Preparation, Identification and Cancer Inhibitory Activity of a novel Pd (II) complex derived from E)-2-((4,5-bis(4-methoxyphenyl)-1H-imidazol-2-yl)diazenyl)-5-iodobenzoic acid

Nada Hasan¹, Raheem Taher²

¹Pathological Analysis Techniques Department, Al-Mustaqbal University College, Al Ḩillah, Iraq,

²Chemistry Department, Education for Women College, Kufa University, Najaf-Iraq.

*Corresponding Author E-mail: Nadahasan@mustaqbal-college.edu.iq

ABSTRACT:

The synthesis  and spectral identification of metal complex for Pd(II) ion with newfangled heterocyclic azo dye as ligand (E)-2-((4,5-bis(4-methoxyphenyl)-1H-imidazol-2-yl)diazenyl)-5-iodobenzoic acid (MPIAIBA) have been organized by reaction of diazonium chloride salt solution of 2-amino-5-iodobenzoic acid with imidazole derivatives in alkaline ethanolic solution. Azo dye ligand and its Pd (II) complex have been characterized by ¹H-NMR, analytical data, Infrared, Mass spectrum, thermal analysis (TG-DTG), Electronic Spectral Data, molar conductance and magnetic susceptibility. The elemental investigation of the metal complexes validate the stoichiometry of the [Pd(L)Cl] type where L=azo dye ligand. Molar conductance measured results for organized Pd (II) complex showed 1:1 electrolyte for Pd (II) ion. The azo dye ligand acts a tridentate and coordinates to the palladium ion via nitrogen atom of azo group of heterocyclic imidazole ring, nitrogen atom of azo group and oxygen of carboxyl group. Square planar geometry is suggested for Pd (II) complex. In this investigation, the cytotoxicity of the azo dye ligand and its Pd(II) complex has screened for in vitro, antitumor movement against human hepatocellular carcinoma HepG-2 utilizing MTT examine. The prepared ligand and its Pd(II) complex demonstrated anticancer movement with IC₅₀ values indicated cytotoxicity against malignant growth cell line with IC₅₀=172.3μg/ml, WRI-68 IC₅₀=238.6μg/ml, while Pd(II)- complex demonstrated specific cytotoxicity in contradiction of disease cell line with IC₅₀ =115.0μg/ml; WRI-68 IC₅₀=192.1μg/ml. The outcomes demonstrated that this sort of compounds has a significant part in the hindrance rate of the development of cells of destructive and normal lines.

KEYWORDS: Synthesis, imidazolylazo dye, hepatocellular carcinoma HepG-2, thermal analysis, spectrum studies.

INTRODUCTION:

Medicinal inorganic chemistry gives considerable important prospects for the employment of mineral complexes in the development anticancer drugs^[1]. Imidazole stands for a biological compound, with C₃H₄N₂ formula. This aromatic hetrocyclic is (1, 3-diaza-2, 4-cyclopentadiene), a planner five-member ring scheme with 3C and 2N atoms in 1 in addition to 3 positions^[2].

The huge therapeutic features of the imidazole attached drugs supported the medicinal chemists to prepare an enormous amount of new chemotherapeutic features. Imidazole drugs have extended scope in treating numerous dispositions in clinical treatments. Many approaches for preparing imidazole and as well their numerous structure reactions have colossal scope in medicinal chemistry field^[3]. Imidazole and its derivatives are notable for its pharmaceutical and in addition medicinal applications^[4]. Imidazole derivatives show various pharmacologic activities: such as Anti-fungal and Anti-bacterial activity^[5,6], Anti-inflammatory activity and analgesic activity^[7], Anti tubercular activity^[8], Anti depressant action^[9], Anti cancer action^[10], Anti viral action^[11], Antileishmanial action^[12].

In the present work, new azo ligand (E)-2-((4,5-bis(4-methoxyphenyl)-1H-imidazol-2-yl)diazenyl)-5-iodobenzoic acid (MPIAIBA) is synthesized with its derived metal for Pd(II)complex were studied by various spectrumsl analysis, thermal analysis. the cytotoxicity of the prepared ligand and Pd (II)-complex on human hepatocellular carcinoma HepG2 and normal cells have been investigated by means of MTT assay.

