Synthesis, Characterization and Biological Activity of heterocyclic compounds derived from Amoxcilline drug.
Enaam Fadhil Mousa * ; Sundus Hadi Merza**
* Department of Chemistry, College of Science for women, University of Baghdad, Iraq.
** Department of Chemistry, College of Education-Al-Haitham, University of Baghdad, Iraq.
Abstract
A first step in this research was to synthesize Schiff's bases(1-3)using an Amoxcilline intensification reaction with different aromatic aldehydes in absolute ethanol. In benzene and refluxing conditions,Schiff's bases were cyclized with succinic and Phthalic anhydride to give a new sequence of 1,3-oxazepine derivatives(4-6) and (7-9),respectively.The last step,cyclization reactions with sodium azide in THF solvent resulted in the formation of [10 and 11], which are supposed to be biologically significant.FT.IR, 1H-NMR and 13C-NMR (for compound 4,7,9, and 11),as well as melting points reported, were used to characterize these prepared compounds ,Bacillus (G+), Staphylococcus (G+), and E.Coli (G-)were screened
against these compounds. .
To illustrate the affinity of the potent hit and the enzyme binding pocket, a docking analysis was performed using autodock pakage of compound 7 within the active location for enzyme to be targeted for antimicrobial agents L.glutamine.D.Fructose.6.phosphate amidotransferase/
glucosamine-6-phosphate synthase.
Keywords: Heterocyclic compounds; Schiff’s base; Amoxcilline; 1,3-oxazepine, Tetrazole.
Introduction
The most popular heterocyclices are those that contain nitrogen, oxygen, and sulfur that act as a main component of a big number of biochemical material necessary for life, such as nucleic acids.The antibiotic amoxicillin is a semi-prepared antibiotic,acid-stable that belongs to the Penicillin family of antibiotics (lactam antibiotics). It has been shown to be effective in humans and animals versus a wide range of different kinds of bacterial infections.2-5. It is a congener of ampicillin (a semi-synthetic aminopenicillin) that differs only in the hydroxylation of the phenyl side chain from the parent drug 6,7.Amoxicillin is (2S,5R,6R)-6- [[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino] carboxylic acid-3,3-dimethyl-7-oxo-4- thia-1-aza-bicycyclo[3.2.0]heptanes-2 (Fig.1).It appears in some pharmacopoeias.The pharmacopoeias of the United States, the United Kingdom, and India all have an amoxicillin monograph. It's in a lot of pharmacopoeias.The monograph for amoxicillin can be found in the pharmacopoeias of the United States,the United Kingdom, and India.8-10
N S
HN CH3
CH3
COOH HO
O O NH2
. Figure 1 portrays Amoxicillin's chemical structure.
Protein–ligand docking represent one of the molecular modelling approach used to bind an organic molecule inside the binding site of target enzyme to estimate the intermolecular interactions in the active pocket which provide the biological activity11.The binding affinity of potent hit (compound 7) inside the active location of L.glutamine.D.Fructose.6.phosphate amidotransferase was investigated using the Autodock program.
Experimental
Instruments
1-Melting points are determined using an uncorrected Gallen electric melting point apparatus.
2- A spectrophotometer SHIMADZU 8300, FT.IR spectra were recorded in the range (4000-
400) cm-1,using KBr discs measurements were made at Ibn Sina company(Baghdad –Iraq).
3-The 1H.NMR and 13C.NMR spectra were measured at Kashan University in Iran using a fourier transformation bruker spectrometer operating at (400MHz) with (DMSO-d6).
4-The prepared compounds' biological activity was investigated in BPC Analysis Center.
preparation Schiff’s bases (1-3) (12, 13)
In ethanol,a solution of substituted benzaldehydes(1.1 mmol) was combined with amoxicillin trihydrate (0.419 g,1.0 mmol) (10 mL).After magnetically mixing the solution, it was refluxed for 6 hours at boiling temperature. In cold water,the obtained brownish red solution was poured (100 mL).Before being dried in the air for two hours, the solid was filtered and washed several times with water.
