Novel metal complexes, their spectrophotometric and QSAR studies

Article abstract of DOI:10.1007/s00044-013-0818-7

One novel Schiff base and its five complexes were synthesized and characterized by elemental analyses, FT-IR, ¹H NMR, ¹³C NMR, UV, LC-MS, thermal analyses and the X-ray powder diffraction method and their antibacterial activities wer

Full text of DOI:10.1007/s00044-013-0818-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:2596–2607
DOI 10.1007/s00044-013-0818-7
ORIGINAL RESEARCH
Novel metal complexes, their spectrophotometric and QSAR
studies
•
Gu¨zin Aslan Zu¨lbiye Onal
Received: 21 March 2013 / Accepted: 1 October 2013 / Published online: 27 October 2013
Ó Springer Science+Business Media New York 2013
Abstract One novel Schiff base and its five complexes
were synthesized and characterized by elemental analyses,
FT-IR, 1H NMR, 13C NMR, UV, LC–MS, thermal analyses
and the X-ray powder diffraction method and their anti-
bacterial activities were investigated against Gram-positive
(Staphylococcus aureus ATCC 25923, Bacillus cereus
ATCC 11778, Enterococcus faecalis ATCC 29212,
Bacillus subtilis ATCC 6633, Staphylococcus epidermidis
ATCC 12228, Enterobacter aerogenes ATCC 13048,
Micrococcus luteus ATCC 10240, Listeria monocytogenes
ATCC 19115 and Corynebacterium renale ATCC 19412)
and Gram-negative bacteria (Pseudomonas fluorescens
ATCC 49838, Klebsiella pneumonia ATCC 13883, Esch-
erichia coli ATCC 25922, Pseudomonas aeruginosa
ATCC 27853 and Proteus mirabilis ATCC 25933) by the
countries around the world (Huebner, 2001; Mitsher et al.,
1999; Berber et al., 2003). A number of recent clinical
reports describe the increasing occurrence of methicillin-
resistant Staphylococcus aureus (MRSA), vancomycin-
resistant enterococci and other antibiotic-resistant human
pathogenic microorganisms in the United States and
European countries (Viksveen, 2003). Infections caused by
these microorganisms pose a serious challenge to the
medical community and the need for an effective therapy
has led to a search for novel antimicrobial agents. For this
reason during the last few decades there has been great
interest in the chemistry of transition metals associated
with nitrogen, oxygen and sulphur donor ligands, for
instance, both five- and six-membered heterocyclic pyra-
zoles, pyridazines and pyrimidines (Viciano-Chumillas
et al., 2007; Roy et al., 2007, 2009; Salih, 2008). Pyrimi-
dine derivatives are an important class of heterocyclic
compounds because of their diverse biological activities
(Varma, 1999; Kappe, 1993; Xie et al., 1999; Kappe et al.,
1997; Hardtmann, 1978). They show various interesting
pharmacological properties including antiviral (Varma,
1999), antibacterial (Kappe, 1993; Xie et al., 1999), anti-
tumour (Kappe et al., 1997) and anti-inflammatory effects
(Hardtmann, 1978). Some of them are frequently encoun-
tered in many of the drugs used for the treatment of
hypothyroidism, hypertension, cancer chemotherapy or
HIV infection (Kleidernigg and Kappe, 1997; Selassie
et al., 1991; Burdge, 2000). Although extensive studies
have been made on various pyrimidine-derived ligands
˙
MIC method. The compound’s quantum mechanical
descriptors were calculated. The QSAR model for antimi-
crobial activity was suggested.
Keywords Antimicrobial activity ꢀ Metal complexes ꢀ
Schiff bases ꢀ Thermal studies, QSAR
Introduction
In recent decades, the problems of multidrug-resistant
microorganisms have reached an alarming level in many
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0818-7) contains supplementary
material, which is available to authorized users.