EXPERIMENTAL:

MATERIALS AND METHOD:

Every employed chemical and solvent in this study are in highest purity supplied from different corporations such as BDH, Fluka and Sigma Aldrich and utilized with no additional cleansing. Distilled water has employed in each experiments. Elemental analysis (C.H.N) has used based on a micro analytical unit of Euroverctor, EA300A, Italy. Measurements of electric molar conductivity of complexes were recorded in DMSO (1x10^-4M) solution at room temperature by Digisun (909) digital conductivity meter. Mass spectrums were recorded by means of a shimadzu Agilent Technologies 5975 C at 70^e and MSD energy at temperature 50-350 °C by means of a direct insertion probe (Acq method 10 W energy).¹H- NMR spectrums have been determined in DMSO-d₆ solvent on a model Bruker 500 MHZ spectrophotometer by means of TMS as interior reference. IR spectrums have measured in KBr medium as dics by means of a shimadzu 8400S, in (4000-400) cm^-1 range. Absorption spectrums were determined in (200-1100) nm range in absolute ethanol as a solvent (10^-3M) at room temperature by using Shimadzu UV-Vis 1700 spectrophotometer. Measurements of magnetic susceptibility of the prepared metal complexes have been recorded via Balance Magnetic (MSB-MKI) equipment. Thermo gravimetric analyses of the ligand and complexes have shown PL-TG by means of Perkin Elmer TGA-4000. Scanning electron microscopy (SEM) images were taken for ligand and Pd (II) complex through micrograph kyky 3200.The melting points were measured for ligand and Pd(II) complex via electro thermal melting point 9300.

Synthesis of 4, 5-bis(4-methoxyphenyl) imidazole:

The method of alpha-bipolar carbonyl condensation^[13] was adopted with ammonia and aldehyde to form imidazole derivative via reacting benzyl derivative and hexamine in the incidence of glacial acetic acid. In a rotund flask (250mL) has inserted 50mL of glacial acetic acid to a combination of benzyl derivative (2.70g, 0.01 mole), ammonium acetate (17.728g, 0.23mole) and hexamine (0.7009g, 0.005mole). By using reflected condenser, the solution reflux was warmed for 90 minutes. The solution has transferred to a beaker (1L) containing 400ml of distilled water and after cooling to a temperature of (10^oC) by using ice cream, add sodium hydroxide solution to neutralize the solution and obtain imidazole derivative. After addition complete, the solution was filtrate and collected the white precipitate, washed numerous times with distilled water and re-crystallized from hot ethanol to acquire white crystalline and dehydrated at room temperature. The yield was 85% of white crystals which decomposes at 182-184^oC. The structural of the imidazole derivative as shown below:

Scheme (1): preparation of the imidazole derivative

Heterocyclic Azo Dye Ligand (MPIAIBA) Synthesis:

The new imidazolylazo dye ligand was prepared according to the general method^[14] by the diazotization coupling reaction. 2-amino-5-iodobenzoic acid (2.6303 gm, 0.01mol) was dissolved in hydrochloric acid 3ml In (35mL) distilled water. A dropwise solution of (0.69gm, 0.01mol) of sodium nitrite (NaNO₂) in 15mL distilled water at (0-5)^oC was added and stirred the mixture for 15 minutes under 0 to 5^oC. The consequential diazonium salt solution has added dropwise with cooling and stirring continuously at (0-5)^oC into a 1000 ml beaker containing (2.8033gm, 0.01mol) of 4,5- bis(4-methoxyphenyl)-1H imidazole dissolved in alkaline media (100ml) ethanol and (30ml) sodium hydroxide (10%) solution at (0-5)^oC. The mixture has been stirring in the ice-bath and tolerable to stand overnight and acidified with dilute hydrochloric acid to pH=6. The precipitate formed was filtered off, washed with distilled water and purified by recrystallization from hot ethanol and dehydrated at room temperature. The yield has been 82% of a reddish brown crystals which decomposes at 196^oC. The structural of the imidazolylazo ligand (MPIAIBA) as shown below:

