Metalloantibiotics: Synthesis and antimicrobial activity of clotrimazole metal chelates, spectroscopic, and thermal characterization

Article abstract of DOI:10.1080/15533174.2011.568440

Metal complexes of clotrimazole (CLMZ) drug were prepared and characterized based on elemental analyses, IR, magnetic moment, molar conductance, and thermal analyses techniques. The complexes have the general formulae [MCl ₂(H₂O)₂(L)₂]·yH₂O (where M = Mn(II), Cu(II)), Co(II), Ni(II), Zn(II), y = 0 - 3) and [MCl ₂(H₂O)₂(L)₂]Cl·yH ₂O (where M = Cr(III) and Fe(III), y=0 - 3). The molar conductance data reveal that bivalent metal chelates are non-electrolytes while Cr(III) and Fe(III) chelates are of 1:1 electrolytes. IR spectra show that CLMZ is coordinated to the metal ions in a neutral unidentate manner with N donor site of the imidazole-N. The geometrical structures of these complexes are octahedral. The thermal behaviour of these chelates was studied and the activation thermodynamic parameters are calculated using Coats-Redfern method. CLMZ and its metal complexes were screened for their antibacterial activity against bacterial and fungi species. The metal complexes are found to have more biological activity than the parent CLMZ drug. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15533174.2011.568440

This article was downloaded by: [Pennsylvania State University]
On: 12 August 2014, At: 06:10
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthesis and Reactivity in Inorganic, Metal-Organic,
and Nano-Metal Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsrt20
Metalloantibiotics: Synthesis and Antimicrobial
Activity of Clotrimazole Metal Chelates,
Spectroscopic, and Thermal Characterization
Hanan F. Abd El-Halim a , F. A. Nour El-Dien b , Gehad G. Mohamed b & Nehad A. Mohmed
b
a Pharmaceutical Chemistry Department, Faculty of Pharmacy , Misr International
University , Cairo, Egypt
b Chemistry Department, Faculty of Science , Cairo University , Giza, Egypt
Published online: 25 May 2011.
To cite this article: Hanan F. Abd El-Halim , F. A. Nour El-Dien , Gehad G. Mohamed & Nehad A. Mohmed (2011)
Metalloantibiotics: Synthesis and Antimicrobial Activity of Clotrimazole Metal Chelates, Spectroscopic, and Thermal
Characterization, Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 41:5, 544-554
To link to this article: http://dx.doi.org/10.1080/15533174.2011.568440
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 41:544–554, 2011
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2011.568440
Metalloantibiotics: Synthesis and Antimicrobial Activity of
Clotrimazole Metal Chelates, Spectroscopic, and Thermal
Characterization
Hanan F. Abd El-Halim,1 F. A. Nour El-Dien,2 Gehad G. Mohamed,2
and Nehad A. Mohmed2
1Pharmaceutical Chemistry Department, Faculty of Pharmacy, Misr International University,
Cairo, Egypt
2Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
mazole has a broad spectrum of in vitro antimicrobial activity.
Its effective therapeutic use as a topical applicant in treating skin
and nail infections in man and in vaginal candidiasis has been
reported.[6]
Metal complexes of clotrimazole (CLMZ) drug were prepared
and characterized based on elemental analyses, IR, magnetic
moment, molar conductance, and thermal analyses techniques.
The complexes have the general formulae [MCl2(H2O)2(L)2].yH2O
(where M = Mn(II), Cu(II)), Co(II), Ni(II), Zn(II), y = 0 − 3)
and [MCl2(H2O)2(L)2]Cl.yH2O (where M = Cr(III) and Fe(III),
y = 0 − 3). The molar conductance data reveal that bivalent metal
chelates are non-electrolytes while Cr(III) and Fe(III) chelates are
of 1:1 electrolytes. IR spectra show that CLMZ is coordinated to
the metal ions in a neutral unidentate manner with N donor site
of the imidazole–N. The geometrical structures of these complexes
are octahedral. The thermal behaviour of these chelates was stud-
ied and the activation thermodynamic parameters are calculated
using Coats-Redfern method. CLMZ and its metal complexes were
screened for their antibacterial activity against bacterial and fungi
species. The metal complexes are found to have more biological
activity than the parent CLMZ drug.
However, in this work, metal chelates of Mn(II), Cr(III),
Fe(III), Co(II), Ni(II), Cu(II), and Zn(II) with CLMZ drug
molecule were prepared. The solid chelates are characterized
using different physico-chemical methods, such as elemental
analyses (C, H, N, Cl, and metal content), IR, 1H NMR, mag-
netic moment, and reflectance spectra, and thermal analyses (TG
and DTA). Biological activities of the complexes are studied us-
ing Gram (+ve) and Gram (-ve) bacteria and Fungi organisms.
