Metal complexes of fenoterol drug: Preparation, spectroscopic, thermal, and biological activity characterization

Article abstract of DOI:10.1007/s10973-009-0421-9

Metal complexes of fenoterol (FEN) drug are prepared and characterized based on elemental analyses, IR, ¹H NMR, magnetic moment, molar conductance, and thermal analyses (TG and DTA) techniques. From the elemental analyses data, the complexes are formed in 1:2 [Metal]:[FEN] ratio and they are proposed to have the general formula [Cu(FEN)₂].2H₂O; [M(FEN)₂(H₂O)₂]. yH₂O (where M = Mn(II) (y = 2), Co(II) (y = 4), Ni(II) (y = 4), and Zn(II) (y = 0) and [Cr(FEN)₂(H₂O)₂]Cl.H₂O. The molar conductance data reveal that all the metal chelates are non-electrolytes except Cr(III) complex, having 1:1 electrolyte. IR spectra show that FEN is coordinated to the metal ions in a uninegative bidentate manner with ON donor sites of the aliphatic -OH and secondary amine -NH. From the magnetic moment measurements, it is found that the geometrical structures of these complexes are octahedral (Cr(III), Mn(II), Co(II), Ni(II), and Zn(II)) and square planar (Cu(II)). The thermal behavior of these chelates is studied using thermogravimetric and differential thermal analyses (TG and DTA) techniques. The results obtained show that the hydrated complexes lose water molecules of hydration followed immediately by decomposition of the coordinated water and ligand molecules in the successive unseparate steps. The FEN drug, in comparison to its metal complexes is also screened for their antibacterial activity against bacterial species (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Salmonella typhi), Yeasts (Candida albicans and Saccharomyces cervisiae), and Fungi (Aspergillus niger and Aspergillus flavus). The activity data show that the metal complexes have antibacterial activity like that of the parent FEN drug against one or more species. Akademiai Kiado, Budapest, Hungary 2009.

Full text of DOI:10.1007/s10973-009-0421-9

J Therm Anal Calorim (2010) 99:639–647
DOI 10.1007/s10973-009-0421-9
Metal complexes of fenoterol drug
Preparation, spectroscopic, thermal, and biological activity characterization
M. H. Soliman Æ Gehad G. Mohamed Æ
Eman A. Mohamed
Received: 25 February 2009 / Accepted: 14 August 2009 / Published online: 16 September 2009
´
´
ꢀ Akademiai Kiado, Budapest, Hungary 2009
Abstract Metal complexes of fenoterol (FEN) drug are
prepared and characterized based on elemental analyses,
aureus, Escherichia coli, and Salmonella typhi), Yeasts
(Candida albicans and Saccharomyces cervisiae), and
Fungi (Aspergillus niger and Aspergillus flavus). The
activity data show that the metal complexes have antibac-
terial activity like that of the parent FEN drug against one or
more species.
1
IR, H NMR, magnetic moment, molar conductance, and
thermal analyses (TG and DTA) techniques. From the
elemental analyses data, the complexes are formed in 1:2
[Metal]:[FEN] ratio and they are proposed to have the
general formula [Cu(FEN)2]ꢀ2H2O; [M(FEN)2(H2O)2]ꢀ
yH2O (where M = Mn(II) (y = 2), Co(II) (y = 4), Ni(II)
(y = 4), and Zn(II) (y = 0) and [Cr(FEN)2(H2O)2]ClꢀH2O.
The molar conductance data reveal that all the metal che-
lates are non-electrolytes except Cr(III) complex, having
1:1 electrolyte. IR spectra show that FEN is coordinated to
the metal ions in a uninegative bidentate manner with ON
donor sites of the aliphatic –OH and secondary amine –NH.
From the magnetic moment measurements, it is found that
the geometrical structures of these complexes are octahe-
dral (Cr(III), Mn(II), Co(II), Ni(II), and Zn(II)) and square
planar (Cu(II)). The thermal behavior of these chelates is
studied using thermogravimetric and differential thermal
analyses (TG and DTA) techniques. The results obtained
show that the hydrated complexes lose water molecules of
hydration followed immediately by decomposition of the
coordinated water and ligand molecules in the successive
unseparate steps. The FEN drug, in comparison to its metal
complexes is also screened for their antibacterial activity
against bacterial species (Bacillus subtilis, Staphylococcus
Keywords Fenoterol ꢀ Metal complexes ꢀ IR ꢀ
1
Molar conductance ꢀ Magnetic moment ꢀ H NMR ꢀ
Thermal analyses ꢀ Biological activity
Introduction
Fenoterol (FEN, Fig. 1) is b_2-adrenoceptor agonist that
may have clinical value in the treatment of congestive heart
failure [1, 2]. FEN possesses two chiral centers and the
drug is supplied as a racemic mixture of (R,R)-FEN and
(S,S)-FEN. Previous studies using cardiomyocytes con-
tractility have demonstrated that (R,R)-FEN is the active
component and this compound is currently under devel-
opment as a therapeutic agent [1, 2]. As part of the pre-
clinical studies, the pharmacokinetics of (R,R)-FEN in rats
was investigated, and an assay was developed to quantify
(R,R)-FEN concentrations in rat plasma. The determination
of FEN in plasma requires a sensitive assay as the plasma
concentrations of the drug were commonly\10 ng/ml due
to the compound’s poor bioavailability and extensive
metabolism via phase II pathways [3]. Plasma concentra-
tions of FEN had been measured using a radioimmunoas-
say [4] and enzyme immunoassay [5] techniques as well as
gas chromatography–MS [6, 7], LC–APCI–MS [8], and
HPLC with fluorescence detection [9]. However, these
methods required either expensive antibodies, derivatiza-
tion procedures, or were not sensitive enough for the
M. H. Soliman ꢀ E. A. Mohamed
Chemistry Department, Faculty of Science, Helwan University,
Helwan, Egypt
G. G. Mohamed (&)
Chemistry Department, Faculty of Science, Cairo University,
Giza, Egypt
e-mail: ggenidy@hotmail.com
123