Scheme (2): Preparation of ligand (MPIAIBA)

General Method for the Preparation Palladium Complex

The Pd(II) complex was prepared by dissolved (0.55434gm, 0.001mol) from ligand (MPIAIBA) in ethanol (15ml) and added dropwise with stirring to (0.17732gm, 0.001mol) of 1:1 (metal: ligand) molar ratio of Pd(II) chloride salt dissolved in acetonitrile .The solid complex formed was filtered off from the ice-cooled reaction mixture, cleaned with purified water and rather warm ethanol for eliminating traces of non-reacted materials and left to be dried under vacuum desiccators over fused CaCl₂. The analytical and physical features of ligand and palladium complex have presented in Table (1).

Table (1): Physical and analytical features for ligand (MPIAIBA) and its Pd(II) complex

Found (Calc.) %				M.f (M.wt)	Yield %	m.p C°	Color	Compound
M	N	H	C
___	(10.10) 10.85	(3.45) 3.11	(52.00) 52.54	C24H19IN4O4 554.34	82	196	Reddish	Ligand = (MPIAIBA)
(14.92) 15.01	(7.85) 8.33	(2.82) 2.26	(40.41) 41.21	C24H20ClIN4O5Pd 713.22	94	230	Dark brown	[Pd(L)Cl].H2O

RESULTS AND DISCUSSION:

Characterization of azo ligand (MPIAIBA) and palladium complex:

The imidazolyl azo ligand is a reddish crystals but the prepared Pd(II) complex was crystalline and Dark brown color. The ligand and the Pd(II) complex are stable toward air at room temperature and insoluble in water. It has been soluble in acetone, methanol, ethanol, chloroform, dimethyl sulfoxide, dimethyl formamide, strongly acidic solutions and alkaline aqueous solutions. The structures of the acquired ligand and the individual Pd(II) complex were elucidated by Infrared, UV– visible, mass spectrums,¹H-NMR, elemental analysis and several techniques.

¹H-NMR Spectrums:

The ¹H-NMR spectrums of the ligand (MPIAIBA) and its Pd(II) complex Fig.(1and 2)have determined by means of TMS as an interior reference and DMSO-d₆ as solvent. The ¹H-NMR spectrums of ligand (MPIAIBA)show signal at 𝛿=13.01ppm due to (N-H) of the imidazole ring and signal at 𝛿=12.42ppm due to (O-H) of the carboxyl group and multiplets around 𝛿= 6.62-8.26ppm have allocated for aromatic protons (Ar-H), and signal at 𝛿 =3.89ppm is ascribed to the protons of methoxy group(O-CH₃). A signal at 𝛿 =2.53 ppm as a result of solvent proton^[15].

¹H-NMR band of Pd(II)-complex shows signal at 𝛿=13.32ppm due to (N-H) of the imidazole ring and multiplets around 𝛿= 6.76 -8.58ppm are allocated to aromatic protons ( Ar-H), and signal at 𝛿 =3.84ppm is ascribed to the protons of methoxy group (O-CH₃). A signal at 𝛿 =2.53 ppm as a result of solvent proton, a signal is appeared in 𝛿=3.39 ppm corresponding to H₂O protons ^[16].

Figure (1): ¹H-NMR spectrum of ligand (MPIAIBA)

Figure (2): ¹H-NMR spectrum of Pd (II)- complex [Pd(L)Cl].H₂O

Mass spectrums:

The mass spectrum of (MPIAIBA) ligand is recorded at room temperature Figs. (3,4), Schemes (3,4) and has shown a molecular ion peak M⁺ at m/z⁺ = 554.34assigned to a main molecular weight of ligand ( 554.34).The spectrum possesses exhibited some peaks assigned to the molecular ions at (m/z⁺ ) 523.35, 297.36, 280.33, 263.03,217.03, 135.21,118.16and 44.08 were due to various fragments ions [C₂₄H₂₀IN₄O₂]⁺, [C₁₇H₁₉N₃O₂]⁺, [C₁₇H₁₆N₂O₂]⁺, [C₇H₆INO₂]^·+, [C₇H₆N]^+, [C₈H₁₁N₂]⁺, [C₈H₈N]^+, [C₆H₅]⁺ and [C₂H₆N]⁺ correspondingly. This wellagree to the equivalent molecular formulain ^[17].

