Synthesis, Characterization and biological evaluation of N-methyl p-

methoxybenzohydroxamic acid and its transition metal (Ni, Co, Cu) complexes

FARIDA BEHLIL a, b*, SAMIULLAH a*, NAQEEBULLAH KHAN a, IRSHAD ALI a, ALI
AKBAR c, SAMMER YOUSUF d, ATTIQ-UR-REHMAN a and WAHEED AHMED SHAH a
a
Department of Chemistry, Faculty of Basic Sciences, University of Balochistan, 87300 Quetta,
Pakistan
b
Department of Chemistry, Faculty of Basic Sciences, Sardar Bahadur Khan women’s
University, 87300 Quetta, Pakistan
c
Department of Microbiology, Faculty of Biological Sciences, University of Balochistan, 87300
Quetta, Pakistan
d
H.E.J Research Institute of Chemistry, International Center for Chemical sciences, University
of Karachi, 75270 Karachi, Pakistan

A new ligand, N-methyl-p- methoxybenzohydroxamic acid (Nmpmbha) and its transition metal complexes
Ni(Nmpmbha)2, Co(Nmpmbha)2 and Cu(Nmpmbha)2 have been synthesized. The ligand and its complexes are
characterized using FT-IR, 1H NMR and 13C NMR spectroscopic techniques, whereas the structure of compound 1
has been investigated by single X-ray diffraction studies. Spectroscopic studies reveal that ligand is coordinated with
metals via O, O donor sites and acts as a bc identate chelator, and forms a five-membered chelating ring on
complexation. Antibacterial activity of the free ligand and its transition metal complexes are tested against four
different species of Gram negative and Gram positive bacterial strains. The complexes exhibit stronger antibacterial
efficacy as compared to free ligand owing to the greater lipophilicity of complexes.

Key words: Hydroxamic acid, transition metal complexes, NMR, X-Ray crystallography, antibacterial activity

1. Introduction

Hydroxamic acids have gained the interest of most of the biochemists by showing versatile
biological activities. Most of their activities are due to their ability to form chelates with metal
ions, particularly with transition metals. In most of the metal-hydroxamic acid complexes such as
iron, nickel, copper and cobalt, the ligands are in keto form and coordinate thorough O, O-donor
sites [1-3]. Various synthetic methods are reported in the literature for the synthesis of
hydroxamic acids [4-7] but some of these methods are tiresome, time consuming and expensive.
These ligands are usually prepared by the reaction of hydroxylamine with acid chlorides or esters
[8-10]. Hydroxamic acids are capable to act as anti-cancer, anti-tuberculosis, hypotensive,
antimalarial, antifungal and antiallergic properties [11-12]. These can act as selective and
effective enzyme inhibitors for specific enzymes such as matrix metalloproteinanses,
histonedeacetylases, peroxidases [13] and ureases [14]. 1

Transition metals show various oxidation states and can react with several negatively charged
molecules [15]. Due to such activity, transition metals have been utilized in many metal based
drugs resulting enhanced pharmacological and therapeutic properties. The transition metal

1*
Corresponding authors: faridabehlil@yahoo.com; sami435889@yahoo.com
complexes exhibit various activities such as anticancer [16], anti-inflammation and antimicrobial
[17]. Transition metal complexes also act as significant catalysts in photochemistry and material
synthesis. These complexes show various chemical, optical and magnetic properties [18].

In this work, we have synthesized a new bidentate ligand, N-methyl-p-

methoxybenzohydroxamic acid and its Ni(II), Co(II) and Cu(II) metal complexes. The
synthesized compounds have been characterized by FTIR, UV/VIS, 1H NMR and 13CNMR
spectroscopic techniques whereas the structure of ligand has been investigated by single X-ray
diffraction technique.