640
M. H. Soliman et al.
H
N
ethylenediaminetetraacetic acid, EDTA were from Analar,
ammonia solution (33% v/v), and ammonium chloride from
El-Nasr pharm. Chem. Co., Egypt. Organic solvents used
included absolute ethyl alcohol, diethylether, and dimeth-
ylformamide (DMF). These solvents were spectroscopic
pure from BDH. Hydrogen peroxide, hydrochloric, and
nitric acids (MERCK) were used. De-ionized water col-
lected from all glass equipments was usually used in all
preparations. The test organisms were kindly supplied from
the microbiological resource center, Ain Shams University,
Faculty of Agricultural, Egypt (CAIM, Cairo Mircen), and
from Bacteriological Department of National Organization
for Drug Control and Research (NODACR), ATCC,
American type culture collection. Bacterial test organisms
were inoculated on nutrient agar slants for 24 h at 37 ꢁC.
Yeast and Fungi organisms were inoculated on Sabouraud’s
dextrose-agar slants and incubated at 28 ꢁC for 48 h (Jacobs
and Gerstein, 1960). Several workers used these organisms
repeatedly as test organisms.
OH
H
HO
.HBr
OH
H
CH3
OH
Fig. 1 Structure of FENꢀHBr drug
350
300
250
200
150
100
50
Instruments
The molar conductance of the solid complexes in DMF was
measured using Sybron-Barnstead conductometer (Meter-
PM.6, E = 3406). Elemental microanalyses of the sepa-
rated solid chelates for C, H, N, and S were performed at the
Microanalytical Center, Cairo University. Infrared spectra
were recorded on a Perkin-Elmer FT-IR type 1650 spec-
trophotometer in wave number region 4000–400 cm-1. The
spectra were recorded as KBr pellets. The 1H NMR spectra
were recorded using 300 MHz Varian-Oxford Mercury.
The molar magnetic susceptibility was measured on pow-
dered samples using the Faraday method. The diamagnetic
corrections were made by Pascal’s constant and Hg[Co
(SCN)4] was used as a calibrant. The thermogravimetric
(TG and DTG) and differential thermal (DTA) analyses
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.
0
50
100
150
200
250
300
350
Mass/charge
Fig. 2 Mass spectrum of FENꢀHBr drug
determination of low FEN plasma concentrations that were
required for pharmacokinetic studies.
However, in this work, metal chelates of Mn(II), Cr(III),
Co(II), Ni(II), Cu(II), and Zn(II) transition metals with
FEN drug molecule are prepared. The solid chelates are
characterized using different physico-chemical methods
like elemental analyses (C, H, N, and metal content), IR,
1H NMR, magnetic moment, and thermal analyses (TG and
DTA). Biological activities of the complexes are studied
(Fig. 2).
Synthesis of metal complexes
The metal complexes were prepared by the addition of hot
solution (60 ꢁC) of the appropriate metal chloride salts
(0.12, 0.13, 0.24, 0.24, 0.14, and 0.14 g of Cr(III), Mn(II),
Ni(II), Co(II), Cu(II), Zn(II), respectively, 1 mmol) in an
ethanol–water mixture (1:1, 25 mL) to the hot solution
(60 ꢁC) of FEN (1.04 g, 2 mmol) in the same solvent
(25 mL). The resulting mixture was stirred under reflux
for 1 h whereupon the complexes precipitated. They were
collected by filtration, washed with a 1:1 ethanol: water
mixture and diethyl ether.
Experimental
Materials and reagents
All chemicals used were of the analytical reagent grade
(AR) and of the highest purity available. They included FEN
(UniPharma), Cu(II) chloride dihydrate (Prolabo), Co(II)
and Ni(II) chlorides hexahydrates (BDH), Zn(II) chloride
dihydrate (Ubichem), Cr(III) chloride hexahydrate (Sigma),
and Mn(II) chloride (Prolabo). Zinc oxide, disodium salt of
123

Metal complexes of fenoterol drug
Biological activity
641
H
N
OH
H
HO
.HBr
OH
H
CH3
The antimicrobial activities were carried out by disc dif-
fusion technique as described in British pharmacopoeia
(2003). Nutrient agar was melted at 45 ꢁC and inoculated
by the cell suspension (1 mL/100 mL) bacteria or yeast.