The structure of the drug is given in Figure 1.
EXPERIMENTAL
Keyords 1H NMR, solid reflectance, biological activity, clotrima-
zole, IR, magnetic moment, metal complexes, molar con-
ductance, thermal analyses
Materials and Reagents
All chemicals used were of analytical reagent grade (AR),
and of highest purity available. They included clotrimazole
(Bayer); CuCl2·2H2O (Prolabo); CoCl2.6H2O and NiCl2.6H2O
(BDH); ZnCl2 (Ubichem), CrCl3.6H2O (Sigma); MnCl2.2H2O
and FeCl3.6H2O (Prolabo). Organic solvent used was absolute
ethyl alcohol. De-ionized water collected from all glass equip-
ment was usually used in all preparations.
INTRODUCTION
Metallopharmaceuticals playing
a significant role in
therapeutic and diagnostic medicine, and the discovery and
development of new metallodrugs remain an ever growing area
of research in medicinal inorganic chemistry.[1–3] The incorpo-
ration of the imidazole nuclei is an important synthetic strategy
in drug discovery. Many imidazoles, such as azomycine, clotri-
mazole, miconazole, ergothionine, clonidine and moxonidine,
have been prepared as pharmacological agents.[4] One of the
most important applications of imidazole derivatives is their use
as reline material for treatment of denture stomatities.[5] Clotri-
Instruments
Elemental microanalyses of the separated solid chelates for
C, H, N, and Cl were performed at the Microanalytical Center,
Cairo University. Infrared spectra were recorded on a Perkin-
Elmer FT-IR type 1650 spectrophotometer in wavenumber
region 4000–400 cm−1. The spectra were recorded as KBr
pellets. The mass spectrum of the drug under investigation was
recorded by EI technique at 70 eV using MS-5988 GS-MS
Hewlett-Packard instrument at the Microanalytical Center,
Cairo University. The 1H NMR spectra were recorded using 300
MHz Varian-Oxford Mercury, the deuterated solvent used was
dimethylsulphoxide (DMSO), and the spectra extended from
Received 15 August 2010; accepted 1 February 2011.
Address correspondence to Hanan F. Abd El-Halim, Pharmaceu-
tical Chemistry Department, Faculty of Pharmacy, Misr International
University,, Cairo, Egypt. E-mail: hanan.farouk2@yahoomail.com
544

METALLOANTIBIOTICS
545
Biological Activity
The main aim of the production and synthesis of any antimi-
crobial compound is to inhibit the causal microbe without any
side effects on the patients; the interest toward transition metal
complexes containing N-donor ligands has increased in order to
obtain metal-based drugs exhibiting a high biological activity
together with a reduced toxicity. In this respect, drugs with their
transition metal complexes have been extensively biologically
investigated.
FIG. 1. Structure of CLMZ drug.
In testing the antibacterial and antifungal activity of CLMZ
drug and its metal complexes, more than one test organism is
used to increase the chance of detecting antibiotic principles in
tested materials. The sensitivity of a microorganism to antibiotic
and other antimicrobial agents is determined by the assay plates
which incubated at 28◦C for two days for yeasts and at 37◦C for
one day for bacteria.
A filter paper sterilized disc saturated with measured quan-
tity of the sample is placed on plate containing solid bacterial
medium(nutrient agar broth)orfungal medium(Doxsmedium),
which has been heavily seeded with the spore suspension of the
tested organism. After inoculation, the diameter of the clear zone
of inhibition surrounding the sample is taken as a measure of the
inhibitory power of the sample against the particular test organ-
ism. 0.1 mL DMSO alone was used as a control under the same
condition for each organism. The antibacterial and antifungal
activities can be calculated as a mean of three replicates.[7]
0 to 15 ppm. The thermal analyses (TG, DTG, and DTA) were
carried out in dynamic nitrogen atmosphere (20 mL.min−1
)
with a heating rate of 10◦C min−1 using Shimadzu TG-60H and
DTA-60H thermal analyzers. The solid reflectance spectra were
measured on a Shimadzu 3101pc spectrophotometer. The molar
magnetic susceptibility was measured on powdered samples
using the Faraday method. The diamagnetic corrections were
made by Pascal’s constant, and Hg [Co (SCN)4] was used as a
calibrant.
Synthesis of Metal Complexes
The metal complexes were prepared by the addition of hot
solution (60◦C) of the appropriate metal chloride (1 mmol) in an
ethanol-water mixture (1:1, 25 mL) to the hot solution (60◦C) of
CLMZ (0.5 g, 2 mmol) in the same solvent (25 mL). The result-
ing mixture was stirred under reflux for one hour whereupon
the complexes precipitated. They were collected by filtration,
then purified by washing several times with a 1:1 ethanol: water
mixture and petroleum ether. The analytical data for C, H, N,
and Cl were repeated twice.
