The homogeneity and purity of the compounds were ascertained by TLC on silica gel G-plates using cyclohexane:ethyl acetate and the spots were visualized using a UV chamber. Anthranilic acid 1 0. The solid obtained was recrystallized with ethanol to get 2-phenyl- 4 H -benzo[1,3]oxazinone 7 Figure 2B. Compound 7 and amino reagent 4 0.
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The reaction mixture was kept overnight and the product obtained was recrystallized using ethanol to get 2-phenyl-4Hsubstituted quinazolinone 8. The homogeneity and purity of the compounds were ascertained by TLC on silica gel G-plates using cyclohexane:ethyl acetate and the spots were visualized using UV chamber.
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By adopting the above synthetic procedures, compounds 5a , 5b , 5c , 5d , 5e , 5f , 5g , 8a , 8b , 8c , 8d , 8e , 8f , and 8g were also synthesized using different amino reagents. The seven amino reagents used are urea, thiourea, guanidine, metformin, isoniazid, phenyl hydrazine, and dinitrophenyl hydrazine. N- dimethylcarbamimidoyl methyloxoquinazoline-3 4 H - carboximidamide 5d.
The synthesized quinazolinones were screened for antitubercular activity using the microplate Alamar blue assay method. Accordingly, each quinazolinone was screened against M. The final drug concentrations tested were 0. A blue color in the well was interpreted as no bacterial growth, and pink color was scored as growth. The antibacterial activity of the synthesized quinazolinones was evaluated using agar cup plate method. Accordingly, the compounds were screened against Gram-negative organisms, namely, E. Ciprofloxacin was employed as a reference standard to compare the results.
Brain heart infusion agar was used at room temperature. The required colonies were transferred to the plates and the turbidity was adjusted visually with broth to equal that of a 0. The inoculated plate was allowed to stand for at least 5 minutes before applying disks. A 5 mm hollow tube was heated, pressed on the inoculated agar plate, and removed immediately five times by making five wells in the plate.
The diameter of inhibition zone was measured to the nearest whole millimeter by holding the measuring device. The 3D crystal structure of M. The 2D chemical structures of the ligands were prepared using ChemBioDraw After energy minimization of each ligand using Uff force field of the Open Babel, the ligands were converted into autodock ligands. Docking was performed using PyRx autodock vina. The highest binding energy values corresponding to the RMSD value of zero were considered as the binding affinity value of the ligands. Applying retrosynthetic analysis suggested the use of substituted primary amines, anthranilic acid, and acetic anhydride for the synthesis of 2-methyl- 4H 3-substituted quinazolinone.
The same strategy suggested the use of substituted primary amine, anthranilic acid, and benzoyl chloride for the synthesis of 2-phenyl- 4H 3-substituted quinazolinone Figure 1. Figure 1 Retrosynthetic analysis of A 2-methyl- 4H 3-substituted quinazolinone and B 2-phenyl- 4H 3-substituted quinazolinone.
Compounds 5a — g were synthesized by condensation of 2-methyl-4H-benzo[d][1. Compounds 8a — g , on the other hand, were synthesized by condensation of 2-phenyl-4H-benzo[d][1,3]oxazinone with primary amines 4a—g in the presence of glacial acetic acid Figure 2B. The method required mild experimental conditions and the yields were satisfactory. Figure 2 General synthetic route for A 2-methyl 4H 3-substituted quinazolinone and B 2-phenyl 4H 3-substituted quinazolinone.
The Chemistry of Anthranilic Acid | Bentham Science
The proposed scheme led to compounds which are in conformity with the structure envisioned. In all cases, the products were obtained in pure form. Moreover, they were purified by recrystallization from ethanol. Different synthetic routes for compounds 5c , 26 5e , 27 5g , 28 and 8c 26 are available. Moreover, synthesis and biological activities other than antibacterial and antitubercular activity of compounds 5a , 29 , 30 5b , 30 5e , 31 5f , 32 8a , 30 8b , 30 and 8e 31 , 33 have been previously reported.