The flask was shaken well and poured into a petri-dish
(15 cm in diameter). Filter paper discs (6 mm) Whatman
No. 2 were thoroughly moistened by antibiotics (50 lg),
the treated discs were aseptically transferred and placed
upon the surface of the inoculated plates with tested
organisms and kept in a refrigerator for 1 h to permit dif-
fusion of antimicrobial substances. The plates were incu-
bated at 37 ꢁC for 24 h in case of bacteria and at 28 ꢁC for
48 h in case of yeast. The zones of inhibition were mea-
sured in mm the mean values of inhibitions were calculated
from triple reading in each test [10].
OH
m/z = 384 (f. = 384, RI = 5%)
OH
H
N
O
N
HO
CH3
H2C
OH
CH3
OH
CH2
OH
m/z = 230 (f. = 230, RI = 11%)
m/z = 301 (f. = 301, RI = 8%)
N
CH2
OH
HN
m/z = 173 (f. = 175, RI = 7%)
CH2
OH
m/z = 148 (f. = 149, RI = 7%)
The following media were used in studying the anti-
microbial properties of FEN drug and its complexes. The
weights are given in gram per one-liter medium.
OH
m/z = 77 (f. = 77, RI = 37%)
m/z = 108 (f. = 107, RI = 100%)
Nutrient agar medium (pH 7.4)
Scheme 1 Mass fragmentation pattern of FENꢀHBr drug
It consists of beef extract (1.0 g), yeast extract (2.0 g),
peptone (5.0 g), sodium chloride (5.0 g), agar (15.0 g), and
distilled water (100 mL).
relative intensity = 5%. The parent ion and the fragments
obtained by cleavage in different positions in FEN mole-
cule are shown in Scheme 1.
Sabouraud’s dextrose agar medium (pH 5.6)
Composition and structures of metal complexes
It consists of peptone (10 g), dextrose (20 g), agar (15 g),
and distilled water (100 mL).
The aim of this work is to prepare the solid complexes of the
drug under investigation and carrying out complete char-
acterization using different physicochemical techniques.
The isolated solid complexes of Cr(III), Mn(II), Co(II),
Ni(II), Cu(II) and Zn(II) ions with the FEN ligand are
subjected to elemental analyses (C, H, N, and metal con-
Results and discussion
The formation of metal complexes with organic com-
pounds has long been recognized. However, the binary
complexes of the 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 these drugs
as certain metal ions were present in relatively appreciable
concentration in biological fluids [11].
1
tent), IR, H NMR, magnetic moment studies, molar con-
ductance, and thermal analyses (TG and DTA), to identify
their tentative formulae in a trial to elucidate their molec-
ular structures. The results of elemental analyses listed
in Table 1 suggest that the complexes are formed in 1:2
[Metal]:[FEN] ratio and they proposed to have the
general formulae [Cu(FEN)2]ꢀ2H2O and [M(FEN)2(H2O)2]ꢀ
yH2O (where M = Cr(III) (y = 1), Mn(II) (y = 2), Co(II)
(y = 4), Ni(II) (y = 4), and Zn(II) (y = 0).
Mass spectrum of FENꢀHBr
The electron impact mass spectrum of FEN is recorded and
investigated at 70 eV of electron energy. The mass spec-
trum of the studied drug is characterized by moderate to
high relative intensity molecular ion peaks at 70 eV. The
abundance of the molecular ion depends mainly on the
structure (and therefore the potential energy surface) of
the molecular ion. The mass spectrum of FEN shows a
well-defined parent peak at m/z = 384 (M?) with a
Molar conductivity measurements
The chelates are dissolved in DMF and the molar con-
ductivities of 10-3 M of their solutions at 25 ꢁC are mea-
sured. Table 1 shows the molar conductance values of the
complexes. It is concluded from the results that, the diva-
lent metal chelates are found to have molar conductance
123

642
M. H. Soliman et al.
Table 1 Analytical and physical data of FEN metal complexes
Complexes
Color/
% yield
Mp/ꢁC %Found (calcd.)
leff
B.M.
/
Km/X-1
mol-1 cm2
C
H
N
M
[Cr(FEN)2(H2O)2]ClꢀH2O
Dark green
(68)
[300
[300
[300
[300
44.62 (44.80) 5.43 (5.30) 3.54 (3.10) 5.99 (5.70) 4.95
38.11 (37.90) 5.32 (5.50) 5.11 (5.30) 6.53 (6.10) 4.82
45.26 (45.30) 5.39 (5.50) 2.90 (3.10) 6.13 (6.50) 5.28
36.17 (36.61) 5.38 (5.70) 2.53 (2.90) 6.69 (6.30) 3.66
57.40 (57.81) 5.56 (5.95) 4.10 (3.95) 9.10 (9.00) 1.74
68.00
18.50
24.50
16.80
19.80
C34H48CrN2O11
[Mn(FEN)2(H2O)2]ꢀ2H2O
Brown (70)
C34H50MnN2O12
[Co(FEN)2(H2O)2]ꢀ4H2O
Violet (62)
C34H50CrN2O12
[Ni(FEN)2(H2O)2]ꢀ4H2O
Yellowish
green (73)
C34H54NiN2O14
[Cu(FEN)2]ꢀ2H2O C34H46CuN2O10 Brown (72)
[Zn(FEN)2(H2O)2] C34H46N2O10Zn White (65)
[300
[300
46.43 (46.80) 4.85 (5.30) 2.82 (3.20) 6.26 (6.10) Diam. 15.40
values of 15.40–24.50 X-1 mol-1 cm2 indicating that all
the divalent metal chelates are non-electrolytes. The Cr(III)
complex is found to have a molar conductance value of
68 X-1 mol-1 cm2 indicating its electrolytic nature and of
the type 1:1 electrolyte.