RESULTS AND DISCUSSION
The formation of metal complexes with organic compounds
has long been recognized. However, the binary complexes of the
TABLE 1
Analytical and physical data of CLMZ metal complexes
% Found (calcd.)
Color
(% yield) M.P. (◦C)
µeff.
ꢀm
Complex
C
H
N
Cl
M
(B.M.) (ꢁ−1mol−1cm2)
[CrCl2(L)2(H2O)2]Cl
C44H40Cl5CrO2
[MnCl2(L)2(H2O)2]
C44H40Cl4MnO
Green
(70)
White
(75)
>300
>300
>300
>300
>300
>300
>300
60.04
3.96
6.33
19.80
5.88
5.70
5.48
5.98
5.38
3.90
2.02
Diam.
80
19
75
20
12
15
18
(59.78) (4.33) (6.34) (20.05) (5.87)
63.33 4.37 6.61 16.20 6.48
(63.34) (4.31) (6.72) (16.60) (6.46)
49.93 5.15 5.92 19.20 6.63
(50.10) (4.71) (5.95) (18.82) (6.61)
57.93 4.10 6.18 15.28 6.47
(58.10) (3.88) (6.59) (15.59) (6.49)
57.75 4.68 5.93 15.32 6.45
(58.12) (4.88) (6.16) (15.59) (6.44)
58.89 3.44 5.93 16.07 7.10
(59.03) (3.69) (6.26) (15.87) (7.09)
57.48 3.77 5.87 19.77 7.15
(57.69) (3.84) (6.12) (19.48) (7.17)
[FeCl2(L)2(H2O)2]Cl·3H2O Brown
C44H47Cl5FeO5
(65)
Blue
(72)
Green
(60)
Green
(68)
[CoCl2(L)2(H2O)2]·3H2O
C44H44Cl4CoO5
[NiCl2(L)2(H2 O)2]·3H2O
C44H47Cl4NiO5
[CuCl2(L)2(H2 O)2]·2H2O
C44H42Cl4CuO4
[ZnCl2(L)2(H2 O)2]·3H2O
C44H47Cl4ZnO5
Brown
(77)

546
H. F. ABD EL-HALIM ET AL.
TABLE 2
IR spectra (4000–400 cm−1) of the CLMZ drug and its metal complexes
Compound
ν(O H) Hydrated water
ν(C N) ν(O H) Coordinated water ν(C Cl) ν(M N)
CLMZ; L
[CrCl2(L)2(H2O)2]Cl
[MnCl2(L)2(H2O)]
[FeCl2(L)2(H2O)2]Cl·3H2O
[CoCl2(L)2(H2O)2]·3H2O
[NiCl2(L)2(H2O)2]·3H2O
[CuCl2(L)2(H2O)2]·2H2O
[ZnCl2(L)2(H2O)2]·3H2O
3447b
3148b
3396b
3396b
3550sh
3351b
3447b
3505b
1654sh
1593m
1593m
1588sh
1650sh
1625m
1654sh
1613sh
——
945sh
926m
900w
945sh
936m
948sh
940sh
1081m
1088m
1084m
1089m
1080sh
1087sh
1088m
1083m
——
453sh
455sh
450m
457m
455sh
452m
455m
sh = sharp, m = medium, s = small, w = weak, br = broad.
cited drug with metal ions have not been studied yet, although
they may be an area of interest. This is because they may affect
the bioavailability of this drug as certain metal ions were present
in relatively appreciable concentration in biological fluids.
IR Spectra and Mode of Bonding
The characteristic peaks of the drug and its metal complexes
are listed in Table 2. Upon comparison, it is found that the
band located at 1654 cm−1 is assigned to the ν(C N) stretching
vibration of imidazole nitrogen for CLMZ drug.[8] Coordination
of the imidazole nitrogen to the metal ion is indicated by a 2–9
cm−1 shift to lower wavenumber, or to higher wavenumber or
disappeared. The band located at 1081 cm−1 is assigned to the
ν(C Cl) in the free drug. This band remains intact in solid
complexes, indicating its non-involvement in coordination to
the metal ions.