¨
(Sonmez et al., 2006; Tojal et al., 2002; Rapheal et al.,
2007; Ketcham et al., 2001), comparatively less research
has been carried out on transition metal chemistry
with Schiff base ligands having pyrimidine as the hetero-
cyclic part. 1-Amino-5-(4-methylbenzoyl)-4-(4-methyl-
phenyl) pyrimidin-2 (1H)-thione obtained from acetophenone
G. Aslan (&) ꢀ Z. Onal
Department of Chemistry, Faculty of Science, Erciyes
University, Melikgazi, 38039 Kayseri, Turkey
e-mail: guzina@erciyes.edu.tr
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Med Chem Res (2014) 23:2596–2607
2597
thiosemicarbazone with 4-(4-methylbenzoyl)-5-(4-methyl-
¨
phenyl) furan-2,3-dione has been reported before (Onal and
were determined using XRD analyses with a Bruker AXS
D8 advanced diffractometer and a Bragg–Brentano geom-
etry with a graphite monochromator. CuKa radiation
operated at 40 kV and 40 mA. Divergence and receiving
slits of 1 and 0.1 mm, respectively, were located on the
diffractometer. Diffraction patterns were scanned by
0.002° (2h) steps over the angle range of 10–90 (2h). The
thermogravimetric analysis (TG/DTA) of the ligand and its
complexes was measured on a Perkin Elmer Diamond TG/
DTA thermal analyser. The experiments were carried out in
a dynamic nitrogen atmosphere (200 mL min-1) with a
heating rate of 10 °C min-1 in a temperature range of
50–1,200 °C using platinum crucibles. All extracted sol-
vents (all from Merck) were dried over anhydrous Na2SO4
and evaporated with a BUCHI rotary evaporator. Reagents
were obtained commercially from Aldrich (ACS grade)
and used as received.
Yildirim, 2007). This prompted us, and we obtained a novel
[1-{[(1Z)-(2-hydroxyphenyl)methylene]amino}-4-(4-methyl
phenyl)-2-thioxo-1,2-dihydroxypyrimidin-5-yl](4-methyl-
phenyl)methanone and its five transition metal complexes:
Trans bis[1-{[(1Z)-(2-hydroxyphenyl)methylene]amino}-
4-(4-methylphenyl)-2-thioxo-1,2-dihydroxypyrimidin-5-yl]
(4-methylphenyl)methanone dichloro metal(II) [(Ni(II),
Pd(II), Pt(II)], and trans bis[1-{[(1Z)-(2-hydroxyphenyl)
methylene]amino}-4-(4-methylphenyl)-2-thioxo-1,2-dihy-
droxypyrimidin-5-yl](4-methylphenyl)methanone metal(II)
chloride [Cu(II), Co(II)] and their structure was charac-
1
terized by FT-IR, H NMR, 13C NMR, magnetic suscep-
tibility, UV, X-ray powder diffraction, DTA/TG,
elementary analysis and LC/MS techniques. We investi-
gated their antibacterial activities against Gram-positive
(S. aureus ATCC 25923, Bacillus cereus ATCC 11778,
Enterococcus faecalis ATCC 29212, Bacillus subtilis
ATCC 6633, Staphylococcus epidermidis ATCC 12228,
Enterobacter aerogenes ATCC 13048, Micrococcus luteus
ATCC 10240, Listeria monocytogenes ATCC 19115 and
Corynebacterium renale ATCC 19412) and Gram-negative
bacteria (Pseudomonas fluorescens ATCC 49838, Klebsi-
ella pneumonia ATCC 13883, Escherichia coli ATCC
25922, Pseudomonas aeruginosa ATCC 27853 and P.
mirabilis ATCC 25933) by the microdilution method. All
the bacteria studied were screened against standard anti-
biotics to compare them with our chemical zone diameters.
Preparation of compounds
EtOH, DMSO, diethyl ether, salicylaldehyde, CuCl2,
CoCl2, NiCl2, K2PtCl4 and K2PdCl4 were obtained from
Merck. All solvents were dried and purified before use.