(2) The NH stretching vibration: t(NH), is found in FEN
drug at 3050 cm-1. Whoever, the participation of the
NH group in the chelation is ascertained from the shift
of this band from 3040 to 3199 cm-1 in the spectra of
the complexes.
(3) New bands are found in the spectra of the complexes in
the regions 520–559 cm-1, which is assigned to t(M–O)
stretching vibrations [12–16]. The bands at 436–510
have been assigned to t(M–N) mode [12–16].
IR spectral studies
The IR data of the spectra of FEN drug and its complexes
are listed in Table 2. The IR spectra of the complexes are
compared with this of the free FEN drug in order to
determine the coordination sites that may be involved in
chelation. The position and/or the intensities of these peaks
are expected to be changed upon chelation. These charac-
teristic peaks are listed in Table 2. Upon comparison it is
found that:
Therefore, from the IR spectra, it is concluded that FEN
behaves as a uninegative bidentate ligand coordinated to the
metal ions via the deprotonated hydroxyl O and NH groups.
Magnetic susceptibility and electronic spectral studies
The magnetic moment values of Cr(III) and Mn(II) com-
plexes are found to be 4.95 and 4.82 B.M., respectively,
which indicate their presence in octahedral structure [17].
The Ni(II) complex reported herein is found to has a
room temperature magnetic moment value of 3.66 B.M.;
which is in the normal range observed for octahedral Ni(II)
complexes (leff = 2.9–3.3 B.M.) [12, 17]. This indicates
that, the Ni(II) complex is probably octahedral.
(1) The t(OH), t(C–O), and d(OH) stretching vibrations
are observed at 3397–3219, 1227, and 1391 cm-1
for FEN drug, respectively. The participation of
the hydroxyl O atom in the complex formation is
evidenced from the shift in position of these bands
to 3567–3152, 1235–1306, and 1403–1466 cm-1 for
FEN–metal complexes, respectively.
Table 2 IR spectra (4000–400 cm-1) of the FEN drug and its metal complexes
Compounds
m(OH)
m(C–O)
d(OH)
m(NH)
m(M–O)
m(M–N)
FENꢀHBr
3397–3219br
3390–3200br
3396–3226br
3410–3250br
3520–3170br
3412–3152br
3567–3328br
1227m
1306m
1272m
1270m
1237m
1235br
1243m
1391sh
1466m
1457m
1413m
1465m
1403m
1404m
3055br
3172br
3050m
3075br
3087br
3040br
3199br
–
–
[Cr(FEN)2(H2O)2]ClꢀH2O
[Mn(FEN)2(H2O)2]ꢀ2H2O
[Co(FEN)2(H2O)2]ꢀ4H2O
[Ni(FEN)2(H2O)2]ꢀ4H2O
[Cu(FEN)2]ꢀ2H2O
555s
552s
520s
559s
554s
537s
497s
506w
510s
498s
436s
502s
[Zn(FEN)2(H2O)2]
sh Sharp, m medium, s small, w weak, br broad
123

Metal complexes of fenoterol drug
643
DrTGA
mg/min
1.00
The magnetic susceptibility value for Co(II) complex is
found to be 5.28 B.M. (normal range for octahedral Co(II)
complexes is 4.3-5.2 B.M.), is an indicative of octahedral
geometry [17–19]. The magnetic moment value of 2.15
B.M. falls within the range normally observed for octahe-
dral Cu(II) complexes [11, 17]. The Zn(II) complex is
diamagnetic and according to the empirical formula of this
complex, an octahedral geometry is proposed.
TGA
%
DTA
uv
100.00
20.00
10.00
0.00
-1.00
-2.00
0.00
50.00
-10.00
-20.00
-30.00
1H NMR spectra
0.00
0.00
200.00
400.00
600.00
800.00
1000.00
The 1H NMR spectra of FEN drug and its Zn(II) complex are
recorded in d6-dimethylsulfoxide (DMSO) solution using
tetramethylsilane (TMS) as internal standard. The chemi-
cal shifts of the different types of protons of the FEN drug
and its diamagnetic Zn(II) complex are listed in Table 3.
The spectrum of the complex is examined in comparison
with those of the parent Schiff base. Upon examinations it
is found that:
Temperature/°C
Fig. 3 TGA, DrTGA, and DTA curve of FENꢀHBr drug
Thermal analyses (TG, DTG, and DTA) of FEN drug
The TG curve of FEN drug (Fig. 3), refers to two stages of
mass losses at temperature ranges from 185 to 815 ꢁC
(Table 4). The first estimated mass loss of 39.30% (calcd.
39.80%) within the temperature range from 185 to 500 ꢁC,
may be attributed to the liberation of C8H9O3 molecule as
gases. In the 2nd stage within the temperature range from
500 to 815ꢁ C, fenoterol losses the remaining part with an
estimated mass loss of 60.70% (calcd. 60.20%) with a
complete decomposition as C9H13NOBr. Figure 3 shows
the DTA curve which shows five exothermic peaks at 250,
300, 400, 480, and 650 ꢁC and six endothermic peaks at
280, 370, 430, 600, 700, and 800 ꢁC.