HO
HN
O NH2
N S
O
CH3 CH3
COOH H
X C H
O
HO
HN
O N
N S
O
CH3 CH3
COOH H
HC X
X = -OH, -Cl, -Br (1-3)
Equ-1: Synthesis of Schiff’s bases
Preparation substituted 1,3-Oxazepine-4,7-dione (4-9)(14)
In 20 mL of dry benzene, a mixture of Schiff base (1-3) (0.01 mol) and (0.01 mol) maleic and phthaleic anhydride was refluxed along one a day, the solvent evaporated, and the precipitate was recrystallized from suitable solvents.
HO
H N
N
S CH3 CH3
COOH O
O N HC X
N S H N HO
O O
CH3 CH3
COOH C
H N O X
O O O
O O
N S H N HO
O O
CH3
CH3
COOH C
N C O O
OC X H
O O
O X = (OH, Cl, Br)
d ry benzene
dry benzene
Scheme-1: Synthesis of 1,3-oxazepine-4,7-dione
Preparation of the derivatives (10,11)(15,16)
To Schiff’s bases (1-3), (0.01 mol.) dissolved in (15 mL) tetrahydrofuran, was added drop wise of (0.01 mol) 2-mercptoacetic acid.Under reflux for 11-12 hours, the mixture was stirred.Thin layer Chromatography was used to confirm the reaction's completion, and it revealed that the starting material had vanished. The solvent was then cooled after being evaporated down to a small amount., and then the obtained reaction mixture was washed with 20% sodium bicarbonate solution to remove non-reacted acid. Solution was filtered to collect solid. The solid thus obtained was recrystallized using dioxane solvent and dried. Physical properties shown in table (1).
HO
HN N
S CHCH3 3 O COOH O HN X C
N S HN N HO
O O N N CH NH X
CH3 CH3
COOH
NaN
3X = (OH, Cl)
THF
Equ-2: Synthesis of Tetrazole
Table - 1 – The physical properties of the substances that have been prepared
Yield
% Color M.P.
0 C M.wt.
gm / mol Formula
Compound Structure No. of
the comp.
80 Orange 166-
169 569
C23H23O6N3S
N S HN CHCH3 3
COOH HO
OO N HC
1 OH
79 Yellow 187-
190 487
C23H22O5N3SCl
N S HN CHCH33
COOH HO
OO N HC
2 Cl
82 Orange 195-
198 532
C23H22O5N3SBr
N S HN CHCH3 3
COOH HO
OO N HC
3 Br
75 Yellow 140-
143 569
C27H27O9N3S
N SCHCH3 3
COOH HN
HO
OO NC C O
CH O HO
4 O
70 Light Yellow 150-
153 588
C27H26O8N3SCl
N S CHCH3 3
COOH HN
HO
OO NC C O
CH O Cl
5 O
73 Deep Yellow 183-
186 632
C27H26O8N3SBr
N SCHCH3 3
COOH HN
HO
OO NC C O
C
H O
Br
6 O
75 Yellow 203-
206 617
C31H27O9N3S
N
S CHCH3 3 COOH HN
HO
O O NC C O
C
H O
HO
7 O
70 Light Yellow 210-
213 636
C31H26O8N3SCl
N S CHCH3 3
COOH HN
HO
O O NC C O
C
H O
Cl
8 O
72 Deep Yellow 230-
233 680
C31H26O8N3SBr
N
S CHCH3 3 COOH HN
HO
O O NC C O
CH O Br
9 O
69 --- Gamy
512 C23H24O6N6S
N S H N HO
O O N N C H N
NH HO
CH3 CH3
COOH
10
70 --- Gamy
530 C23H23O5N6SCl
N S HN HO
OO N N CH NNH Cl
CH3 CH3
COOH
11
Docking study
The intermolecular interactions of the potent derivatives7 with L.glutamine D.fructose.6.phosphate synthase connect location were investigated using the AutoDock 4.2 kit.The Protein Data Bank's PDB file (PDB code 1MOQ) was used as a fixed structure for the target enzyme.The ligand was removed from the protein residues, hydrogen atoms were added, and water molecules were removed.The two-dimensional structure of the tested hit was built using ChemDraw ultra 7.0 software. The free Babel 2.3.1 program was then used to convert the file to a mol formatted file.The numbers 30.5, 17.5, and 2.2 were allocated to the 62 grids in three axcis respectively, during the docking process,and dots isolated by 0.358 were created in the center of the enzyme's catalytic site.The docking study went well.17
Results and Discussion