2. Material and methods

All materials were bought from Sigma-Aldrich and used without further purification. All the
chemicals were of analytical grade. Purity of ligand and its complexes was assured by TLC.
Melting points were determined on an electro-thermal melting point apparatus in open glass
capillaries. Elemental analysis of C, H and N were determined using Elemental Fison EA 1108
CHNS-O Analyzer. IR spectrum was recorded using KBr pellets on FTIR spectrophotometer.
UV/VIS spectrum was recorded in Dimethylformamide (DMF) with UV/VIS spectrophotometer
(UV-VIS 1700, Shimadzu). The NMR studies were carried out on a BRUKER FT-NMR
spectrometer. 1H NMR (500MHz) and 13C NMR (100 MHz) studies of samples were analyzed in
deuterated chloroform (CHCl3 -d). The single-crystal X-ray diffraction measurements were
performed using Bruker SMART APEXII CCD diffractometer.

2.1 Synthesis of N-methyl-p-methoxybenzohydroxamic acid (1)

p-Methoxybenzoyl chloride (4.3 g, 25 mmol) was added dropwise in an ice-cooled mixture of

sodium bicarbonate (4.2 g, 50 mmol) and N-methylhydroxylamine hydrochloride (2.1g, 25
mmol) in methanol (100 mL), and continued stirring for 30 min. This mixture was filtered and
evaporated at low pressure. Dissolved the resulting mass in boiled ethyl acetate (50 mL) and
filtered to remove any undissolved matter. The ligand started to precipitate on cooling and left-
over night in the fridge to afford crystals. Pure crystals of the ligand were dried over silica [8,10].
Synthesis of ligand is shown in Scheme 1.
O
O

OH
N
Cl NaHCO3
+ CH3NHOH.HCl
MeOH
-NaCl O
O

Scheme 1: Synthesis of N-methyl-p-methoxybenzohydroxamic acid

2.2 Synthesis of complexes

An equivalent mixture of free ligand and potassium hydroxide were stirred for 15 min in
methanol at room temperature. An aqueous solution of metal salts of transition elements (Cu, Ni,
and Co) were added stirred for two hours. The ratio of ligand and metals salts was kept 2:1,
respectively. The solid products were collected by filtration and washed with water, methanol,
and petroleum ether, and dried [11]. Synthesis of complexes is shown in Scheme 2.

N O

OH
MeOH/ KOH
MCl2

OH2
O
N O O

O O N
O
OH2

Scheme 2: Synthesis of complexes of N-methyl-p-methoxybenzohydroxate with transition metals

2.3 X-ray crystallography:

Slow evaporation of the ligand in ethyl acetate yielded pure and colourless crystals. Suitable
crystal of ligand 1 was selected for X-ray diffraction analysis. Data was measured on Bruker
APEX-II CCD area diffractometer furnished with graphite monochromatic Mo Kα radiation (𝜆 =
71073 ˚A) at 293 (2) ∘K. Cell refinement and data reduction were measured by Bruker SAINT
[19]. Structure was solved by SHELXS-97 [20-21]. The final refinement was carried out by full
matrix least-squares techniques with anisotropic thermal data for nonhydrogen atoms on F2. All
the hydrogen atoms were placed in calculated positions. The crystal structure of ligand was
finally refined with R factor of 4.24% for 1660 unique reflections (Figure 1).

2.4 Antibacterial activity

The antibacterial activity of the synthesized ligand and its transition metal complexes were
determined by using Agar well method [22] against Staphylococcus aureus a Gram positive
bacteria and Klebsiella pneumoniae, Salmonella typhi and Escherichia coli as Gram negative
bacteria. The Agar Well medium was prepared by pouring molten Mueller Hinton agar on petri
dishes and solidified. Wells of 6 mm were made by using sterilized borers. Each well was loaded
with the 100 mL of stock solutions (5 mg/mL in DMSO) of synthesized compounds. Pure
DMSO was loaded as control. Amoxicillin (30 𝜇g/mL) was used as antibacterial standard drug.
The petri plates were then incubated for 24 h at 37ºC. Inhibition zones were measured in
millimeter (mm) [23-25].