(1) The OH signal, appeared in the spectrum of FEN drug
at 4.760 ppm (Table 3), completely disappeared in the
spectrum of its Zn(II) complex indicating that the OH
proton is removed by the chelation with metal ion.
(2) The signal observed at 8.536 ppm for FEN drug, is
assigned to NH protons. This signal is found at
8.90 ppm for Zn(II) complex. This indicates that the
NH group is coordinated to the Zn(II) ion without
proton displacement.
Therefore, it is clear from these results that the data
1
obtained from the elemental analyses, IR, and H NMR
Thermal analyses (TG, DTG, and DTA) of the metal
chelates
spectral measurements are in agreement with each other.
Figure 4 and Table 4 show the TG, DTG, and DTA results
of thermal decomposition of FEN chelates. From these
results it can be conclude that: the thermogram of
[Cr(FEN)2(H2O)2]ClꢀH2O chelate shows five decomposi-
tion steps within the temperature range from 30 to 600 ꢁC.
The first two steps of decompositions within the tempera-
ture range 30–120 ꢁC correspond to the loss of water mol-
ecule of hydration and HCl with a mass loss of 5.99%
(calcd. 5.11%). The subsequent steps (120–600 ꢁC) corre-
spond to the removal of the organic part of the drug leaving
metal oxide as a residue. The overall weight loss amounts to
86.74% (calcd. 85.76%). The DTA data are listed in Table 4
and represented graphically in Fig. 4a. It is clear from these
data that these mass losses are accompanied by exothermic
(230 ꢁC) and endothermic (90 and 435 ꢁC) peaks.
Table 3 1H NMR spectral data of the FEN drug and its Zn(II) chelate
Compounds
FEN
Chemical shift (d)/ppm Assignment
9.284
(S, 3H, phenolic OH)
8.536
(br, 1H, NH)
5.994–7.019
4.760
(m, 7H, ArH)
(br, 1H, aliphatic OH)
(s, 3H, CH3)
3.360
2.896–3.096
2.489–2.569
1.078
(m, 2H, C–CH2)
(m, 2H, C–CH2)
(s, 2H, CH)
[Zn(FEN)2(H2O)2] 9.280
8.900
(S, 6H, phenolic OH)
(br, 2H, NH)
6.062–6.917
(m, 14H, ArH)
(s, 6H, CH3)
3.505
The TG curve of the [Mn(FEN)(H2O)2]ꢀ2H2O chelate is
shown in Fig. 4b and listed in Table 4. It decomposes in six
steps in the temperature range from 30 to 650 ꢁC. The first
step is the loss of the hydrated water with mass loss of
2.657–2.819
2.490–2.529
0.927
(m, 4H, C–CH2)
(m, 4H, C–CH2)
(s, 4H, CH)
123

644
M. H. Soliman et al.
Table 4 Thermal analyses (TG and DTA) data of FEN drug and its metal complexes
Compounds
TG
DTG
DTAa/ꢁC
Mass loss % nb Total mass
found (calcd) loss
Assignment
Metallic
residue
range/ꢁC max/ꢁC
FENꢀHBr
185–500 323
500–815 588
250(-), 280(?), 300(-),
370(?), 400(-), 430(?),
480(-), 600(?), 650(-),
700(?), 800(?)
39.30 (39.80) 1 100.0 (100.0) Loss of C8H9O3
60.70 (60.20) 1 Loss of
C9H13NOBr
–
[Cr(FEN)2(H2O)2]ClꢀH2O 30–120 88
120–600 132, 220
90(?), 230(-), 435(?)
5.99 (5.11)
2
86.74 (85.76) Loss of H2O
and HCl
‘Cr2O3
85.76 (86.47) 3
Loss of
C34H42N2O6…5
and 2H2O
[Mn(FEN)2(H2O)2]ꢀ2H2O 30–200 55,101,
200–650
50(-), 70(?), 100(-),
150(?), 200(-), 525(?).
4.01 (5.03)
2
92.61 (93.43) Loss of 2H2O
MnO
CoO
NiO
157
88.60 (88.40) 4
Loss of
C34H42N2O7
and 2H2O
[Co(FEN)2(H2O)2]ꢀ4H2O 30–100 63,118,
100–650
60(-), 100(?), 130(-),
497(?), 510(-), 560(?)
7.95 (7.72)
1
92.55 (91.96) Loss of 4H2O
560,
335
84.60 (84.24) 2
Loss of
C
34H42N2O7
and 2H2O
92.40 (92.90) Loss of 4H2O
Loss of
[Ni(FEN)2(H2O)2]ꢀ4H2O
30–120 67, 189, 40(?), 72(-), 192(-),
7.60 (7.70)
1
433,
567
430(?), 600(?),
700(-), 730(?)
120–650
84.80 (85.20) 3
C
34H42N2O7
and 2H2O
88.42 (88.73) Loss of 2H2O
Loss of
[Cu(FEN)2]ꢀ2H2O
30–270 77, 261
200(?), 270(-), 300(?),
330(-), 460(-), 520(?),
550(-), 620(?)