Synthesis of [1-{[(1Z)-(2-hydroxyphenyl)
methylene]amino}-4-(4-methylphenyl)-2-thioxo-1,2-
dihydroxypyrimidin-5-yl](4-methylphenyl)methanone
(Hsalmpp)1
A solution of 1-amino-5-(4-methylbenzoyl)-4-(4-methyl-
phenyl) pyrimidine-2-(1H)-thione (0.01 mol) in 15 mL
ethanol was mixed with a solution of salicylaldehyde
(0.02 mol) in 5 mL ethanol and boiled for 45 min. The
product was refluxed with rotary evaporator and was re-
crystallized from ethanol twice. The results were light-yel-
low solids, stable at normal conditions and soluble only in
DMSO and DMF. The following results were found: yield
58 %; m.p. 205 °C (disintegration); FT-IR; 764(mC=S),
1278(mC–O), 1639(m C=N); 1H NMR (DMSO-d6,400 MHz,
dppm);9.08 (s, 1H, N=CH), 7.83–6.95 (m, 13H, Ar–H), 8.90
(s, 1H, Pyr.CH), 2.50–2.11 (m, 6H, CH3), 10.76 (s, 1H, OH);
13C NMR (DMSO-d6,400 MHz, dppm); 192.25 (N=C),
145.84–117.26 (Ar–C), 166.67 (Pyr.C), 21.66–21.33 (CH3),
10.76 (OH); LC–MS (70 eV, APC1): 440.1 [M?], elemental
analysis found (calcd.) C26H21N3O2S: C, 70.86(71.05); H,
4.85(4.81); N, 9.60(9.56); S, 7.27(7.29).
Experimental methods
Materials
All the common laboratory chemicals used in the synthesis
of the ligand and its metal complexes were purchased from
commercial sources and used without further purification.
Instrumentation
The infrared spectra of the compounds were recorded in the
range of 4000–400 cm-1 with a Shimadzu 8400 FT-IR
spectrometer. LC/MS-APC1 was recorded on an AGI-
˙
LENT 1100. UV–Vis spectra were recorded on a UNI-
CAM-UV 2-100 spectrophotometer. The melting point was
recorded on an Opti MELT 3 hot stage apparatus. TLC was
conducted on 0.25 mm silica gel plates (60F254, Merck).
Visualisation was made with ultraviolet light. The molar
magnetic susceptibilities were measured on powdered
samples using the Gouy method. The molar conductance
measurements were carried out using a Siemens WPA C 35
conductometer. The powder diffraction data of the samples
Synthesis of complexes
All complexes were prepared by the following general
method. A sample of the Hsalmpp (0.02 mol) solution in a
mixture of DMSO and anhydrous MCl2 (M: Ni, Pd, Pt, Cu,
Co) (0.01 mol) was dissolved in a mixture of ethanol and
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Med Chem Res (2014) 23:2596–2607
DMSO was added dropwise. The reaction mixture was
boiled for 40 min and stirred at room temperature all night.
The solid complexes which formed were collected by fil-
tration, washed with a small volume of ethanol and ether,
and then dried in desiccators over CaCl2. The following
results were found:
8.89–6.15 (m, 28H, Ar–H), 9.08 (s, 2H, Pyr.CH), 2.66–1.44
(m, 6H, CH3), 10.75 (s, 2H, OH); 13C NMR (DMSO-
d6,400 MHz, dppm); 190.65 (N=C), 146.32–124.73 (Ar–C),
170.67 (Pyr.C), 21.91–19.04 (CH3); LC–MS (70 eV,
APC1): 1005 [M?-5], elemental analysis found (calcd.)
C52H42N6O4S2CoCl2: C, 61.675 (61.905); H, 4.189 (4.196);
N, 8.321 (8.329); S, 6.349 (6.356); Co, 5.820 (5.841); Cl,
7.000 (7.028).
[Ni(1)2Cl2] (light green); yield 49 %; mp 188 °C (disin-
tegration); FT-IR; 730(mC=S), 1280(mC–O), 1618(mC=N);
1H NMR (DMSO-d6,400 MHz, dppm);9.05 (s, 2H, N=CH),
8.29–6.93 (m, 28H, Ar–H), 8.87 (s, 2H, Pyr.CH), 2.48–2.04
(m, 6H, CH3), 10.76 (s, 2H, OH); 13C NMR (DMSO-
d6,400 MHz, dppm); 191.55 (N=C), 145.89–117.26 (Ar–C),
166–159 (Pyr.C), 21.40–21.65 (CH3); LC–MS (70 eV,
APC1): 1006.7 [M?], elemental analysis found (calcd.)
C52H42N6O4S2NiCl2: C, 61.912 (61.919); H, 4.191 (4.197);
N, 8.321 (8.331); S, 6.349 (6.358); Ni, 5.809 (5.819); Cl,
7.032(7.029).
