxazolidinone compounds and we have investigated their antibacterial activity. For the synthesized oxazolidinone derivatives, a study of the characteristics and molecular properties has been realized. The docking studies revealed that the all compounds showed good docking score. The docking score is a measure of the antimicrobial activity of the studied compounds.