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Synthesis and studies molecular docking of some new thioxobenzo[g]pteridine derivatives and 1,4-dihydroquinoxaline derivatives with glycosidic moiety

ABSTRACT The present work is mainly dedicated to heterocyclic compounds as well as S-glycoside. 1,4-dihydroquinoxaline derivatives 3 were obtained from the reaction 2 with carbon disulfide in presence of potassium hydroxide. S-glycoside 4 was prepared from the reaction of compound 3 with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide. Several heterocyclic derivatives containing thioxobenzo[g]pteridine ring systems were obtained starting from ethyl 3-amino-1,4-dihydroquinoxaline-2-carboxylate 1. These newly synthesized compounds were docked within the active site of cyclooxygenase-2 (COX-2). The results of this docking study revealed that the new compounds might exhibit good anti-inflammatory activity. The structure of new compounds was demonstrated by elemental analysis, IR, 1H NMR spectra and mass spectra.


Introduction
Pteridine is an important compound of heterocyclic system fused of pyrimidine ring with pyrazine ring [1][2][3]. studies of pteridines have an important role in biological activities, such as metabolism of amino acids [4][5][6]. Pteridine is an introduction to the synthesis of dihydrofolic acid in many microorganisms. Where pteridine and 4-Aminobenzoic acid are converted by dehydrotatease enzyme to daihydrobolic acid in the presence of glutamate [7]. In addition, there are three major categories of naturally occurring patiridines: lumazines [8], isoalloxazine [9] and pterins [10]. The lumazines, isoalloxazines and 5,10-dihydro isoalloxazines have oxosubtubents in positions 2 and 4 with the phenyl ring in position 6-and 7 in isoalloxazine (benzo[g]pteridine-2,4(3H,10H)-dione). The most common category of naturally occurring pteridines are the pterins that have the amino group in position 2 and the oxo group in position 4 [11]. Studies on the development of new methods synthesized new pteridines derivatives increased here we aim to clarify all available structures and methods related to pteridines Quinoxaline is important of the heterocyclic compounds containing nitrogen atom which playing a broad spectrum of biological and pharmacological activities like as insecticide [12], fungicide [13], herbicide [14], anthelmintic [15], antibacterial [16], antimycobacterial [17], antiprotozoal [18], anticancer properties [19] and anti-inflammatory activity [20]. For example, Wagly et al [21]recorded that the quinoxaline derivative (A) showed anti-inflammatory activity (63.33%) as showed by the standard drug indomethacin. Furthermore, thioether derivatives of 2-chloro-3methylquinoxaline had been prepared and evaluated for their anti-inflammatorry activity using carrageenan induced rat paw edema method [22]. The biological study of these derivatives demonstrated that derivative (B) exhibited the highest inflammatory inhibition (40.09%) at dose 100 mg/ kg. In the view of the aforesaid facts and in continuation of our work in the synthesis of biologically active heterocycles [23][24][25][26][27][28][29]. In the view of the aforesaid facts and in continuation of our work in the synthesis of biologically active heterocycles [30][31][32][33][34][35][36],we aimed at synthesis of novel quinoxaline and pteridine derivatives of expected anti-inflammatory activity.
Benzo[g]pteridin derivatives 5 and/ or 7 reacted with 2,3,4, 6-tetra-O-α-acetyl glucopyranosyl bromide in aqueous potassium hydroxide afforded the corresponding glycosyl derivatives 8, 9 respectively. The 1 HNMR of the product determined thioglycosides led to appearance four single peak due to acetyl group in addition to the other protons of the sugar chain. The formation of these thioglycosides and linkage of the sugar part at a sulfur centre was determined by the 1 HNMR. The 1 HNMR appearance anomeric proton (H-1) at 5.72 ppm.
In addition, methylation of compounds 5 and 7 by methyl iodide in presence of potassium hydroxide produced 2-(methylthio)benzo[g]pteridin derivatives 10 and 11 respectively, as shown in Scheme 3. 1 HNMR spectra of compounds10 and 11 gave a single peak at 2.69 ppm for methyl group and the site attack found on sulfur not found on the nitrogen. Compounds 10, 11 were reacted with hydrazine hydrate in ethanol to afford 12 and 13 respectively. The structures of compounds 12 and 13 were confirmed by 1 HNMR spectra which showed signals for NHNH 2 at 5.16 and 10.07, respectively. Furthermore, Schiff bases 14 and 15 were prepared by heating under reflux compounds 12 and 13 with D-glucose in presence of glacial acetic acid. Acetylated of Hydrazone derivative 14 was produced by heating with acetic anhydride gave acetylated glycoside 16. The IR spectrum of the compound 16 confirmed the absence of hydroxyl and NH 2 group, and apparent absorption bands at 1748 cm −1 due to (C = O).