Scheme (3): Mass spectrum fragmentation of ligand (MPIAIBA)

Figure (3): Mass spectrum of ligand (MPIAIBA)

The mass spectrums of Pd(II)- complex contain molecular ion peaks at m/z⁺ 713.22, 523.3, 339.4, 280.3, 235.3,119.1, 97.1 and43.1 for structures respectively [C₂₄H₂₀ClIN₄O₅Pd]⁺,[C₂₄H₂₀IN₄O₂]⁺, [C₁₉H₂₃N₄O₂]⁺, [C₁₇H₁₆N₂O₂]⁺, [C₁₆H₁₅N₂]⁺, [C₉H₁₁]^·+, [C₇H1₃]^·+ and [C₃H₇]⁺.This data have been in worthy concurrence with the equivalent molecular formulae^[18].

Scheme (4): Mass band fragmentation of Pd-complex [Pd(L)Cl].H₂O

Figure (4): Mass band of Pd-complex [Pd(L)Cl].H₂O Infrared spectrums of the ligand(MPIAIBA) and Pd(II) complex

Infrared spectra of the ligand(MPIAIBA) and Pd(II) complex

The important IR bands of ligand (MPIAIBA)in addition to its Pd(II)complex have displayed in Table 2. The FT-IR spectrums of the ligand show three bands located in the regions (2835.45, 2904.89 and 2933.83) cm^-1which were assigned to the aromatic and aliphatic (C-H) stretching vibrations, respectively. The IR spectrum exhibits width band at region (3003.27-3134.43) cm^-1 which may be related to (O–H) carboxyl^[19]. while the bands observed at region (3380.21) cm^-1 which may be related to (N–H) imidazole. The band at (1649.19 cm^-1)as a result of ν(C═N) of the N3 imidazole nitrogen, while the bands detected at (1465.95cm^-1) as well as(1298.19cm^-1) allocated for (N=N)^[20] and (C–N=N–C) correspondingly. The band of (N=N) assay in the IR spectrums of the free ligand shows change at position (frequency, shape and intensity band) in the IR spectrums of the complex. These confirm its participation in coordination with palladium ion. The complex spectrums exhibited new weak bands at frequency range (472.58 – 621.10 cm^-1) related to stretching frequency of (M-N) bond^[21], FT-IR spectrums of the ligand and palladium complex have presented in Figs. (5 and 6).

Figure (5): FT-IR Spectrums of ligand (MPIAIBA)

Figure (6): FT-IR Spectrums of Pd-complex [Pd(L)Cl].H₂O

Table (2): Designated IR absorption bands (4000-400) cm^-1 for ligand andits Pd (II) complex (KBr disc)

ν (M–N)	υH2O (inner –sphere coordination)	υH2O(outer-sphere coordination)	v(C-O)	v(C-N)	v(C=C)	ν (N=N)	v(N-H)	v(O-H) carboxyl	Compounds
-----	-----	-----	1174.69	1251.84	1298.19	1465.95	3380.21	3134.21	Ligand = MPIAIBA
522.73	-----	3390.97	1172.76	1253.77	1300.07	1458.30	3090.97	-------	[Pd(L)Cl]. H2O

Magnetic susceptibility and electronic spectrums measurements:

UV-Visible spectrums data for the ligand (MPIAIBA) and its Pd(II) complex were recorded at 200–1100 nm using absolute ethanol as a solvent. The UV-Visible. spectrums of the ligand (MPIAIBA) and Pd(II) complex have presented in Figs. (7 and 8) and the absorption regions, bands assignment and the proposed geometries are given in Table (3). The proposed geometry of the palladium complex are given in Fig.(9).

The electronic spectrum of the ligand (MPIAIBA) is categorized through three absorption bands. These bands are at the position 239nm, 293 nm and 477nm. The initial band can be attributed to a n→π*transition of the azo collection(-N=N-) while the 2^nd band assigned to n →π* of the π-electrons of the phenyl system^[22]. The third band can be assigned to the π →π* transition resulted from the hetro imidazole ring through the azo group (-N=N-)^[23] This band has been depicted at the red transference on direction with palladium ion^[24].