3. Results and discussion

3.1 Synthesis of ligand

The preparation of bidentate ligand N-methyl-p- methoxybenzohydroxamic acid was carried out
by the nucleophilic substitution of p-methoxy benzoyl chloride with N-methylhydroxylamine
hydrochloride in the presence of a weak base such as sodium bicarbonate. Transition metal
complexes (TMCs) were synthesized by reaction of free ligand with MCl2 [Ni (II), Cu(II) and
Co(II)] in the presence of KOH in methanol. Purity of the synthesized ligand and its transition
metal complexes was assured by TLC. The physical properties and analytical data of the ligand
and its complexes are given in Table 1. The calculated values are in good agreement with
experimental ones.

Table1: Physical data of ligand and its transition metal complexes

Compound State Yield (%) MP ºC %C %H %N

Nmpmbha(1) colourless 85 107-108 58.13 5.82 6.58

crystals (59.66) (6.12) (7.73)
Ni(Nmpmbha)2 Light green 61 204-205 50.68 4.06 5.12
(1a)
 (51.59) (4.81) (6.68)
Co(Nmpmbha)2 Pink solid 75 156-157 50.63 4.53 5.86
(1b) (51.56) (4.81) (6.68)
Cu(Nmpmbha)2 Dark green 72 163-164 48.15 3.58 5.78
(1c) (51.00) (4.76) (6.61)

3.2 Infrared spectroscopy

Infrared spectra of ligand and its complexes have been recorded in solid state in the range 4000-
400 cm-1. The principle absorption bands are given in Table 2. In IR spectrum of free
hydroxamic acid, the main stretching vibrations are v(OH), v(C=O), v(N-C) and v(N-O) observed
in the range of 3152 cm -1, 1606 cm-1, 1434 cm-1, and 914 cm-1, respectively. The broad band in
the range of 3152 cm-1 for v(OH) shows the existence of intramolecular hydrogen bonding. The
important band of v(C=O) positioned in the range 1606 cm -1 is notably below the ketonic range
(1650 cm-1) indicates the existence of ligand in ketonic form [26-27].

In IR spectra of complexes, the absence of ν(O-H) absorption in the range 3152cm -1 is the most
important characteristic. The complexes are easily recognized by observing the absence of ν(O-
H) peak of hydroxyl group present in spectra of ligand. Therefore, it is interpreted that the proton
of hydroxyl group has been replaced by metal ions on complexation. It also indicates the
existence of ligand in deprotonated form in complexes. The carbonyl group ν(C=O) appears in
the range of 1601-1591 cm-1 in spectra of complexes. This lower range existence of ν(C=O)
vibrations suggest the coordination of ligand via oxygen of carbonyl group complexation. The
absence of ν(O-H) vibration and existence of carbonyl group in the lower range as compared to
normal ketonic peak indicates the bidentate nature of ligand and existence of a five membered
chelating ring on complexation [11]. The IR peaks in the range of 1480-1457cm- 1 show the
presence of (C-N) bond. Strong absorption band occurring in the range of 948-943 cm- 1 in
spectra of complexes are due to v(N-O) stretching vibrations. A broad band appears in the region
3500 to 3300 cm-1 along with a characteristic peak in the range 715-719 cm-1 in spectra of
complexes suggest coordination of water molecules with metal ions and six coordinated
geometry around metals.

Short and weak bands appearing in the low energy region because of lower energy vibrations
indicate the formation of metal oxygen bonds (M-O). These M-O stretching vibrations appearing
in spectra of complexes at 608 cm -1, 563 cm-1, 516 cm-1 have been assigned to M-O bonds of
Ni(Nmpmbha)2, Co(Nmpmbha)2 and Cu(Nmpmbha)2, respectively. This strongly supports the
formation of transition metal hydroxamates [28-29].
 Table: 2 Infrared data for ligand and its transition metal complexes
Compound v(OH) cm-1 v(C=O)cm-1 v(C-N) cm-1 v(N-O) cm-1 v(M-O) cm-1