Composition and Structures of Metal Complexes
The isolated solid complexes of Cr(III), Mn(II), Fe(III),
Co(II), Ni(II), Cu(II), and Zn(II) ions with the CLMZ drug
are subjected to elemental analyses (C, H, N, Cl, and metal
content), IR, 1H NMR, magnetic moment, molar conductance,
and thermal analyses (TG and DTA), to identify their ten-
tative formulae in a trial to elucidate their molecular struc-
tures. The results of elemental analyses listed in Table 1
suggest the formula [MCl2(H2O)2(L)2].yH2O (where M =
Mn(II) (y = 0), Cu(II) (y = 2), and Co(II), Ni(II), Zn(II)
(y = 3), and [MCl2(H2O)2(L)2]Cl.yH2O (where M = Cr(III)
(y = 0) and Fe(III) (y = 3). The results obtained are in
a good agreement with those calculated for the suggested
formulae.
According to the IR data, it is concluded that CLMZ drug
behaves as a neutral unidentate ligand coordinated to the metal
ions via the imidazole N.
1H NMR Spectra
1
The H NMR spectra of CLMZ and its diamagnetic Zn(II)
complex are carried out in DMSO-d6 solvent. The signal due to
the aromatic protons, exists in CLMZ at 7.37–7.54 ppm while
it exists in the Zn(II) complex at 7.41–7.68 ppm. The small
shift may attribute to the changes in the electronic environment
around the protons attached to the group that contain the site of
donation and involvement in the complexation.
Molar Conductivity Measurements
The molar conductivity measures the ability of an aqueous
solution to carry an electric current. Table 1 shows the molar
conductance values of the complexes (10−3M in DMF at 25◦C).
It is concluded from the results that the chelates are found to
have molar conductance values of 12–20 ꢁ−1 mol−1 cm2, in-
dicating that the bivalent metal complexes are non-electrolytes.
For Cr(III) and Fe(III) complexes, the molar conductance values
indicate the ionic nature of these complexes, and they are of the
type 1:1 electrolytes.
Magnetic Susceptibility and Electronic Spectra
Measurements
The important role played by magnetic and electronic spectra
in determining the geometrical structures of the above investi-
gated metal chelates will be discussed in detail.
From the diffused reflectance spectrum it is observed that the
Fe(III) chelate exhibits bands at 20,820 to 21,350 cm−1, which
4
may be assigned to the 6A1g → T2g (G) transition in octahedral
Mass Spectra of MCNZ Drugs
geometry of the complex. The observed magnetic moment of
the Fe (III) complex is found to be 5.98 B.M., thus confirming
the octahedral geometry.[8,9] The spectrum also shows band
at 27,690 cm−1, which may attributed to ligand-metal charge
transfer.
The different pathways of the possible fragments of CLMZ
with its respective relative intensities (RI) are given in
Scheme 1. Fragment at m/z = 345 (RI = 100%) represents the
base peak of CLMZ. The order molecular ion peaks appeared
in the mass spectrum is attributed to the fragmentation obtained
from the rupture of different bonds inside the drug molecule.
The diffused reflectance spectrum of the Mn(II) com-
plex shows three bands at 18,760, 21,739, and 27,770 cm−1

METALLOANTIBIOTICS
547
SCH. 1. Mass fragmentation pattern of CLMZ drug.

548
H. F. ABD EL-HALIM ET AL.
6
assignable to 4T1g → A1g, 4T2g(G) → A1g and 4T1g(D) → A1g
transitions, respectively.[9,10] It has a magnetic moment value
5.48 BM, which indicates the presence of Mn(II) complexes in
octahedral structure.
The electronic spectrum of the Co(II) complex with the for-
mula [CoCl2(L)2(H2O)2]·3H2O gives three bands at 15,550,
17,820, and 19,683 cm−1. The bands observed are assigned to
6
6
The TG curve of the [CoCl2(L)2(H2O)2]·3H2O chelate
(Figure 2c) shows six stages of decomposition within the tem-
perature range 25–750◦C. The stages at 25–330 correspond to
the loss of 4H2O, 2HCl, and C9H9N2 molecules. While the sub-
sequent stages (from 330–500◦C) involve the loss of C19H13Cl
molecule, with a mass loss of 32.46% (calcd. 31.40%). The
remaining decomposition steps found within the temperature
range 500–750◦C with an estimated mass loss of 27.66% (calcd.
= 27.61%) can reasonably be accounted for the removal of
C16H12N2 molecule as gases.
4
4
4
4
the transitions T1g (F) → T2g (F) (ν1), T1g (F) → A2g (F)
(ν2), and 4T1g (F) → T2g (P) (ν3), respectively, suggesting that
4
the Co(II) complex has octahedral geometry.[10,11] The complex
has magnetic moment value of 5.38 BM (Table 1), which indi-
cates the octahedral geometry. The region at 24,880 cm−1 refers
to the charge transfer band.