Synthesis of substituted benzene rings II
All the synthesized quinazolinones were screened for their antitubercular activity according to microplate Alamar blue assay method Table 1. It is interesting to note that synthesized compounds 5a—e and 8a—c exhibited MICs at a concentration ranging from 6. The rest of the compounds 5f—g and 8d—g exhibited no antitubercular activity at the studied concentration interval. Accordingly, the presence of amido, thioamido, and guanidino groups at 3-position of quinazolinone nucleus, as in compounds 5a—c and 8a—c , may be necessary for the antitubercular activity.
In particular, a thioamido or guanidino group can greatly increase the antitubercular activity of quinazolinones, as noted by 6. Table 1 The antitubercular activity minimum inhibitory concentration [MIC] values and the binding affinities to InhA for quinazolinone derivatives Abbreviation: InhA, enoyl-acyl carrier protein reductase. In addition, all the synthesized quinazolinones were screened for their antibacterial activity using agar cup plate method. The antibacterial activity of the synthesized quinazolinones in comparison with ciprofloxacin is shown in Figures 3 — 6.
This result showed the importance of 2,4-dinitrophenyl hydrazine or N,N—dimethyl guanidinyl group at 3-position of quinazolinones for activity against Gram-positive bacteria. However, the general activity of the synthesized quinazolinones against Gram-negative bacteria was found to be low.
Figure 3 The antibacterial activity of compounds 5a — g against Gram-positive bacteria, Staphylococcus albus and Streptococcus pyogenes. Abbreviation: std, standard. Figure 4 The antibacterial activity of compounds 5a — g against Gram-negative bacteria, Escherichia coli and Klebsiella.
Figure 5 The antibacterial activity of compounds 8a—g against Gram-positive bacteria, Staphylococcus albus and Streptococcus pyogenes. Figure 6 The antibacterial activity of compounds 8a—g against Gram-negative bacteria, Escherichia coli and Klebsiella. Moreover, the number of residues in outlier region was zero Figure 7.
The Structural Analysis and Verification Server was also used for checking and validation of the protein structure. The docking validation showed that the X-ray crystallographic conformer was nearly identical with the docked conformer, as deducted from the alignment of the two structures with an RMSD value of 0. Figure 8 The alignment of the docked ligand on the X-ray crystal ligand in the active site of InhA. Abbreviation: InhA, enoyl-acyl carrier protein reductase.
The binding energy of each ligand against InhA macromolecule was predicted using autodock vina, which is one of the most commonly used docking software. In the docking procedure, eight binding poses were obtained, and the binding pose with the highest binding energy corresponding to the RMSD value of zero was considered as the binding affinity value of the ligand. The 2-phenyl quinazolinone series, however, showed better binding energy than the 2-methyl quinazolinone series.
The amino acid residues interacting with the quinazolinone derivatives are given in Table 2. With the exception of compounds 5d and 5f , all derivatives in the 2-methyl series showed hydrogen bond interactions. Compound 5g , the most active in 2-methyl series, showed two hydrogen bond interactions Figure 9A and many hydrophobic contacts with different amino acid residues in the binding site.
Note: The magenta lines show the hydrogen bond and the hydrophobic contacts are shown in yellow lines. In general, the 2-phenyl series of quinazolinones were found to have more binding affinity than the 2-methyl series. This is due in part to an increased number of hydrophobic contacts with the amino acids of the binding site or stronger hydrophobic interaction of a 2-phenyl moiety with I20, F40, F, and G Close Print this page. Content: Citation Only. Citation and Abstract. Article Metrics PDF: Related Journals.
Related eBooks. And we know this carbonyl carbon here is partially positive, which makes this a meta director. Now, we haven't covered any reactions that would install an amino group meta to a carboxylic acid group. But we have talked about how to put a nitro group meta to a carboxylic acid group. So let's turn that amino group into a nitro group. So let's go ahead and draw our benzene ring here. And we'll go ahead and put our carboxylic acid down here.