The experimental magnetic moment for Pd(II)-complex has been diamagnetic as a consequence of palladium location is in additional round (d⁸-low spin) and points to a square planar (hybridization dsp²). It approves the square planar of this complex. Electronic spectrum of the Pd (II)- complex exhibits band at 499 nm (20040.08cm^-1) can be allocated for the transition: ¹A₁g→¹B₁g that stands for the stereochemistry for this complex a tetra coordinate. The Pd(II) complex can possibly have D₄h symmetrical organization^[25].

Table (3): Electronic spectrums (nm and cm^-1), electronic transition, magnetic moments, suggested structure and hybridization of the organized ligand besides its Pd(II) Complex

Compounds	λ max (nm)	Absorption bands (cm^-1)	Transitions	μ eff (B.M)	Geometry	Hybridization
Ligand = MPIAIBA	239	41841.00	n →π*	----------	__________	_________
	293	34129.69	n →π*
	477	20964.36	π →π*
[Pd(L)Cl].H2O	321	31250.00	Ligand field	Dia.	Square planer	dsp^2
	499	20040.08	^1A1g→^1B1g

Figure (7): UV-Visible spectrum of ligand (MPIAIBA)

Figure (8): UV-Visible spectrum of Pd-complex [Pd(L)Cl].H₂O

Figure (9): The suggested structural formula of Pd-complex [Pd(L)Cl].H₂O

Effect of the solvent:

The following Fig. (10) shows the Ligand spectrum in the solvents mentioned above. Table (4) shows the obtained absorption values.

Table (4): Maximum absorption values for the ligand in varies solvents

Solvent	(nm)	Absorption
Ethanol	477	0.698
Acetone	515	0.060
DMSO	526	0.797
THF	532	1.723
Hexan	415	0.837

Figure (10): UV-Visible spectrums of ligand (MPIAIBA) in varies solvents

Thermal analysis:

Thermo gravimetric analyses (TGA) and differential thermo gravimetric (DTG) for the azo ligand in addition to its Pd(II) complex were done from room temperature to 900°C. An illustrative TG,DTG diagram is given in Figs. (11 and 12). Calculated and found mass losses are listed in Table (5)^[26].

Table (5). Thermal investigational data for (TGA, DTGA) of ligand and Pd (II)-complex

Residue	Decomposition assignment	Estimated (calculated) %	DTG peak (˚C)	TG Range (˚C)	Dissociation stages	Compound
		Mass loss %
C10H8N2O2	CH2	1.144(2.512)	119.51	39.62.-179.97	Stage I	Ligand=MPIAIBA
	H2O and I	24.521(24.533)	303.04	179.97-393.72	Stage II
	C13H20O	35.876(34.689)	417.47	393.72-899	Stage III
C8H7PdN4O2	The loss of the H2O molecule outer -sphere coordination	1.448(2.526)	128.92	39.84-211.49	Stage I	[Pd(L)Cl].H2O
	C2H9O2Cl	14.773(14.091)	298.40	211.49-335.34	Stage II
	I	17.687(17.934)	361.41	335.34-474.39	Stage III
	C14H14	25.548(25.585)	------	474.39-898.1	Stage IIII

Figure (11):Thermal investigation (TGA and DTG) of ligand (MPIAIBA)

Figure (12): Thermal investigation (TGA and DTG) of Pd-complex [Pd(L)Cl].H₂O

SEM analysis:

The properties of the surface morphology of the ligand (MPIAIBA) and Palladium complex based on the size and outline of the particles and their aggregations were studied along with the distribution of these particles. However, The properties and effectiveness of both of the ligand and Palladium complex are largely determined by the shape and nature of the surface.The SEM image of ligand besides palladium complex were exemplified in Figs.(13 and 14).SEM image presents the ligand (MPIAIBA) with marginal spherical outline with typical size of 45.424 nm with a ratio of a lesser amount as compared with aggregation. The SEM image of Pd(II)-complex appeared in the form of heterogeneous surface with 29.02 nm average particle size.