Nmpmbha 3152 1606 1434 914 -----

Ni(Nmpmbha)2 ---- 1601 1480 946 608
Co(Nmpmbha)2 ---- 1598 1479 943 563
Cu(Nmpmbha)2 ---- 1591 1457 948 516

3.3 NMR spectroscopy

The 1HNMR and 13CNMR spectra of the ligand and N-methyl-p-methoxybenzohydroxamic acid
1 and 1HNMR spectra of its complexes 1a and 1b were recorded in CDCl3. The 1H NMR
spectrum of the ligand clearly confirms the formation of the ligand by showing number of
protons determined in spectrum equivalent to the total number of protons calculated from the
expected molecular formula. The analysis based on 1H NMR results was further supported by 13C
NMR studies. The chemical shifts in ppm of various protons and carbon for the hydroxamic
acids are presented in Tables 3 and 4, respectively. The low field absorption of OH proton at
7.78 ppm in 1HNMR spectrum indicates the occurrence of intramolecular hydrogen bonding
between the OH proton and oxygen of the CO group. The protons of aromatic ring appeared in
the range 7.52-6.89 ppm. The protons of methyl group attached with oxygen atom are found
down field and more deshielded due to the more electronegative nature of oxygen as compared
to the methyl group protons attached to the nitrogen atom. The protons of methyl group attached
to nitrogen atom occur as a singlet at 3.42 ppm. In 1HNMR spectra of complexes, the
disappearance of OH absorption clearly evidences the formation of complexes and coordination
of ligand 1 through oxygen atom of deprotonated hydroxyl group, which is in accordance with
the IR spectral interpretation. The unaffected position of –NCH 3 protons indicates the non-
involvement of nitrogen donor atom in coordination. 13C NMR spectrum of ligand shows a
downfield peak at 167.2 ppm due to carbon of carbonyl group. The signals at 134.0-113.7 ppm
appear for aromatic carbon atoms. The signals at 55.41 and 38.64 ppm are assigned to methyl
groups carbon atoms attached with oxygen and nitrogen atoms, respectively [8,10].

Table 3. 1H NMR chemical shift values of N-methyl p-methoxybenzohydroxamic acid

Compound OH C6H4 O-CH3 N-CH3

Nmpmbha 1 7.78b 7.50-6.89m (4H) 3.82s (3H) 3.42s (3H)

(1H)

Ni(Nmpmbha)2 7.50-6.9m(4H) 3.83s (3H) 3.40s(3H)

1a
Co(Nmpmbha)2 7.50-6.89m (4H) 3.83s (3H) 3.40s (3H)
1b
 Table 4. 13C NMR chemical shift values of N-methyl p-methoxybenzohydroxamic acid
Compound C=O C6H4 O-CH3 N-CH3

Nmpmbha 167.2 134.0-113.7 55.41 38.64

3.4 Electronic spectrum

In electronic spectrum of Ni(II) complex, three absorption bands are observed corresponding to
the transitions 3A2g→3T2g (F), 3A2g→3T1g (F) and 3A2g→3T1g (P). The values of these absorption
bands are 13200 cm-1, 17410 cm-1 and 27345 cm-1, respectively which fall in the range of
distorted octahedral geometries. The absorption band at 13200 cm -1 is due to d-d electronic
transitions [30-31].

In electronic spectrum of Co(II), three absorption bands are found corresponding to the
transitions 4T1g →4T2g(F), 4T1g→4A2g(F) and 4T1g→4T2g(P). The values observed for these
transitions are 9315 cm-1, 17300 cm-1 and 23435 cm-1, respectively. These values suggest a
distorted octahedral geometry around Co(II) in complex 1b [32].

The electronic spectrum of Cu(II) displays three absorption bands at 13250 cm-1, 18445 cm-1and
33230 cm-1. The bands in the region 13000-19000 cm-1 due to d-d transitions suggests a distorted
octahedral geometry around complex 1c [33].