In recent years, heterocyclic compounds have become of great importance because of their excellent properties in life,and medical treatment.(18)Substituted aromatic Schiff's bases(1-3) are obtained by reacting amoxcilline with various aromatic aldehyde(19,20), which were thereafter cyclized with succinic and phthaleic anhydride in dry benzene solvent to yield derivatives of Oxazepine (4-9).(21)
One water molecule is taken away and a nucleophilic addition to the carbonyl group occurs are needed for forming Schiff's base.(22)The imine group(N=CH-) identifies Schiff's bases,which is an essential compounds due to its stability and structural diversity.Absence for the primary amine's (N-H) stretching band at(3316.2asym.and 3286.7 sym.)and formation of the imino group (HC=N) is particular by the presence of a stretching band in the FT-IR spectra of Schiff's bases at (1640-1600.09) cm-1(23) figs2 and3.Imines have been used to prepare nitrogen-containing heterocyclics effectively for many years and they are expected to play an increasingly important role in the future(24).
Compounds (4-9) were produced by reacting Schiff base compounds (1-3) with Succinic anhydride and phthalic anhydride in dry benzene as a solvent.These compounds were investigated and characterized using melting points,FT-IR,1H-NMR spectra for compounds (4,7,and 9),13C-NMR spectrum for compound(4).
The absence of the (-N=CH-)group and the presence of a new band at (1689.64-1670.35 cm-1) relative to the lactone group were revealed in the FT-IR spectra of these compounds.
(1616.35-1593 cm-1) relative to the lactum group, and (CHAr.) at (2978.09-2931 cm-1) and (2900-2865.51cm-1) figs.4 and 5.
The tetrazole cycle is a promising pharmacophore fragment that's widely used in drug production.This is a reliable moiety.(25)The tetrazole compounds [10 and11] were synthesized by the reaction of imines (1-3) with sodium azide; these compounds were checked by TLC,
1H-NMR spectrum for compound [11].
The reaction mechanism, such as [3 + 2] cyclo additions,which are taken as 1,3 -dipolar cyclo additions, was systematically investigated.(26)
An unsaturated molecule is added to a 1,3-dipole molecule with positive and negative charges divided towards the 1,3-positions comparative to any other in the addition reaction.(27)The cycloaddition reaction gives a five-member ring.azides that undergo1,3 dipolar cycloadditions are the most important and prominent type of 1,3- dipoles. T.S. is involved in the 1,3- cycloaddition mechanism. Above or below the dipolarphile and its ligands, the azide is arranged in a level and in a parallel level,allowing orbitals perpendicular to the levels to overlap and take shape bonds.(28)
In the FT.IR spectra, the stretching band due to (N-H) group appears at (3325, 3235) and the stretching band due to (-N=N-) group appears at(1492.2cm-1).The bands at about (1273 cm-1) and (1153 cm-1) were characteristic for the tetrazole cycle.This was the most telling proof of the cyclization step's progress.In addition to this the absence of imine group (C=N) stretching band at (1593cm-1) is good indication of the success of this step of reaction fig 6 .
The 1H-NMR spectrum of compounds [ 4,7,9and 11] showed the signal at (11.92,10.65, 10.02 and 9.97) ppm due to (O-H) proton of carboxylic group and signal at (9.80, 9.81, 9.39 and 9.97) ppm due to proton of phenolic (O-H), and signal at (8.32, 8.52, 8.33, and 8.41) ppm due to (N-H) proton of amide , while the other signals are listed in Table (2) as shown in Figs(7 and8), table 3
.