4.90 (5.10)
2
CuO
ZnO
270–1000 669, 943
83.52 (83.63) 2
C
34H42N2O7
[Zn(FEN)2(H2O)2]
100–200 175, 317, 179(-), 370(-), 434(?),
4.10 (5.30)
1
92.60 (91.70) Loss of 2H2O
Loss of
453,
538
538(?),
200–680
86.50(87.40) 3
C
34H42N2O7
a
(?) endothermic, (-) exothermic
n = number of decomposition steps
b
4.01% (calcd. 5.03%). The subsequent steps correspond to
the removal of coordinated water and the residue of the
drug molecules with mass loss of 88.60% (calcd. 88.40%).
These steps are accompanied by exothermic peaks at 50,
100, and 200 ꢁC. Also these steps are accompanied by
endothermic peaks at 70, 150 and 525 ꢁC.
The TG curves of the [Ni(FEN)2(H2O)2]ꢀ4H2O (Fig. 4c),
[Cu(FEN)2]ꢀ2H2O, and [Zn(FEN)2(H2O)2] (Fig. 4e) che-
lates show four stages of decomposition within the tem-
perature range from 30 to 650, 30 to 1000, and 100 to
680 ꢁC, respectively. The first stage corresponds to the loss
of water molecules of hydration (in case of Ni(II) and Cu(II)
complexes) and the loss of coordinated water molecules (in
case of Zn(II) complex). While the subsequent steps involve
the loss of organic part of FEN drug molecules. The overall
weight losses amount to 92.40% (calcd. 92.90%), 88.42%
(calcd. 88.73%), and 92.60% (calcd. 91.70%). The DTA
data are listed in Table 4 and represented graphically in Fig.
4c, e. It is clear from these data that these mass losses are
accompanied by exothermic and endothermic peaks within
the temperature ranges of decomposition.
On the other hand, [Co(FEN)2(H2O)2]ꢀ4H2O chelate
exhibits three decomposition steps (Fig. 4d). The first step
in the temperature range 30–100 ꢁC in which the complex
losses the hydrated water molecules with estimated mass
loss = 7.95% (calcd. 7.72%) (Table 4). The total mass
losses of the decomposition steps are found to be 92.55%
(calcd. 91.96%), leaving CoO as a residue. The DTA data
are listed in Table 4 and represented graphically in Fig. 4d.
It is clear from these data that these mass losses are
accompanied by three exothermic (60, 130, and 510 ꢁC)
and three endothermic (100, 497, and 560 ꢁC) peaks.
Calculation of activation thermodynamic parameters
The thermodynamic activation parameters of decomposi-
tion processes of dehydrated complexes namely activation
energy (E*), enthalpy (DH*), entropy (DS*), and Gibbs free
123

Metal complexes of fenoterol drug
645
energy change of the decomposition (DG*) are evaluated
graphically by employing the Coats-Redfern relation [20].
60
40
20
0
a
100
ꢀ
ꢁ
ꢀ
ꢂ
ꢃꢁ
logfWf=ðWf ꢁ WÞg
AR
hEꢂ
2RT
Eꢂ
log
¼ log
1 ꢁ
T2
50
Eꢂ
ꢁ
ð1Þ
2:303 RT
-20
-40
where Wf is the mass loss at the completion of the reaction,
W is the mass loss up to temperature T, R is the gas constant,
E* is the activation energy in kJ mol-1, h is the heating
rate, and (1 - (2RT/E*)) % 1. A plot of the left-hand
side of Eq. 1 against 1/T gives a slope from which E* was
calculated and A (Arrhenius factor) was determined from
the intercept. The entropy of activation (DS*), enthalpy of
activation (DH*), and the free energy change of activation
(DG*) are calculated using the following equations:
0
0
200
400
600
800
1000
Temperature/°C
40
20
0
100
b
50
-20
-40
DSꢂ ¼ 2:303½logðAh=kTÞꢃR
ð2Þ
ð3Þ
ð4Þ
DHꢂ ¼ Eꢂ ꢁ RT
0
0
0
0
0
200
200
200
200
400
600
800
800
800
800
1000
DGꢂ ¼ DHꢂ ꢁ TDSꢂ
Temperature/°C
20
0
c
150
100
50
The data are summarized in Table 5. The activation ener-
gies of decomposition were found to be in the range 11.20–
26.90 kJ mol-1. The entropy of activation is found to have
negative values in all the complexes which indicate that the
decomposition reactions proceed with a lower rate than the
normal ones.
-20
-40
-60
0
Structural interpretation
400
600
1000
Temperature/°C
The structures of the complexes of FEN drug with metals
1
are confirmed by the elemental analyses, H NMR, IR,
10
100
50
d
0
molar conductance, magnetic and thermal analyses data.
The structures proposed for the complexes are given as
shown below in Fig. 5.