3.5 X-ray crystallography

The suitable quality single crystal of ligand was each fixed and placed on the BRUKER
SMART CCD diffractometer, equipped with the radiation source (𝜆 = 71073 ˚A). The ranges
2.64 to 25.49 for ligand was selected for the data collections. Calculation was done by using
SHELXTL-97 program. The data collection and refining parameters are described in Table 5.
Figure 1 represents the molecular structure of the ligand. Selected bond distances and bond
angles of the ligand is recorded in the table 6 and 7 respectively. Single crystal X-ray structure
determination of ligand demonstrated that the compound exists in E conformation. The carbonyl
oxygen and the hydroxyl oxygen in the ligand are trans to each other, probably due to the steric
influence between the methyl substituent on the hydroxamate fragment with the methoxy group
and the hydroxamate moiety is in the E conformation [8]. The torsion angles O=C-N-O observed
in the hydroxamates groups are 0º for Z and 180º for E conformations. Therefore, in this case the
torsion angle in the crystal structure is -171.30(16) º presenting that the molecular skeleton is
approximately planar with some out of plane deformations.

Figure 1. Crystal structure of N-methyl p-methoxybenzohydroxamic acid

Table 5: Crystal data and structure refinement for N-methyl p methoxybenzohydroxamic

acid
Empirical formula C9 H11 N O3
Formula weight 181.19 g
Temperature 298(2) K
Wavelength 0.71073 A
Crystal system, space group Orthorhombic, P212121
Unit cell dimensions a = 7.5454(10) A alpha = 90 deg.
b = 10.8085(15) A beta = 90 deg.
c = 10.9892(14) A gamma = 90 deg.
Volume 896.2(2) A^3
Z, Calculated density 4,1.343 Mg/m^3
Absorption coefficient 0.102 mm^-1
F (000) 384
Crystal size 0.32 x 0.21 x 0.13 mm
Theta range for data collection 2.64 to 25.49 deg.
Limiting indices -9<=h<=8,
-13<=k<=13,
-13<=l<=9
Reflections collected / unique 5303 / 1660 [R(int) = 0.0241]
Completeness to theta = 25.49 100.00%
Max. and min. transmission 0.9869 and 0.9682
Refinement method F^2 Full-matrix least-squares on
Data / restraints / parameters 1660 / 0 / 123
Goodness-of-fit on F^2 1.072
 R1 = 0.0342,
Final R indices [I>2sigma(I)] wR2 = 0.0766
R1 = 0.0424,
R indices (all data) wR2 =0.0814
Absolute structure parameter 1.2(14)
Extinction coefficient 0.023(3)
Largest diff. peak and hole 0.117 and -0.126 e.A^-3

Table 6. Selected bond lengths of N-methyl p methoxybenzohydroxamic acid, 1

O(1)-C(7) 1.244(2) C(3)-H(3A) 0.93
O(2)-C(1) 1.366(2) C(4)-C(5) 1.382(2)
O(2)-C(9) 1.414(2) C(4)-C(7) 1.486(3)
O(3)-N(1) 1.3958(19) C(5)-C(6) 1.379(3)
O(3)-H(1A) 0.95(3) C(5)-H(5A) 0.93
N(1)-C(7) 1.336(2) C(6)-H(6A) 0.93
N(1)-C(8) 1.440(2) C(8)-H(8A) 0.96
C(1)-C(6) 1.378(3) C(8)-H(8B) 0.96
C(1)-C(2) 1.391(3) C(8)-H(8C) 0.96
C(2)-C(3) 1.374(3) C(9)-H(9A) 0.96
C(2)-H(2A) 0.93 C(9)-H(9B) 0.96
C(3)-C(4) 1.385(2) C(9)-H(9C) 0.96

Table: 7: Selected bond angles [deg] of N-methyl p methoxybenzohydroxamic acid, 1