Biological activity: in vitro evaluation
The biological activity of the synthesized Hsalmpp and its
complexes was individually screened against a panel of
microorganisms, including Gram-positive (S. aureus ATCC
25923, B. cereus ATCC 11778, E. faecalis ATCC 29212, B.
subtilis ATCC 6633, S. epidermidis ATCC 12228, E. aer-
ogenes ATCC 13048, C. renale ATCC 19412, M. luteus
ATCC 10240 and Lysteria monocytogenes ATCC 19115),
Gram-negative bacteria (P. fluorescens ATCC 49838, K.
pneumonia ATCC 13883, E. coli ATCC 25922, P. aeru-
ginosa ATCC 27853 and Proteus mirabilis ATCC 25933).
Cultures were obtained from Erciyes University’s Faculty of
Sciences, Department of Chemistry. Bacterial strains were
cultured overnight at 35 °C in Triptic Soy Broth (TSB) in a
rotary shaker at 200 rpm. Overnight cultures were then
transferred to fresh medium and the turbidity of all broth
cultures was adjusted to 0.1 absorbance at 640 nm on a
spectrophotometer. These stock cultures were stored in the
dark at 4 °C during the survey.
[Pd(1)2] Cl2 (orange); yield 38 %; m.p. 166 °C (disinte-
gration); FT-IR; 681(mC=S), 1279(mC–O), 1600(mC=N);1H
NMR (DMSO-d6,400 MHz, dppm);9.51 (s, 2H, N=CH),
7.87–6.96 (m, 28H, Ar–H), 8.90 (s, 2H, Pyr.CH), 2.54–2.24
(m, 6H, CH3), 10.77 (s, 2H, OH); 13C NMR (DMSO-
d6,400 MHz, dppm); 191.58 (N=C), 145.98–117.33 (Ar–C),
159.29–155.07 (Pyr.C), 21.74–21.42 (CH3); LC–MS
(70 eV, APC1): 1057.1 [M?], elemental analysis found
(calcd.) C52H42N6O4S2PdCl2: C, 60.000 (59.122); H, 4.085
(4.007); N, 8.038 (7.955); S, 6.180 (6.071); Pd, 10.085
(10.074); Cl, 6.714 (6.712).
[Pt(1)2] Cl2 (reddish brown); yield 42 %; m.p. 204 °C
(disintegration); FT-IR; 732(mC=S), 1280(mC–O), 1602
(mC=N);1H NMR (DMSO-d6,400 MHz, dppm);8.97 (s, 2H,
N=CH), 7.84–6.88 (m, 28H, Ar–H), 8.94 (s, 2H, Pyr.CH),
2.50–2.17 (m, 6H, CH3), 10.26 (s, 2H, OH); 13C NMR
(DMSO-d6,400 MHz, dppm); 191.97 (N=C), 145.81–
117.33 (Ar–C), 171.84 (Pyr.C), 21.73–21.27 (CH3); LC–MS
(70 eV, APC1): 1097.00 [M?], elemental analysis found
(calcd.) C52H42N6O4S2PtCl2: C, 54.499 (54.544); H, 3.694
(3.697); N, 7.328 (7.339); S, 5.580 (5.601); Pt, 17.050
(17.037); Cl, 6.187 (6.192).
Minimal inhibitory concentration
Minimal inhibitory concentrations (MIC) (Kretov et al.,
1968; Boss et al., 2002) were determined by the microdi-
lution broth method following the procedures recom-
mended by the National Committee for Clinical Laboratory
Standards (NCCLS 2000). Briefly, synthesized molecules
dissolved in dimethylsulphoxide (DMSO) were first diluted
to the highest concentration, and then serial twofold dilu-
tions were made in a concentration range from 1.31 to
84 lg/mL in a sterile 2.4 mL 96-well Masterblock dish
containing MHB for the bacterial strains. For the test, the
96-well plates were prepared by dispensing into each well
195 lL of the serial dilutions of the synthesized molecules
which were then transferred into seven consecutive wells in
each column. The last well, containing only 195 lL of
MHB without compound, was used as a negative control.
For each column of the plate, 5 lL of the strains to be
tested was inoculated into each well individually. The final
volume in each well was brought up to 200 lL. For the
bacterial cells, trimethoprim and tetracycline were used as
standard drugs for positive control (Martindalr, 1999).