Figure (13): Scanning electron micrographs of ligand (MPIAIBA)

Figure (14): Scanning electron micrographs of Pd-complex [Pd(L)Cl].H₂O

Pharmacology Results:

Cell viability and cytotoxicity assay:

The MTT cell viability assay is commonly employed in determining medicine susceptibility outlines for patients with hematological malignancies and in incipient screening of probable chemotherapeutic drugs.

In this procedure that was originally developed by Mossman^[27,28], the density of cells is evaluated in accordance with cell color in tiny volumes. Next to adapting spheroids to monocular cells, dualdissimilar densities of monocular cells comprising 8000 and 10,000 cells in dissimilar platelets have been selected for MTT assay. After 24 hours, dissolved MTT in PBS with finishing density of 0.5mg/ml has been inserted and after nursery for 4 hours, MTT solution has been taken and DMSO at that point as inserted and has shaken for 20 minutes. Lastly, absorption of the samples has been measured through changeable 570nm filter as the foremost wavelength and as well 630nm filter as the referenced wavelength. The absorption rate of the wells deprived of cells has decreased from absorbing of the wells with cells to get pure cellular absorbing. In relation to this subsequent equation, there is a straight forward relationship amid pure absorption and rate of practical cells:

                      Mean absorption of sample

% viable cells =---------------------------------------------

                       Mean absorption of reference

The effect of ligand (MPIAIBA) and [Pd(L)Cl].H₂O on growth of hepatocellular carcinoma cellsHepG2 As well as healthy cells (WRL). The concentrations used to inhibit cell growth ranged from (6.25- 400 μg / ml) to hepatocellular carcinoma cells HepG2 and thus to healthy cells (WRL) are shown in table (6)

The cytotoxicity of the prepared compounds was stated as a result of (IC50) median growth inhibitory concentration that involved generating 50% cytotoxic effect in contradiction of cancer cells after 24 hours exposure to tested compounds. The screening results are given in Figs. (15 and 16). In vitro cytotoxicity of the ligand (MPIAIBA), on human cell lines HePG2, Ligand exhibited cytotoxicity against cancer cell line with IC50 =172.3.0 μg/ml; WRI-68 IC50 =238.6μg/ml, while Pd(II)-complex showed selective cytotoxicity in contradiction of cancer cell line with IC50 =115.0 μg/ml; WRI-68 IC50 = 192.1μg/ml. The outcomes of this investigation explained that the sort of compound has a significant role in the rate of inhibition for development of cells with tumorous and natural lines.

Table (6): Consequence of ligand (MPIAIBA) and Pd(II)-Complex on hepatocellular cancerous cells HepG2 viability and comparison with natural cells line (WRL-68) for equivalent concentration via 24-hour MTT test at 37 °c

Mean Percentage (%) for each cell line								Con. (μg.mL^−1)
[PdL) Cl]. H2O				L=(MPIAIBA)
Normal line cells of breast WRI-68		Cancerous line cells of breast HepG2		Normal line cells of breast WRI-68		Cancerous line cells of breast HepG2
Cell Inhibtion	Cell Viability	Cell Inhibtion	Cell Viability	Cell Inhibtion	Cell Viability	Cell Inhibtion	Cell Viability
4.32	95.68	3.63	96.37	4.05	95.95	3.9	96.10	6.25
3.36	96.64	3.36	96.64	4.05	95.95	3.12	96.88	12.5
4.63	95.37	3.78	96.22	4.78	95.22	5.44	94.56	25
4.17	95.83	9.95	90.05	4.67	95.33	9.03	90.97	50
5.71	94.29	31.98	68.02	6.4	93.60	22.38	77.62	100
22.45	77.55	59.68	40.32	15.2	84.80	42.72	57.28	200
36.57	63.43	70.79	29.21	28.05	71.95	61.07	38.93	400

Figure (15): Showing anticancer performance data ligand (MPIAIBA) in contradiction of human cancer cell lines

Figure (16): Showing anticancer performance data of Pd(II)- Complex in contradiction of human cancer cell lines