-10
-20
-30
-40
-50
Biological activity
0
The main aim of the production and synthesis of any
antimicrobial 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 which depends essentially on the
specific control of only one biological function and not
multiple ones. The chemotherapeutic agent affecting only
one function has a highly sounding application in the field
of treatment by anticancer, since most anticancers used in
the present time affect both cancerous diseased cells and
healthy ones which in turn affect the general health of the
patients. Therefore, there is a real need for having a che-
motherapeutic agent which controls only one function. In
testing the antibacterial activity of FEN drug and its metal
complexes, more than one test organism are used to
400
600
1000
Temperature/°C
100
e
10
0
-10
-20
-30
-40
-50
50
0
400
600
1000
Temperature/°C
Fig. 4 Thermal analyses (DTA and TGA) of a Cr(III), b Mn(II),
c Ni(II), d Co(II), and e Zn(II)–FEN complexes
123

646
M. H. Soliman et al.
Table 5 Thermodynamic data of the thermal decomposition of FEN and its metal complexes
Compounds
Decomp. temp/ꢁC
E*/kJ mol-1
A/s-1
DS*/J K-1 mol-1
DH*/kJ mol-1
DG*/kJ mol-1
FENꢀHBr
185–500
500–815
30–120
26.90
2.5 9 10-3
-101.9
24.70
12.60
65.10
51.40
[Ni(FEN)2(H2O)2]ꢀ4H2O
[Cu(FEN)2]ꢀ2H2O]
15.30
11.20
4.6 9 10-3
7.2 9 10-3
-134.0
-157.1
56.00
95.40
120–650
30–270
270–1000
OH2
investigated bacteria and fungi to different extent. The size
of the inhibition zone depends upon the culture medium,
incubation conditions, rate of diffusion, and the concen-
tration of the antibacterial agent. The activities of all the
tested complexes may be explained on the basis of chela-
tion theory; chelation reduces the polarity of the metal
atom mainly because of partial sharing of its positive
charge with the donor groups and possible p electron
delocalization within the whole chelate ring. Also, chela-
tion increases the lipophilic nature of the central atom
which subsequently favors its permeation through the lipid
layer of the cell membrane [21].
H
OH2
N
O
H
N
O
M
.yH2O
Cr
.
.Cl H2O
O
N
H
OH2
O
N
H
M = Mn(II), Co(II), Ni(II) and Zn(II), y = 0-4
OH2
H
N
O
Cu
.2H2O
O
N
On comparing the biological activity of the FEN drug
and its metal complexes, the following results are obtained:
H
Fig. 5 Structure of metal complexes of FEN drug
(1) Biological activity against Gram-positive bacteria
follow the order: FEN = [Zn(FEN)2(H2O)2] [ [Mn
(FEN)2(H2O)2]ꢀ2H2O = [Co(FEN)2(H2O)2]ꢀ4H2O =
[Ni(FEN)2(H2O)2]ꢀ4H2O = [Cu(FEN)2]ꢀ2H2O [ [Cr
(FEN)2(H2O)2]ClꢀH2O. It is obvious that the biolog-
ical activity of the metal complexes are more or less
comparable with the parent FEN drug which means
that the complexes can have the same action like the
parent drug.
increase the chance of detecting antibiotic principles in
tested materials. The sensitivity of a microorganism to
antibiotics and other antimicrobial agents is determined by
the assay plates which are incubated at 37 ꢁC for 2 days for
bacteria. All the tested compounds show a remarkable
biological activity against different types of Gram-positive
(G?) bacteria, Gram-negative (G-) bacteria, yeast, and
fungi. The data are listed in Table 6. The data show that
FEN drug is under investigation and its metal complexes
have the capacity of inhibiting the metabolic growth of the
(2) Biological activity against Gram-negative bacteria
follow the order: [Co(FEN)2(H2O)2]ꢀ4H2O = [Zn
(FEN)2(H2O)2][FEN = [Mn(FEN)2(H2O)2]ꢀ2H2O =
Table 6 The antibacterial and antifungal activity of FEN drug and its metal complexes
Complexes
Biological agent
Bacteria (G?)
Bacteria (G-)
Fungi
Yeast
S. aures
B. subtilis
E. coli
S. typhi
A. niger
A. flavas
S. cervisiae
C. albicans
FENꢀHbr
??
?
??
?
??
?
?
?
-
?
-
?
-
?
-
?
-
?
-
?
-
?
-
-
?
?
-
?
?
-
?
-
?
-
?
[Cr(FEN)2(H2O)2]ClꢀH2O
[Mn(FEN)2(H2O)2]ꢀ2H2O
[Co(FEN)2(H2O)2]ꢀ4H2O
[Ni(FEN)2(H2O)2]ꢀ4H2O
[Cu(FEN)2]ꢀ2H2O
?
?
??
?
?
??
??
?
??
??
??
??
??
??
??
??
?
?
?
[Zn(FEN)2(H2O)2]
??
??
? Inhibition values up to 10 mm, ?? inhibition values = 11–15 mm, ??? inhibition values = 16–22 mm, ???? inhibition values more
than 23 mm
123

Metal complexes of fenoterol drug
647
mass spectrometry and tandem mass spectrometry. J Mass
Spectrom. 1995;30:911–6.
9. Kramer S, Blaschke G. High-performance liquid chromatographic
determination of the b2-selective adrenergic agonist fenoterol in
human plasma after fluorescence derivatization. J Chromatogr B
Biomed Sci Appl. 2001;751:169–75.
[Ni(FEN)2(H2O)2]ꢀ4H2O = [Cu(FEN)2]ꢀ2H2O [ [Cr
(FEN)2(H2O)2]ClꢀH2O.
(3) The complexes also show antifungal and anti-yeast
activities which are comparative to the parent FEN
drug which shows such activity which make these
complexes of interest.
10. Grayer RJ, Harbone JB. A survey of antifungal compounds from
higher plants. Phytochemistry. 1994;37:19–42.