The compound's 13C-NMR spectrum 4 showed the carbon of two methyl groups at (29.33- 29.46) ppm while the aromatic C-H carbon of two rings benzene are assigned at their expected location(116.32-128.92 ) ppm. The carbon of carbonyl group of amide is located at (163.64 -163.82 ) ppm while the carbons of carbonyl of oxazepine rings were appeared at 173.85 ppm and 174.12) ppm .As shown in Fig (9) .
Table 2 Absorption bands in the FT.IR spectra of synthesized derivatives 1-11
Dert. C-OH N-H C-H
Arom.
C-H Aliph.
C=O Others
1 3271
Overlap
Overlap 2831.5 , 2970.3
1670.35 ᶹ C=N 1600.09 ᶹ C-N 1200.06 ᶹ C-O 1167.29
2 3437.15
3294.4
3093.8 2974.2, 2935.3
1681.93 ᶹ C=N 1640 ᶹ C-N 1250 ᶹ C-O 1130.29 ᶹ C-Cl 783.81
3 3437.66
3294.4
2 3066.82 2931.2,
2973.6
1662.64
ᶹ C=N 1616.35 ᶹ C-N 1176.58 ᶹ C-O 1130.29 ᶹ C-Br 682
4 3420 3310 3043.67 2750.4, 2931.8
1669.64 ᶹ C-N 1199.72 ᶹ C-O 1161.15
5 3425 3330 3032.10 2931.6 1689.64 ᶹ C-Cl 802.39
ᶹ C-N 1176.58 ᶹ C-O 1130.29
6 3406.29 3275 3039.61 2978.09,
2931.60
1689.64 ᶹ C-Br 640.39 ᶹ C-N 1176.58 ᶹ C-O 1130.29
7 3456.4 3335 3078.39 2856.19,
2931
1681.93 ᶹ C-O 1157.29 ᶹ C-N 1157.29 ᶹ C-O 1138
8 3425 3232.7
0
3070.68 2900.54, 2974.23
1685.79 ᶹ C-Cl 798.53 ᶹ C-N 1176.58 ᶹ C-O 1130.29
9 3450 3290.5
6
3066.82 2974.23, 2931.80
1670.35 ᶹ C-Br 636.81 ᶹ C-O 1134.14
10 3402.43 3235 Overlap 2865.51,
2951.09
1674.21 ᶹ C-N 1273.02 ᶹ C-O 1153.43
11 3402.49 3325 3030 2889.37,
2958.8
1680 ᶹ C-N 1273 ᶹ C-O 1 126
Table -3 - : Chemical changes in 1H-NMR for chosen compounds (ppm).
Chemical shifts Structure
Der t.
𝛿11.92(S,H,OH1) ; 𝛿9.80(S,H,OH2)
; 𝛿8.27(S,H,NH3); 𝛿7.79 − 6.71 𝑚, 𝐻8 𝐴𝑟 ; 𝛿5.82(S,CH- N);𝛿5.61(d,H,CH5); 𝛿4.89
(d,H,CH6); 𝛿4.34(S,H,CH7); 𝛿3.16(T,2H,CH28); 𝛿2.44(
S,H,2CH39) .
S CH3
CH3 N COOH O
N H H
O N
HO CH O OC
C O HO
1 2
2
3
4 5
6
7 8
8
9 9
4
𝛿10.65(S,H,OH1); 𝛿9.81(S,H,OH2);
8.52(S,H,NH3); 𝛿8.28-.6.20(m, 12H
Ar); 𝛿5.78(S,H,CH4);𝛿5.14(d, H , CH5); 𝛿4.87(d, H , CH6); 𝛿4.53(S,H,CH7 ); 𝛿2.40(S,H,2CH38
).