[MnCl2(L)2(H2O)] complex (Figure 2d) is thermally decom-
posed in five decomposition steps within the temperature range
of 30–650◦C. The decomposition steps with an estimated mass
loss of 13.62% (calcd. 13.59%) within the temperature range
30–273◦C that may be attributed to the liberation of the 2HCl,
H2O, and CH2 molecule. The activation energy is 37.13 and
66.10 kJ mol−1. The 3rd stage within the temperature range
273–420◦C may be accounted to the liberation of C24H16N2Cl
molecule as gases with a mass loss of 43.88% (calcd.
43.03%).The remaining decomposition step found within the
temperature range 420–650◦C with an estimated mass loss of
35.83% (calcd. = 36.65%) can reasonably accounted for the
removal of C19H14Cl2N2 molecule as gases. The TG curve of
the [NiCl2(L)2(H2O)2]·3H2O chelate (Figure 2e) represents five
decomposition steps as shown in Table 3. The first decomposi-
tion step within the temperature range 20–130◦C corresponding
to the loss of 3H2O and 2HCl molecules with a mass loss of
13.93% (calcd. 13.96%). The energy of activation for this de-
hydration step is 21.56 kJ mol−1. The 2nd and 3rd stages within
the temperature range from 130–360◦C, which may be attributed
to the loss of H2O and C10H9ClN molecules with a mass loss
of 21.07% (calcd. 21.77%). The subsequent steps (360–700◦C)
correspond to the removal of C34H25ClN3 molecule leaving
metal oxide as a residue. The overall weight loss amounts to
91.13% (calcd. 92.73%).
The Ni(II) complex is found to have a room temperature
magnetic moment value of 3.90 BM, which is in the normal
range observed for octahedral Ni(II) complexes. The diffused
reflectance spectrum shows the π-π∗ and n-π∗ bands of free
drug and displays three bands, in the solid reflectance spectrum
at ν1: 15,770 cm−1: A2g → T2g; ν2: 19,250 cm−1: A2g
→
3
3
3
3T1g(F) and ν3: 22,350cm−1: A2g → T1g(P). The spectrum
shows also a band at 25,390 cm−1, which may attributed to
ligand to metal charge transfer.
3
3
The reflectance spectrum of the Cu(II) chelate consists of
a low intensity shoulder bands at 14,777 and 17,493 cm−1
.
The Eg and T2g states of the octahedral Cu(II) ion (d9) split
2
2
under the influence of the tetragonal distortion to cause the
three transitions 2B1g → B2g; B1g → Eg and 2B1g → A1g to
remain unresolved in the spectra. The magnetic moment of 2.02
B.M. falls within the range normally observed for octahedral
Cu(II) complexes.[9−11] A moderately intense peak observed in
the range 21,555 cm−1 is due to ligand - metal charge transfer.
The Zn(II) complex is diamagnetic, and according to its em-
pirical formula, octahedral geometry is proposed.
2
2
2
2
Thermal Analyses (TG, DTG, and DTA)
The thermogram of [FeCl2(L)2(H2O)2]Cl·3H2O complex
(Figure 2f) shows five decomposition steps within the tem-
perature range 30–750◦C. The first two steps of decomposi-
tion within the temperature range 30–285◦C correspond to the
loss of 3H2O, 3HCl and C4H4O0.5 molecules with a mass loss
of 27.26% (calcd. 27.49%). The energy of activation is 21.55
and 54.80 kJ mol−1 for the first and second steps, respectively.
The 3rd step within the temperature range 285–420◦C, may at-
tributed to the liberation of C20H16N3 molecule with a mass loss
of 30.29% (calcd. 30.15%). The subsequent steps (420–750◦C)
correspond to the removal of C20H15NCl leaving metal oxide
as a residue. The overall weight loss amounts to 90.8 % (calcd.
89.97%).
The data present in Table 3 show the differential thermal
analysis (DTA) of the complexes. It is shown from these data
that the loss of hydrated and coordinated water molecules, an-
ions, and ligand molecules are accompanied by endothermic or
exothermic processes within the temperature ranges given in
Table 3.
The TG curve of CLMZ (Figure 2a) exhibits an estimated
mass loss of 79.95% (calcd. 80.66%) within the temperature
range 30–385◦C, which may be attributed to the liberation of
C19H13 and HCl molecules as gases. In the 3rd and 4th stages
within the temperature range 385–700◦C (estimated mass loss
= 17.01%, calcd. = 16.41%), the loss of C3H3N with a complete
decomposition of the drug as gases occurs.