CONCLUSION:

New azo ligand and its palladium complex have prepared and described by spectrum and analytical data. TGA analysis fixed that the ligand and palladium complex are thermally stable up to 150°C.Elemental analysis has shown the chemical composition of the prepared compounds. The [M:L] ratio of the Pd(II) complex was [1:1] and accordingly, azo ligand appear tridentate corresponding with the palladium ion. Depending upon all results was suggested an square planner for palladium complex. The cytotoxicity of Pd (II)-complex on human hepatocellular carcinomaHepG2 and normal cells have been investigated by means of MTT assay. Through conducted check to recognize the potency of (MPIAIBA)ligand and Pd (II)-complex as drugs to cure several tumorous illnesses that affect humans.

REFERENCES:

1. Sokolova, V., Shi, Z., Huang, S., Du, Y., Kopp, M., Frede, A.,  and Epple, M. (2019). Session 5: Biomaterials-Inorganic. Biomedical Engineering/Biomedizinische Technik, 64(s1), 36-40.

2. Jacob Jincy, Dey Tathagata, Ghate Manjunath, Baby Shaji. Synthesis of Some Novel Coumarino Benzimidazoles Derivatives for Anti-Inflammatory Screening. Asian J. Research Chem. 3(1): Jan.-Mar. 2010; Page 116-120.

3. Das, M., Baro, S., and Kumar, S. (2019). Evaluation of imidazole and its derivative against Newcastle disease virus infection in chicken: A drug repurposing approach. Virus research, 260, 114-122.

4. Sen, C., Patra, C., Mondol, S., Datta, A., Mallick, D., Mondal, T. K., ... and Sinha, C. (2018). Platinum (II)-azoimidazole drugs against TB and cancer: structural studies, cytotoxicity and anti-mycobacterial activity. Polyhedron.

5. Abass, A. K. (2017). Synthesis, Structural and Biological Efficiency Studies of New Azo Ligands and Their complxes with Zn (II), Cd (II) and Hg (II) Metal ion. Ibn AL-Haitham Journal For Pure and Applied Science, 28(3), 169-186.

6. Hu, Y., Shen, Y., Wu, X., Tu, X., and Wang, G. X. (2018). Synthesis and biological evaluation of coumarin derivatives containing imidazole skeleton as potential antibacterial agents. European journal of medicinal chemistry, 143, 958-969.

7. Geromichalos, G. D., Tarushi, A., Lafazanis, K., Pantazaki, A. A., Kessissoglou, D. P., and Psomas, G. (2018). In vitro and in silico study of the biological activity of manganese (III) inverse-[9-MC-3]-metallacrowns and manganese (II) complexes with the anti-inflammatory drugs diclofenac or indomethacin. Journal of inorganic biochemistry, 187, 41-55.

8. Rossi, R., Lessi, M., Manzini, C., and Bellina, F. (2018). Synthesis and Biological Profiles of 4, 5-, 1, 5-, and 1, 2-Diaryl-1H-imidazoles. In Vicinal Diaryl Substituted Heterocycles (pp. 83-160).

9. Hadizadeh, F., Hosseinzadeh, H., Motamed-Shariaty, V. S., Seifi, M., and Kazemi, S. H. (2010). Synthesis and antidepressant activity of N-substituted imidazole-5-carboxamides in forced swimming test model. Iranian Journal of Pharmaceutical Research, 29-33.

10. Hamzah, M. A. M., Jebur, I. K., and Ahmed, A. K. (2018). Synthesis, Characterization and Biological Activity Evaluation of Some New Azo Derivatives from 2-Amino Benzothiazole and Their Derivatives. kirkuk university journal for scientific studies, 13(1), 212-227.

11. Tonelli, M., Simone, M., Tasso, B., Novelli, F., Boido, V., Sparatore, F., ... and Ibba, C. (2010). Antiviral activity of benzimidazole derivatives. II. Antiviral activity of 2-phenylbenzimidazole derivatives. Bioorganic and medicinal chemistry, 18(8), 2937-2953.