11. Salama F, El-Abasawy N, Abdel Razeq SA, Ismail MMF, Fouad
MM. Validation of the spectrophotometric determination of
omeprazole and pantoprazole sodium via their metal chelates.
J Pharm Biomed Anal. 2003;33:411–21.
12. Mohamed GG, Nour El-Dien FA, Khalil SM, Mohammad AS.
Metal complexes of omeprazole. Preparation, spectroscopic and
thermal characterization and biological activity. J Coord Chem.
2009;62:645–54.
Also the data listed in Table 6 shows that E. coli is
inhibited by Co(II), Ni(II), Cu(II), and Zn(II) complexes.
The importance of this lies in the fact that these complexes
could be applied fairly in the treatment of some common
diseases caused by E. Coli e.g., septicemia, gastroenteritis,
urinary tract infections, and hospital-acquired infections
[22, 23].
¨
13. Icbudak H, Heren Z, Kose DA, Necefoglu H. bis (nicotinamide)
and bis (N, N-diethyl nicotinamide) p-hydroxybenzoate com-
plexes of Ni(II), Cu(II) AND Zn(II). J Therm Anal Calorim.
2004;76:837–51.
References
˘
¨
14. Kose DA, Necefoglu H. Synthesis and characterization of bis
(nicotinamide) m-hydroxy-benzoate complexes of Co(II), Ni(II),
Cu(II) and Zn(II). J Therm Anal Calorim. 2008;93:509–14.
15. Ko¨se DA, Go¨kc¸e G, Go¨kc¸e S, Uzun I. bis (N, N-diethylnicotina-
mide) p-chlorobenzoate complexes of Ni(II), Zn(II) and Cd(II).
Synthesis and characterization. J Therm Anal Calorim. 2009;95:
247–51.
1. Beigi F, Bertucci C, Zhu W, Chakir K, Wainer IW, Xiao RP, et al.
Enantioselective separation and online affinity chromatographic
characterization of R,R- and S,S-fenoterol. Chirality. 2006;18:
822–7.
´
2. Jzwiak K, Khalid C, Tanga MJ, Berzetei-Gurske I, Jimenez L,
´
Kozocas JA, et al. Comparative molecular field analysis of the
binding of the stereoisomers of fenoterol and fenoterol derivatives
to the beta-2-adrenergic receptor. J Med Chem. 2007;50:2903–15.
3. Wilson AA, Wang J, Koch P, Walle T. Stereoselective sulphate
conjugation of fenoterol by human phenolsulphotransferases.
Xenobiotica. 1997;27:1147–54.
4. Rominger KL, Mentrup A, Stiasni M. Radioimmunological
determination of fenoterol. Part II: antiserum and tracer for
the determination of fenoterol. Arzneimittelforschung. 1990;40:
887–95.
16. Santos AFO, Basılio ID, de Souza FS, Medeiros AFD, Pinto MF,
de Santana DP, et al. Application of thermal analysis in study of
binary mixtures with metformin. J Therm Anal Calorim. 2008;93:
361–4.
17. Cotton FA, Wilkinson G, Murillo CA, Bochmann M. Advanced
inorganic chemistry. 6th ed. New York: Wiley; 1999.
18. Zayed MA, Nour El-Dien FA, Mohamed GG, El-Gamel NEA.
FT-IR, magnetic, mass spectra, XRD and thermal studies of metal
chelates of tenoxicam. J Mol Struct. 2007;841:41–50.
19. Mohamed GG. New cyclodiphosph(V)azane complexes of
Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and UO2(II): preparation,
characterization and biological studies. Phosphorus Sulfur Silicon
Relat Elem. 2005;180:1569–84.
5. Haasnoot W, Stouten P, Lommen A, Cazemier G, Hooijerink D,
Schilt R. Determination of fenoterol and ractopamine in urine by
enzyme immunoassay. Analyst. 1994;119:2675–80.
6. Damasceno L, Ventura R, Cardoso J, Segura J. Diagnostic evi-
dence for the presence of b-agonists using two consecutive
derivatization procedures and gas chromatography–mass spec-
trometric analysis. J Chromatogr B Analyt Technol Biomed Life
Sci. 2002;780:61–71.
7. Couper FJ, Drummer OH. Gas-chromatograpic-mass-spectro-
metric detractions of beta-2-agonists in post mortem blood.
J Chromatogr B Biomed Appl. 1996;685:265–72.
20. Coats AW, Redfern JP. Kinetic parameters from thermogravi-
metric data. Nature. 1964;20:68–79.
21. Caudhary A, Singh RV. Synthetic, structural and biological
studies on divalent tin complexes of sixteen to twenty-four mem-
bered tetraaza macrocycles. Phosphorus Sulfur Silicon Relat
Elem. 2003;178:603–13.
22. Jawetz E, Melnick JL, Adelberg EA. Review of medical micro-
biology. 16th ed. Los Anglos, CA: Lang Medical Publications;
1979.
23. Hughes WH, Stewart HC. Concise antibiotic treatment. London:
Butter Worth; 1970.
8. Doerge DR, Bajic S, Blankenship LR, Preece SW, Churchwell
MI. Determination of b-agonist residues in human plasma using
liquid chromatography/atmospheric pressure chemical ionization
123