[CuCl2(L)2(H2O)2]·2H2O complex (Figure 2b) is thermally
decomposed in three decomposition steps, within the temper-
ature range 25–750◦C. The first decomposition step with an
estimated mass loss of 36.71% (calcd. 35.49%) within the tem-
perature range 25–290◦C may be attributed to the liberation
of the 3H2O, 2HCl, and C12H11Cl molecules. The activation
energy is 31.23 kJ mol−1. The remaining decomposition steps
found within the temperature range 290–750◦C with an esti-
mated mass loss of 55.21% (calcd. = 55.72%) can reasonably
be accounted for the removal of C32H23ClN4O molecule as gases
(as shown in Table 3).

METALLOANTIBIOTICS
549
FIG. 2. Thermal analyses of (a) CLMZ drug, (b) Cu(II), (c) Co(II), (d) Mn(II), (e) Ni(II), and (f) Fe(III) complexes. (Figure is provided in color online.)

550

METALLOANTIBIOTICS
551
TABLE 4
Thermodynamic data of the thermal decomposition of CLMZ drug and its metal complexes
Complex
CLMZ; L
Decomp. temp. (◦C) E∗ kJmol−1
As−1
ꢂS∗ JK−1mol−1 ꢂH∗ kJmol−1 ꢂG∗ kJmol−1
30–200
200–385
385–550
550–700
30–160
160–275
275–420
420–480
480–650
30–150
150–285
285–420
420–580
580–750
25–160
18.44
89.57
94.14
204.3
37.13
66.10
77.60
100.0
206.7
21.55
54.80
90.82
117.8
236.44
29.7
9.65 × 106
6.41 × 107
2.66 × 105
1.99 × 1011
1.02 × 109
3.85 × 106
6.45 × 105
6.61 × 1010
1.30 × 105
1.79 × 106
6.23 × 107
1.46 × 105
3.10 × 105
3.73 × 106
9.39 × 105
1.68 × 108
1.79 × 108
3.63 × 109
3.98 × 107
7.19 × 1010
1.79 × 106
6.23 × 107
1.46 × 105
3.10 × 105
3.73 × 106
2.90 × 109
2.48 × 108
1.52 × 105
−34.39
−95.01
−96.37
−145.1
−41.21
−63.75
−117.1
−135.1
−152.1
−92.72
−113.4
−124.4
−143.0
−145.3
−43.65
−65.43
−86.18
−88.95
−104.4
−120.5
−92.71
−113.4
−124.5
−143.1
−145.3
−64.80
−88.65
−152.4
18.03
85.57
91.79
199.3
3.14
22.84
118.6
155.4
219.8
63.23
122.5
124.3
179.1
223.9
41.23
91.87
151.3
185.7
291.2
39.56
113.4
146.6
212.0
222.1
235.1
29.12
41.19
91.98
150.2
183.7
72.04
113.8
207.7
[MnCl2(L)2(H2O)]
57.36
74.65
95.44
205.5
20.95
52.55
87.15
114.2
219.1
28.96
91.37
112.8
182.3
165.2
206.8
20.95
21.91
52.54
87.15
112.1
27.05
97.98
107.1
[FeCl2(L)2(H2O)2]Cl·3H2O
[CoCl2(L)2(H2O)2]·3H2O
160–330
330–430
430–500
500–600
600–750
20–130
130–210
210–30
360–500
500–700
25–290
93.51
115.9
169.8
186.1
212.2
21.56
23.64
54.80
90.82
117.8
31.23
80.02
112.7
[NiCl2(L)2(H2O)2]·3H2O
[CuCl2(L)2(H2O)2]·2H2O
290–520
520–750
Kinetic Data
The data are summarized in Table 4. The activation energies
of decomposition are found to be in the range 18.44–236 kJ
mol−1. The high values of the activation energies reflect the
thermal stability of the complexes. The entropy of activation
is found to have negative values in all the complexes, which
indicates that the decomposition reactions proceed with a lower
rate than the normal ones.
The thermodynamic activation parameters for the decompo-
sition processes of the dehydrated complexes, namely activa-
tion energy (E∗), enthalpy (ꢂH∗), entropy (ꢂS∗), and Gibbs
free energy change of the decomposition (ꢂG∗), are evaluated
graphically by employing the Coats-Redfern relation.[12]
ꢀ
ꢁ
ꢀ
ꢂ
ꢃꢁ
{Wf/(Wf−W)}
AR
θE∗
E∗
2RT
E∗
log
= log
1 −
T2
Biological Activity
The main aim of the production and synthesis of any antimi-
crobial compound is to inhibit the causal microbe without any
side effects on the patients. In addition, it is worthy to stress here
on the basic idea of applying any chemotherapeutic agent that
−
[1]
2.303RT
Where Wf is the mass loss at the completion of the reaction, depends essentially on the specific control of only one biological
W is the mass loss up to temperature T; R is the gas constant, function and not multiple ones.