[Cu(1)2Cl2] (dark brown); yield 33 %; m.p. 161 °C (dis-
integration); FT-IR; 729(mC=S), 1280(mC–O), 1618
(mC=N);1H NMR (DMSO-d6,400 MHz, dppm);10.25 (s,
2H, N=CH), 9.08–6.91 (m, 28H, Ar–H), 9.83 (s, 2H,
Pyr.CH), 2.66–2.07 (m, 6H, CH3), 10.79 (s, 2H, OH); 13C
NMR (DMSO-d6,400 MHz, dppm); 192.18 (N=C),
136.89–117.67 (Ar–C), 161.17 (Pyr.C), 21.71–21.34 (CH3);
LC–MS (70 eV, APC1): 1039.2 [M??Na?], elemental
analysis found (calcd.) C52H42N6O4S2CuCl2: C, 61.653
(61.623); H, 4.168 (4.177); N, 8.289 (8.292); S, 6.320
(6.328); Cu, 6.401 (6.269); Cl, 6.929 (6.996).
[Co(1)2Cl2] (black); yield 49 %; m.p. 189 °C (disinte-
gration); FT-IR; 681(mC=S), 1280(mC–O), 1602(mC=N); 1H
NMR (DMSO-d6,400 MHz, dppm);10.04 (s, 2H, N=CH),
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Med Chem Res (2014) 23:2596–2607
2599
(a)
(b)
Scheme 1 The general synthetic route to prepare ligand and its
complexes. Trans[bis([1-{[(1Z)-(2-hydroxyphenyl)methylene]
amino}-4-(4-methylphenyl)-2-thioxo-1,2-dihydroxypyrimidin-5-yl]
(4-methylphenyl)methanone dichloro] M(II) (M: Ni(II), Cu(II),
Co(II)).
b
Trans[bis([1-{[(1Z)-(2-hydroxyphenyl)methylene]
a
amino}-4-(4-methylphenyl)-2-thioxo-1,2-dihydroxypyrimidin-5-yl]
(4-methylphenyl)methanone M(II)chloride (M: Pd(II), Pt(II))
Results and discussion
geometry is observed around the nickel, copper and cobalt
complexes and a square planar geometry is observed around
the palladium and platinum complexes, in which the ligand
acts as a neutral bidentate one, coordinating though its nitro-
gen and sulphur atoms. Carbonyl (C=O) and –OH groups are
more effective than C=S group. Therefore, these attachment
points are waitedfor complexationreactions. But accordingto
1H NMR results, the phenolic –OH signals of all compounds
are detected between 10.26 and 10.79 ppm, and C=O signals
are detected between 163 and 171 ppm and 1H NMR spectra
Scheme 1 illustrates the general synthetic route used to
prepare our compounds.
The report presented in this study includes the synthesis
and spectral characterization of ligand(1) and its five new
(2)nickel(II), (3)palladium(II), (4)platinum(II), (5)copper(II)
and (6)cobalt(II) complexes with the formula [Ni(1)2Cl2],
[Cu(1)2Cl2], [Co(1)2Cl2], [Pd(1)2]Cl2, [Pt(1)2]Cl2 and their
antimicrobial activity. As shown below an octahedral
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Med Chem Res (2014) 23:2596–2607
1
Fig. 1 The H NMR spectra of
Hsalmmp
of the free ligand assigned to (C=O) is not shifted. The IR
spectra of the free ligand assigned to m(C=N) and m(C=S) are
shifted by -35, -63 and -21, -39 cm-1, respectively, but
they are not shifted by –OH and C=O signals. According to
these results, it is indicated as the azomethine nitrogen and
thiocarbonyl of the Schiff base.
azomethine nitrogen. Strong bands at 1,639 and 764 cm-1
in the IR spectra of the free ligand assigned to m(C=N) and
m(C=S) are shifted by -35, -63 and -21, -39 cm-1
,
respectively, in the spectra of the complexes, indicating
coordination via the azomethine nitrogen and thiocarbonyl
of the Schiff base.
The results of elementary analysis shows 1:2 (metal/
ligand) stoichiometries for all the complexes and two
additional values for the chloride ligands which are coor-
dinated to the metal atoms (only Ni, Cu, Co). All com-
plexes are found to be very stable at room temperature in
the solid state and generally soluble in DMSO, DMF and
The ligand and complexes display bands at
1,278–1,280 cm-1 which are assigned to m(C–O) stretching
vibrations of the phenolic –OH.