S CH3 CH3 N COOH O N H H
O N
HO CH O OC
C O HO
1 2
2
3
4 5
6
7 8 8
7
fig2Compound's FTIR 1
Fig3 Compound's FTIR 3
Fig4 Compound's FTIR 6
𝛿10.02(S,H,OH1); 𝛿9.39(S,H,OH2);
8.33(S,H,NH3); 𝛿8.14-.6.62(m,12H
Ar); 𝛿5.62(S,H,CH4);𝛿5.15(d,H , CH5); 𝛿4.87(d, H , CH6); 𝛿4.80(S,H,CH7); 𝛿2.28(S,H,2CH38
).
S CH3
CH3 COOH N O
H N H
O N
HO C H O
C O
C O
Br
2 1
3
4 5
6
7 8 8
9
𝛿9.97(S,H,OH1); 𝛿9.34(S,H,OH2);
8.41(S,H,NH3); 𝛿7.90-.6.63(m,8H
Ar); 𝛿5.02(S,H,CH4);𝛿4.50(d,H , CH5); 𝛿4.31-4.26(S,H
, CH6); 𝛿3.74(S,H,CH7 ); 𝛿1.98(S,H,NH8)
; 𝛿1.42(S,H,2CH39).
S CH3 CH3 COOH N
O H N H
O N
HO C H
N NH
Cl
N
2 1
3
4 4
5
6 7
8
9 9
11
Fig5Compound's FTIR 8
Fig6Compound's FTIR 10
Fig7 compound's 1H.NMR 4
Fig8 compound's 1H.NMR 7
Fig9 compound's 13C.NMR 4.
Antibacterial activity test (biological screening)
Antibiotic activity was assessed in vitro against Gram-negative bacteria such as Escherichia coliand Gram-positive bacteria such as Bacillus subtilis and Staphylococcus aureus using the disc deposition process.
The sterilization of the prepared agar and petridishes took 15 minutes at 121 degrees Celsius.
Many of the cavities in the solidified medium were 6mm in diameter and were spaced apart accordingly 0.1 mL of prepared compounds solvated in1mL DMSO is used to fill these gaps.In the disk,DMSO was used as a control.The antibiotic Cephalexine (Keflex), which is used to treat Salmonella, was dissolved in the same solvent. The antibiotic cephalexine was used to equate E. coli Klebsiella, and Bacillus subtilis.Bacteria were incubated for 24 hours at 37 degrees Celsius on plates.Different compounds' inhibition areas were studied.(29)
The preliminary assay results showed that compound [eN7, eN11, eN10, eN5, eN6, eN9, and eN8] had the highest activity against Staphylococcus aureus and Bacillus subtilis (G +), whereas compound eN12 had the lowest activity against these bacteria.
Compounds[eN11, eN10, eN6, and eN12] showed Slightly activity against E.coli(G- ).Compound [eN7, eN5, eN9 and eN8] has no effect on E. coli., (table -4), figs 10, and 11.
Table -4: Antibacterial influence for some synthesized compounds
Dert. (As seen in the image) pattern No.
)
Escherichia coli (g-)
Bacillus subtilis (g+)
Staphylococcus aureus (g+)
7 eN7 - + + + + + +
6 eN11 - + + + + + +
10 eN10 - + ++ + + +
4 eN5 - + ++ + +
5 eN6 - + + + + + +
1 eN9 - + + + + + +
Inhibition zone > 25 mm (Highly active) = +++
Inhibition zone 15-20 mm(moderately active) = ++
Inhibition zone 10-15 mm (slightly active) = +
e = - (inhibition zone <5 m
Fig-10: Antibacterial influence for synthesized compound 7
Fig- 11: Antibacterial influence for synthesized compound 6
Docking Approach
Glucosamine-6-phosphate synthase (GlcN6-P synthase) is required for the conversion of glucosamine.6.phosphate to uridine diphosphate.N-acetyl glucoseamine of (UDP-GlcNAc)(GlcN-6-P).These sequence bioformation represent vital for the cell wall buiding in a microorganism30.The synthesis of organic molecules that bind the binding pocket and preventing enzyme biosynthetic reaction cascades represent a good strategy for discovering antimicrobial agents. The amino acid residues cys300,gly 301,thr 302,ser303,ser347,gln348,ser349,thr 352,val 399,ser 401, ala602, andlys 603 make up the active site of the enzyme, as seen in the X-ray..31This study using the Autodock 4.2 to study the intermolecular
8 eN12 - + +
9 eN8 - + ++ + + +
interactions between the derivative 7 and enzyme active site.The docking parameters summarized in Table(5) .