12. Bhandari, K., Srinivas, N., Marrapu, V. K., Verma, A., Srivastava, S., and Gupta, S. (2010). Synthesis of substituted aryloxy alkyl and aryloxy aryl alkyl imidazoles as antileishmanial agents. Bioorganic and medicinal chemistry letters, 20(1), 291-293.

13. K. Hofmann (1953). "Imidazole and it's derivatives", Interscience, New York,

14. S. Shibata, M. Furukawa, and R. Nakashima (1976),Syntheses of azo dyes containing 4, 5-diphenylimidazole and their evaluation as analytical reagents. Analytica Chimica Acta, 81(1): 131-141.

15. Revathi, B., Balachandran, V., Raja, B., Anitha, K. and Kavimani, M., (2017). Journal of Molecular Structure, 1141, pp.81-92.

16. Khajehzadeh, M., Rajabi, M., and Rahmaniasl, S. (2019). Synthesis, spectroscopic (UV–vis, FT-IR and NMR), solubility in various solvents, X–ray, NBO, NLO and FMO analysis of (L1) and [(L1) PdCl2] complex: A comprehensive experimental and computational study. Journal of Molecular Structure, 1175, 139-151.

17. Kumar, S., Krishnamurthy, G., Bodke, Y. D., Malojirao, V. H., Kandagalla, S., and Prabhakar, B. T. (2019). Synthesis, characterization and tumor inhibitory activity of a novel Pd (ii) complex derived from methanethiol-bridged (2-((1 H-benzo [d] imidazol-2-yl) methylthio)-1 H-benzo [d] imidazol-6-yl) (phenyl) methanone. New Journal of Chemistry, 43(2), 790-806.

18. R. Mathammal, K. Sangeetha, M. Sangeetha, R. Mekala, S. Gadheeja.(2016). Journal of Molecular Structure, 1118 316-324.

19. S. Demir, A. Guder, T. K. Yazıcılar, S. Çaglar, O. Buyukgungor.(2015). Spectrochim. Acta, Part A 150 821–828.

20.  Sujan Biswas, Samik Acharyya, Deblina Sarkar, Saswati Gharami, Tapan Kumar Mondal. (2016). spectrochimica acta, S1386-1425(16)1-25

21. Khaligh, N.G. (2017). Dyes and Pigments, 139, pp.556-560.

22. Bayoumi, H. A., Alaghaz, A. and Aljahdali, M. S. (2013). Int. J. Electrochem Sci, 8, 9399-9413.

23. Ozlem Ozdemir. (2016). Journal of Molecular Structure, S0022-2860(16)1-46.

24. M. BAL, G. CEYHAN1, B. AVAR,M.OSE1, A. KAYRALDIZ, M. KURTOGLU.(2014).Turk J Chem., 38: 222 - 241 .

25. Thakor, K. P., Lunagariya, M. V., Bhatt, B. S., and Patel, M. N. (2019). Fluorescence and absorption studies of DNA–Pd (II) complex interaction: Synthesis, spectroanalytical investigations and biological activities. Luminescence, 34(1), 113-124.

26. El-Shafei, A. M., Adel, A. M., Ibrahim, A. A., and Al-Shemy, M. T. (2019). Dual functional jute fabric biocomposite with chitosan and phosphorylated nano-cellulose (antimicrobial and thermal stability). International journal of biological macromolecules, 124, 733-741.

27. Henderson, R. A., and Fergusson, C. L. (2019). Growth and provenance of a Paleozoic subduction complex in the Broken River Province, Mossman Orogen: evidence from detrital zircon ages. Australian Journal of Earth Sciences, 1-18.

28. Rettondin, A. R., Carneiro, Z. A., Gonçalves, A. C., Ferreira, V. F., Oliveira, C. G., Lima, A. N., ... and Maia, P. I. (2016). Gold (III) complexes with ONS-Tridentate thiosemicarbazones: Toward selective trypanocidal drugs. European journal of medicinal chemistry, 120, 217-226.

Received on 07.05.2019           Modified on 18.06.2019

Accepted on 21.07.2019         © RJPT All right reserved

Research J. Pharm. and Tech. 2019; 12(11): 5361-5370.

DOI: 10.5958/0974-360X.2019.00931.4