NMR spectra
CH2Cl2. The molar conductivity (Km) of the 10-3
M
DMSO is used as a solvent to measure the 1H NMR spectra of
the ligand and its complexes. The sharp singlet observed at
10.76 ppm is assigned to the phenolic proton of the ligand.
The singlet peaks at 9.08 and 8.90 ppm, respectively, are
assigned to the azomethine proton and the pyrimidine ring
(C–H) proton in the spectrum of the ligand. The phenyl
multiplet is observed between 7.83 and 6.95 ppm.
solutions of the complexes in DMSO at 25 °C are mea-
sured, and the nickel, cobalt and copper complexes are
found to have a non-electrolytic nature, while the platinum
and palladium complexes are found to have an electrolytic
nature.
[1-{[(1Z)-(2-hydroxyphenyl)methylene]amino}-4-(4-
methylphenyl)-2-thioxo-1,2-dihydroxypyrimidin-5-yl]
(4-methylphenyl)methanone and its complexes have
not been previously reported in the literature.
The 1H NMR spectrum of the Hsalmmp shows signals at
2.50 and 2.11 ppm corresponding to the signals of –CH3.
1
The H NMR spectra diagram of Hsalmmp(1) is given
in Fig. 1.
FT-IR spectra
In the 13C NMR spectrum, the aromatic C peaks are
observed between 117.26 and 145.98 ppm. The C peaks at
190.65–192.25 and 155.07–171.84 ppm, respectively, are
assigned to the azomethine proton and the pyrimidine ring
C in the spectrum of the ligand. Methyl carbons are
observed between 19.04 and 21.91 ppm.
The IR spectra of the Schiff base ligand shows a broad
band at 3,616 cm-1 (Bellamy, 1978). The observed low
frequency of this band (3,080 cm-1) is due to intramole-
cular hydrogen bonding between the H of OH and the
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Med Chem Res (2014) 23:2596–2607
2601
Fig. 2 X-ray diagram of
Hsalmmp and its complexes
UV spectra
X-ray powder diffraction
DMSO is used as a solvent to measure the electronic
absorption spectral data of the complexes. In the spectrum
of the ligand, the bands in the 280–325 nm range are
assigned to the n ? p* transitions of the azomethine
group. During the complexation reaction, these bands are
shifted to lower wavelength.
The powder patterns of the ligand (Hsalmmp) is indexed in
orthorhombic crystal systems with unit cell parameters of
a: 13.71, b: 10.05, c: 8.78 pm. The X-ray diagram of
Hsalmmp and its complexes are shown in Fig. 2.
The [Ni(1)2Cl2] complex is indexed in an orthorhombic crystal
˚
system with unit cell dimensions of a: 9.75, b: 8.92, c: 6.87 A.
[Ni(1)2Cl2] complex shows d–d transition at 411.6 and
3
The [Pd(1)2]Cl2 complex is indexed in a tetragonal
crystal system with unit cell dimensions of a: 7.07, c:
3
500(weak) nm corresponding to A2g ? T1g and
3
3A2g ? T2g, respectively, which suggest octahedral geom-
etry. The magnetic moment values for Ni(1)2Cl2 complex at
2.23 A. The [Pt(1)2]Cl2 complex is indexed in a hexagonal
˚
crystal system with unit cell dimensions of a: 3.64, c:
2.23 pm. The copper and cobalt complexes of Hsalmmp
did not have any peaks with CuKa radiation.
room temperature is found to be 4.3 B.M.
The electronic spectra of the Pd(II) and Pt(II) complexes
1
1
at 416–413 nm assignable to the A2g ? Eg and
1A2g ? 3Eg transitions, respectively, indicated a square
planar environment around the metal ions. The observed
magnetic moments of the palladium (II) and platinum (II)
complexes are 0.73 and 1.16 B.M., respectively.
All the complexes are burned in a furnace and the X-ray
powder diffraction diagram of the residue of each complex
is obtained. All the residues, ECPDS numbers and crystal
systems are summarized in Table 1. The X-ray diagrams of
all the complexes were almost the same. Therefore, the
X-ray diagram of [Pt(1)2]Cl2 (residue) is given in Fig. 3.