E∗ is the activation energy in kJ.mol−1, θ is the heating rate and
Since the use of CLMZ drug as effective antifungal drug,
∗
∼
(1-(2RT/E )) 1. A plot of the left-hand side of equation (1) the interest toward transition metal complexes containing N-
=
against 1/T gives a slope from which E∗ is calculated and A donor ligands has increased in order to obtain metal-based drugs
(Arrhenius factor) is determined from the intercept.
exhibiting a high biological activity together with a reduced

552
H. F. ABD EL-HALIM ET AL.
toxicity. In this respect, drug with their transition metal com- tivity of the complexes, therefore, are found to follow the order
plexes have been extensively investigated.
Zn(II) > Fe(III) = Cr(III) > CLMZ = Ni(II) = Cu(II) = Co(II)
The data obtained show that CLMZ drug under investiga- = Mn(II).
tion and its metal complexes have the capacity of inhibiting
the metabolic growth of the investigated bacteria and fungi to
different extent. The size of the inhibition zone depends upon
Using S. aureus ( G+ bacteria)
The antibacterial activity of CLMZ and its metal complexes
the culture medium, incubation conditions, rate of diffusion, are found to follow the order: CLMZ > Cu(II) = Mn(II) > Co(II)
and the concentration of the antibacterial or antifungal agents. > Ni(II) = Zn(II) = Cr(III) = Fe(III).
The activities of all the tested complexes may be explained on
Using P. aeruginosa (G+ bacteria)
the basis of chelation theory where chelation reduces the polar-
ity of the metal atom mainly because of partial sharing of its
positive charge with the donor groups and possible π electron
delocalization within the whole chelate ring. Also, chelation
increases the lipophelic nature of the central atom, which sub-
sequently favors its permeation through the lipid layer of the cell
membrane.
In testing the antibacterial and antifungal activity of CLMZ
drug and its metal complexes, more than one test organism is
used to increase the chance of detecting antibiotic principles in
tested materials. The sensitivity of a microorganism to antibi-
otics and other antimicrobial agents is determined by the assay
plates which incubated at 28◦C for two days for yeasts, and
at 37◦C for one day for bacteria. All of the tested compounds
show a remarkable biological activity against different types of
fungi (Aspergillus fumigatus, Penicillium italicum, Syncepha-
lastrum racemosum, and Candida albicans), Gram-positive bac-
teria (Staphylococcus aureu and Pseudomonas aeruginosa) and
Gram-negative bacteria (Bacillus subtili and Escherichia coli).
The data are listed in Table 5. It is clear from the obtained results
that:
The data listed in Table 5 show that Co(II) and Zn(II) com-
plexes of CLMZ drug are found to have an activity at higher
concentrations (5 mg L −1).
Using B. subtilis bacteria
CLMZ and its metal complexes are found to have antibacte-
rial activity against B. subtillis bacteria and the Zn(II) complex
is found to have a high biological activity than the CLMZ drug
and the remaining metal complexes (Table 5).
Using E. Coli bacteria
The results listed in Table 5 reveal that the antibacterial ac-
tivity follows the order
Zn(II) = Ni(II) > Fe(III) = CrI(II) = CLMZ = Cu(II)
= Co(II) = Mn(II).
It is obvious from these data that insertion of metal ions in the
drug structure increase the drug activity against P. italicum, S.
racemosum, C. albican, B. Subtilis, and E. coli. The variation
in the effectiveness of different biocidal agents against different
organisms, as suggested by Sexena and Singh,[13] depends on
the impermeability of the cell. The effect of resonating rings on
the toxicity may be appraised in the light of modern electronic
theory. The resonant energy is the energy in excess of the sum
of the energy of the separate bonds making up the molecules.
Resonating structures, such as benzene rings (in the present
case), may serve as powerhouses to activate potentially reactive
groupings. If the toxicity is dependent on one or more chemical
reactions, then the molecule that would increase the rate of
chemical reactions must enhance toxicity.[14]
Using A. fumigatus and P. italicum fungi
CLMZ and its complexes show lower biological activity than
that of the standard terbinafin. The biological activity of the
complexes are found to follow the order CLMZ = Ni(II) >
Fe(III) = Cr(III) = Mn(II) = Cu(II) >Co(II) = Zn(II), in case
of A. fumigatus. While in case of P. italicum, the order is found
to be:
Fe(III) = Cr(III) = Mn(II) > Zn(II) > Ni(II) > CLMZ
= Cu(II) = Co(II).