Molecular simulation study
Non-steroidal anti-inflammatory drugs (NSAIDs) are used to alleviate and treat inflammation, fever, and pain. It was recognized that these NSAIDs produce their action mainly via inhibiting the cyclooxygenase enzymes (COXs) which biosynthesize prostaglandins (PGs), prostacyclin (PGI2) and thromboxanes (TXA2) [38][39][40]. Nonselective COX inhibitors as aspirin and indomethacin showed severe side effects as ulcers and renal damage [34][35][36]. These side effects directed scientists to synthesize COX-2 selective drugs like celecoxib and rofecoxib [37,38] but unfortunately, some of these such as (rofecoxib) was withdrawn from the market due to the reported increase in the risk of the cardiovascular disease [39,40]. So there is a great need for a synthesis of more selective COX-2 inhibitors with fewer side effects.
The secondary pocket present in COX-2 has been attributed to the presence of the smaller valine (Val523). Replacement of histidine (His513) in COX-1 by arginine (Arg513) in COX-2 has been reported to play a key role in the hydrogen-bond network of the COX active site. Histidine (His90), glutamine (Gln192), and tyrosine (Tyr355) control the access of ligands into the secondary pocket. The interaction of Arg513 with the bound ligand has been reported to be a requirement for the time-dependent inhibition of COX-2 [41].
The target compounds 4, 8, 9 and 16 were subjected to molecular simulation study to expect their biological activity as anti-inflammatory agents.COX-2 X-ray crystal structure downloaded from the protein data bank with code (PDB: ID 1CX2). This study In this work, the compounds 4, 8, 9 and 16 were docked within COX-2 active site to explore the activity of these novel benzo[g]pteridine and 1,4-dihydroquinoxalin derivatives as COX-2 inhibitors. The ligand used in this study was S-58 (bromocelecoxib) which was redocked into COX-2 with a score energy (S) = −11.93 kcal/mol.S-58 showed two hydrogen bonding interactions with Arg513and His90 amino acids with -SO2 group through in a distance equal to 2.41 and 2.30 Å. The docking results including the associated energy with intermolecular interactions obtained upon docking for the docked compounds(4,8, 9,16 and S-58) within COX-2 active site and hydrogen bonding interactions between the amino acid residues and functional groups of compounds are explained in Table 1.
Moreover, the target compound 8 showed good fitting with COX-2 enzyme and performed three hydrogen bonding interactions. One hydrogen bond between Leu352 and pteridine NH, the other one between Gln292 and pteridine C = O and last hydrogen bond interaction between Arg513 and acetyl C = O ( Figure 2).
Docking of the target compound 9 recorded three hydrogen bonding interactions with energy score = −12.62kcal/mol: i) Ser530 with acetyl C = O, ii) Tyr385 with acetyl C = O and iii) Arg513 with pteridine C = O. In addition, this compound showed two arene cation interactions between the phenyl ring attached to pteridine moiety and Arg513 and Arg120 (Figure 3).    Finally, compound 16 showed hydrogen bonding interactions similar to that exhibited with S-58 (with Arg513 and His90), in addition to other hydrogen bonding interaction between Arg120 and C = O. Furthermore, arene cation interaction had been recorded between Arg120 and benzene ring (Figure 4).

General Procedures
Melting points were determined on Electro thermal IA 9,100 series digital melting point apparatus in capillaries and are uncorrected. IR spectra obtained in the solid state as potassium bromide discs using a Perkin-Elmer model 1430 spectrometer. 1 H-NMR spectra were recorded on a Varian/Gemini 400 MHz spectrometer in DMSO-d 6 as a solvent and TMS as an internal standard (chemical shifts in δ, ppm). Mass spectra measured on an instrument VG-7035 at 70 or 15 eV. Elemental analyses has performed at the Microanalytical Centre, Cairo University, and Giza, Egypt.

Molecular docking study
The crystal structures of bromocelecoxib bound at COX-2 isoform (Protein Data Bank; PDB: ID 1CX2). Docking was done using London dG force and sophistication of the results was performed using force field energy. Preparation of the synthesized compounds for docking was attained via their 3D structure built by Molecular Operating Environment (MOE, Version 2005.06, Chemical Computing Group Inc., QC, Canada). Definite procedures were in use before docking which includes: 3D protonation of the structures, running conformational analysis using systemic search, selecting the least energetic conformer and applying the same docking protocol used with ligands. Docking for the synthesized compounds was applied.