The electronic spectrum of the Cu (II) complex consists
2
2
of a band at 455.9 nm, arising from the B1g ? Eg tran-
sition similar to those found for the octahedral complexes.
At room temperature, its magnetic moment (2.15 B.M.)
corresponds to an octahedral symmetry.
Thermal studies
TG/DTA analysis for the ligand and its metal complexes are
recorded in nitrogen atmosphere from 50 to 1,200 °C. The
thermal behaviours of all complexes are almost the same.
Therefore, Hsalmmp and Hsalmmp Ni complex are dis-
cussed here in detail. The thermal decomposition of the
ligand (C26H21N3O2S) takes place in three stages. In the first
stage from 0 to 200 °C one mole of the –CH–C6H4OH group
is decomposed, shown as one maximum in the DTG curve at
189.76 °C with 24 % mass loss (calc. = 24.1 %). The sec-
ond stage starts at 200 °C and ends at 300 °C. In the second
stage one mole of the –COC6H4CH3 and one mole of the
–C6H4CH3 groups are decomposed with 48 % mass loss.
The DTG curve shows one peak at 277.87 °C for this stage.
The third stage is related to the decomposition of the
remaining part of the ligand molecule with 28 % mass loss
and decomposition finishes at 1,100 °C. The complex with
[Co(1)2Cl2] complex shows d–d transition at 443 and
3
3
3
500(weak) nm corresponding to A2g ? T1g and A2g
?
3T2g, respectively, which suggest octahedral geometry (Lever,
1984). The magnetic moment values for Co(1)2Cl2 complex at
room temperature is found to be 3.51 B.M.
LC–MS spectra
LC/MS shows that the Co complex gives the molecular ion
[Co(1)2Cl2]-5 at 1,005 m/z; the Cu complex gives the
molecular ion [Cu(1)2Cl2] ? Na? at 1,039.2 m/z; the Ni
complex gives the molecular ion [Ni(1)2Cl2] at 1,006.7
m/z; the Pd and Pt complexes give the molecular ions
[Pd(1)2]Cl2, [Pt(1)2] Cl2 at the desired position at 1,057.1
and 1,097 m/z.
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Med Chem Res (2014) 23:2596–2607
Table 1 The thermal behaviours of The Hsalmmp and its complexes
Substance
Peaktemp.
in DTG (oC)
Temp.ranges
in TG (oC)
Mass loss % TG
theoretical
Evolved moiety
Residue (ECPDS number)
–
Hsalmmp
189.76
277.87
0–200
24.00 24.10
65.19 65.60
–CH–C6H5OH
–COC6H4CH3
–C6H4CH3
200–300
[Ni(1)2Cl2]
[Co(1)2Cl2]
[Cu(1)2Cl2]
250
0–250
7.00 6.95
62.00 63
–2-Cl
NiO (44-1159) hexagonal
186.09–1050
250–1100
–2-COC6H4–CH3,
–2-CHC6H5OH
–2-C6H4CH3
–2-Cl
186.18
270.00
348.75
0–200
6.00 6.93
CoOꢀCo2O3
(02-1079)
200–400
400–1100
49.50 51.40
68.00 69.57
–2-CH–C6H4OH
–2-COC6H4–CH3
–2-C6H4CH3
–2-Cl
Face-centred cubic
154.41
296.64
-
50–150
6.00 6.93
CuO (tenorite)
(01-1117)
150–450
400–1000
49.50 51.40
70.00 69.57
–2-COC6H4CH3
–2-CH–C6H4OH
–2-C6H4CH3
–2-Cl
Monoclinic
[Pd(1)2]Cl2
[Pt(1)2]Cl2
166.25
207.5
50–200
7.00 6.63
PdS (74-1060), PdO2 (34-1101)
Tetragonal
200–300
300–500
50–200
25.00 26.70
50.00 49.26
6.00 6.24
–2-CH–C6H4OH
–2-COC6H4–CH3,
–2-Cl
327.50
170.34
283.86
870.78
Pt (04-0802)
Cubic
150–300
300–900
47.00 45.49
63.00 61.41
–2-COC6H4CH3
–2-CH–C6H4OH
–2-C6H4CH3
200
190
180
170
160
150
140
130
120
110
Fig. 3 X-ray diagram of
[Pt(1)2]Cl2 residue
I(cps)
100
90
80
70
60
50
40
30
20
10
0
10
20
30
40
50
60
70
80
90
2Θ
[Pt(1)2]Cl2 : Residue Cubic
Pt (04-0802) Cubic
123

Med Chem Res (2014) 23:2596–2607
2603
Antimicrobial activity
Our ligand and its complexes are evaluated by the mic-
rodilution procedure for their in vitro antibacterial activity
against five Gram-negative and nine Gram-positive path-
ogenic bacteria. Data for the trimethoprim and tetracy-
cline antibacterial agents are used for comparison.