The binding energy of high ranking generated conformer (ten by default) was -8.33 with - 11.01 (kcalmol-1) intermolecular energy. the 3D structure of the target enzyme and all the generated conformers inside the active site
illustrated in 12 fig.
21. The best conformer (the first generated as shown in figure 13) fit the binding site with four hydrogen bonds through two hydroxy hydrogens with the enzyme residue (LIG:H:ASP354:OD2;LIG:H:ASN600:O);while the other interactions were between the carbonyl oxygen (ALA602:HN:LIG:O) and the carboxyl oxygen of compound 7 (SER401:HG:LIG:O)
Table -5: Docking parameters of compound 7 ranked by energy
Creating a bond Hydroge
n-bonds Intermolecular
energy (kcalmol-1) Constant of
inhibition (µM) Energy that
binds (Kcal mol-1 ) Generated
Conformer
LIG - H - ASP354 - OD2 ALA602-HN-LIG-O SER401-HG-LIG-O LIG-H-ASN600-O 4
- 11.01 0.783
-8.33 1
THR302-HN-LIG-O LYS603-HZ3-LIG-O GLN348-HE21-LIG-OXT 3
- 10.79 1.14
-8.11 2
SER401-HG-LIG-O LYS603-HZ3-LIG-O 2
- 10.69 1.35
-8.01 3
THR302-HN-LIG-O GLN348-HE21-LIG-OXT
VAL605-HN- LIG-O SER349-HN-LIG-O 4
- 10.67 1.41
-7.98 4
THR302-HN-LIG -O GLN348-HE21-LIG-OXT
VAL605-HN-LIG-O SER349-HN- LIG-O 4
- 10.63 1.51
-7.94 5
SER303-HG - LIG-O VAL605-HN-LIG- O SER349- H- LIG- OXT LIG- H - GLU488- OE2 4
- 10.51 1.85
-7.82 6
SER401-HG - LIG- OXT SER328- HG- LIG- O LIG- H- ASP354- OD2 3
- 10.41 2.16
-7.73 7
SER349-HN- LIG- O GLN348 -HE21-LIG-OXT
VAL605-HN- LIG- O THR302- HN- LIG-O 4
- 10.27 2.76
-7.58 8
LIG-H-GLU488-OE2 VAL605 – HN – LIG- O
LIG- H- ASN600- O GLN348- HE21- LIG- OXT
GLN348-HN- LIG-O 5
- 10.14 3.45
-7.45 9
ALA602-HN-LIG-O 1
- 10.13 3.47
-7.45 10
3D structure of GlcN-6-P[ glucoseamine-6-phosphate synthase ]
All of the produced conformers for compound 7 are contained within the enzyme's binding
pocket . Compound 7
The second conformer for compound 7 The first conformer for compound 7
Fig- 12: The most potent newly detected hit 7 conformers were docked into the binding pocket for glucoseamine-6-phosphate synthase
The fourth conformer for compound 7 the third conformer of compound 7
sixth conformer of compound 7 fifth conformer of compound 7 .
eighth conformer of compound 7 was created.
seventh conformer of compound 7 was created.
tenth conformer produced of compound7 ninth generated conformer of derivative 7
Fig- 13: Continue with docking of the most effective conformers.
Conclusion
Many bioactive heterocyclic compounds contain 1,3 oxazepine and tetrazole derivatives, which have a wide range of biological, pharmaceutical, therapy, and clinical applications. Tetrazoles with the most promising structure forms for use as anticancer drugs have been identified.The docking study of the discovered hit 7 inside the active site of target enzyme strongly enhanced the antimicrobial activity.
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