C(1)-O(2)-C(9) 117.94(15) C(4)-C(5)-H(5A) 119.4
N(1)-O(3)-H(1A) 104.9(16) C(1)-C(6)-C(5) 119.66(18)
C(7)-N(1)-O(3) 120.62(15) C(1)-C(6)-H(6A) 120.2
C(7)-N(1)-C(8) 124.33(16) C(5)-C(6)-H(6A) 120.2
O(3)-N(1)-C(8) 114.89(15) O(1)-C(7)-N(1) 119.75(17)
O(2)-C(1)-C(6) 124.63(18) O(1)-C(7)-C(4) 121.44(16)
O(2)-C(1)-C(2) 115.58(16) N(1)-C(7)-C(4) 118.81(16)
C(6)-C(1)-C(2) 119.79(17) N(1)-C(8)-H(8A) 109.5
C(3)-C(2)-C(1) 119.83(17) N(1)-C(8)-H(8B) 109.5
C(3)-C(2)-H(2A) 120.1 H(8A)-C(8)-H(8B) 109.5
C(1)-C(2)-H(2A) 120.1 N(1)-C(8)-H(8C) 109.5
C(2)-C(3)-C(4) 120.89(17) H(8A)-C(8)-H(8C) 109.5
C(2)-C(3)-H(3A) 119.6 H(8B)-C(8)-H(8C) 109.5
C(4)-C(3)-H(3A) 119.6 O(2)-C(9)-H(9A) 109.5
C(5)-C(4)-C(3) 118.55(16) O(2)-C(9)-H(9B) 109.5
C(5)-C(4)-C(7) 121.97(16) H(9A)-C(9)-H(9B) 109.5
C(3)-C(4)-C(7) 119.38(16) O(2)-C(9)-H(9C) 109.5
C(6)-C(5)-C(4) 121.21(18) H(9A)-C(9)-H(9C) 109.5
C(6)-C(5)-H(5A) 119.4 H(9B)-C(9)-H(9C) 109.5
3.5. Antibacterial Activity:

Hydroxamic acid and its TMCs were analysed for antibacterial activity against Gram-positive (S.
aureus) and Gram-negative bacteria (S. typhi, K. pneumoniae and E. coli) by using agar well
method and the activity was compared with the standard drug doxycycline at 30 𝜇g/mL. The
ligand and TMCs were found to inhibit all tested bacterial stains (Table 8). It was found that
transition metal complexes have high activity than the ligand. The enhanced antimicrobial
activity of the complexes as related to ligand is because of chelation property which enhances the
complexes lipophilicity and results in the inhibition of the growth of the bacterial strains [22, 30,
34-32]. Among the TMCs Cu(II) complex exhibited the higher antibacterial activity which may
de due to the higher stability of Cu(II) complexes.

Table 8. Antibacterial activity of ligand and its transition metal complexes

Inhibition zone (mm)*
Compound
E. coli S. typhi K. pneumoniae S. aureus
Nmpmbha 1 16 16 13 19
Ni(Nmpmbha)2 1a 18 17 16 21

Co(Nmpmbha)2 1b 18 19 17 20

Cu(Nmpmbha)2 1c 20 20 19 24

Amoxicillin 28 28 26 25

DMSO --- --- --- ---

*Inhibition zone: 6mm

Conclusion: The novel ligand and its transition metal complexes are successfully synthesized
and characterized by FT-IR, UV/VIS, 1H NMR and 13C NMR spectroscopic technique. The
structure of the ligand was confirmed by X-ray diffraction method. The IR spectroscopic data
indicated that the metal ions are complexed with oxygen atom of the hydroxamic acid. The
ligand and its complexes showed positive activity against gram positive and gram-negative
strains of bacteria. These compounds can be used as antibacterial agent and can also be screened
for synthesizing new drugs for different illnesses.

Supplementary material
Crystallographic data for the ligand 1 reported in the article has been deposited at the Cambridge
Crystallographic Data Centre, CCDC reference number 1812534 And can be obtain free of
charge on application from the Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
(fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk; website: http://www.ccdc.cam.ac.uk).

Acknowledgements

The authors are grateful to the Department of Chemistry, University of Balochistan, Department
of Microbiology, University of Balochistan and H.E.J research institute Karachi, University of
Karachi for supporting this research work.

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