From the bactericidal activity, it is apparent that the com-
plexes were more toxic toward Gram (+) strains than Gram (−)
strains. The reason is the difference in the structure of the cell
walls. The walls of Gram (−) cells are more complex than those
of Gram (+) cells. The lipopolysaccharide forms an outer-lipid
membrane and contributes to the complex antigenic specificity
of Gram (−) cells.
Using S. racemosum fungus
It is clear from Table 5 that CLMZ and its metal complexes
show remarkable antifungal activity. The activity is found to
follow the order:
Zn(II) = Cu(II) > Cr(III) = Fe(III) = CLMZ > Ni(II)
= Co(II) = Mn(II)complexes
Structural Correlation with Biocidal Activity
From the results of biological activity, it is concluded that
there is a direct relationship between the biocidal activity and
Using C. albican fungus
CLMZ and its metal complexes show much higher biological the coordination environment of the metal, the function of the
activity than that of CLMZ drug (Table 5). The biological ac- ligand is to support the transport of the active metalocomplex

553

554
H. F. ABD EL-HALIM ET AL.
FIG. 3. Structure of metal complexes.
moiety to the site of the action where it is released by hydroly-
sis,[15] and that the anionic ligand also plays an important role in
determining the degree of the activity of metalocomplex com-
pounds.
2. Kostova, I. Platinum complexes as anticancer agents. Recent Pat. Anti-
Cancer Drug Discover 2006, 1, 1–22.
3. Guo, Z.; Sadler, P.J. Advances in Inorganic Chemistry; Academic Press:
San Diego, CA, USA, 2000; 49, 183–306.
¨
4. Uc¸ucu, U.; Gu¨ndog˘du, N.; and Is¸ikadag˘ I. IL Farmaco 2001, 56,
285–290.
Structural Interpretation
5. Al-Azzawi, R.W. Evaluation of Some Properties of Three Types of Denture
Reline Materials with Miconazole (Antifungal agent) Preparation. A master
thesis, Prosthetic Department, University of Baghdad, 2007.
6. Sreedhara, S.H.; Sirsi, M.; and Ramanandarao, G. Microbiology and Phar-
macology Laboratory, Indian Institute of Science, Bangalore-560012,
India.
7. Sari, N.; Arslan, S.; Logoglu, E.; Sakiyan, I. Antibacterial activities of some
amino acid Schiff bases. G.U. J. Sci. 2003, 16, 283–288.
8. Mohamed, G.G.; Soliman, M.H. Spectrochim. Acta A 2010, 76, 341–
347.
9. Cotton, F.A.; Wilkinson, G.; Murillo, C.A.; Bochmann, M. Advanced Inor-
ganic Chemistry, 6th edn.; Wiley: New York, 1999.
10. Mohamed, G.G.; Zayed, M.A.; Abdallah, S.M. J. Molecular Structure,
2010, 979, 62–71.
11. Biswas, S.; Mitra, K.; Schwalbe, C.H.; Lucas, C.R.; Chattopadhyay, S.K.;
Adhikary, B. Inorg. Chim. Acta 2005, 358, 2473–2481.
12. Coats, A. W.; and Redfern, J.P. 376. Kinetic parameters from thermogravi-
metric data. Nature 1964, 20, 68.
The structures of the complexes of CLMZ drug with Cr(III),
Mn(II), Fe(III), Co(II), Ni(II), Cu(II), and Zn(II) ions are con-
firmed by the elemental analyses, IR, molar conductance, mag-
netic, solid reflectance, mass, and thermal analyses (TGA and
DTA) data. Therefore, from the IR spectra, it is concluded that
CLMZ drug behaves as a neutral undentate ligand coordinated
to the metal ions via the pyridine-N. It is found from the molar
conductance data that the complexes are electrolytes. On the
basis of the above observations and from the magnetic and solid
reflectance measurements, octahedral geometry is suggested for
the investigated complexes. As a general conclusion, the inves-
tigated CLMZ drug complexes structurs can be given as shown
below (Figure 3).
REFERENCES
13. Sexena, C.; Singh, R.V. Phosphorus Sulfur Silicon 1994, 97, 17.
14. Jain, M.; Gaur, S.; Singh, V.P. Appl. Organomet. Chem. 2004, 18, 73.
15. Molloy, K.C. Bioorganotin Compounds. The Chemistry of Metal- Carbon
Bond; Hartley, F.E. (ed.), Wiley: New York, 1989.
1. Mascini, M.; Bagni, G.; Pietro, M.L.D.; Ravera, M.; Baracco, S.; Osella,
D. Electrochemical biosensor evaluation of the interaction between DNA
and metallo-drugs. BioMetals 2006, 19, 409–418.