Trimethoprim binds to dihydrofolate reductase and
inhibits the reduction of dihydrofolic acid (DHF) to tet-
rahydrofolic acid (THF). THF is an essential precursor in
the thymidine synthesis pathway and interference with
this pathway inhibits bacterial DNA synthesis. Trimeth-
oprim’s affinity for bacterial dihydrofolate reductase is
several thousand times greater than its affinity for human
dihydrofolate reductase. Tetracycline antibiotics are pro-
tein synthesis inhibitors, inhibiting the binding of ami-
noacyl-tRNA to the mRNA–ribosome complex. They do
so mainly by binding to the 30S ribosomal subunit in the
mRNA translation complex. The chemical structures of
tetracycline and trimethoprim is given in Fig. 5. Almost
all the compounds displayed activity against M. luteus.
On the other hand none of the compounds displayed
activity against P. aeruginosa, E. aerogenes and B. sub-
tilis bacteria. E. aerogenes is a pathogenic bacterium that
causes opportunistic infections; this includes most types
of infections. The fact that our compounds did not show
any activity against these bacteria is unfortunate; how-
ever, the copper and cobalt complexes displayed very
good activity against M. luteus and C. renale, when
compared with the above-mentioned antibiotics. The Cu
and Co complexes generally seemed to be more active
against Gram-positive bacteria, but the ligand and its Ni,
Pd and Pt complexes seemed to have poor activity against
all Gram-positive and Gram-negative bacteria. This is
unlike the situation in previous studies, in which the
ligand and its Pd, Pt complexes are found to be more
active (Aslan et al., 2011, 2012). The antimicrobial
activity results are given in Table 2.
Fig. 4 TG and DTG diagram of Hsalmmp and its complexes
the molecular formula [C52H42N6O4S2Cl2Ni] is thermally
decomposed in three stages. In the first stage from 0 to
200 °C two mole of chloride molecules is decomposed,
shown as one maximum in the DTG curve at 250 °C with a
7 % mass loss (calc. = 6.94 %). The second stage starts at
250 °C and ends at 1,050 °C. In this stage mass loss of 62 %
is due to the degradation of two moles –COC6H4CH3, two
moles of the –C6H4CH3 and two moles of the –CHC6H4OH
molecules, which is in agreement with the calculated value
(calc. = 62.73 %). The DTG curve shows two peaks at
186.09 and 1,050 °C. The third stage is related to the
decomposition of the remaining part of the complex mole-
cule, which is in agreement with the calculated value
(calc. = 24 %). The total residue (calc. = 7.41 %) is nickel
oxide (ECPDS Number: 44-1159). The residue is indexed in
a hexagonal crystal system with unit cell dimensions of a:
As shown in Table 1 the most active complex is Cu(II)
and the least active complex is Pd(II). The molecular elec-
trostatic potential maps for the Cu(II) and Pd(II) complexes
are shown in Fig. 6.
The major differences between the high and the low
active complexes consist of the amount of distribution of
the negative electrostatic potential around the sulphur and
nitrogen atoms. The Cu(II) complex has a high value for
the negative electrostatic potential around the sulphur and
nitrogen atoms, which is the most potent compound. On the
other hand Pd(II), with the least activity, has lower nega-
tive electrostatic potential around its sulphur and nitrogen
atoms.
o
˚
2.9552, c: 7.2275 A. The thermal behaviours of the obtained
ligand and complexes are summarized in Table 1.
The TG and DTG diagram of Hsalmmp and its com-
plexes is given in Fig. 4.
The DTA/TG studies show us thermal behaviours of
complexes and the total residue of metal.
123

2604
Med Chem Res (2014) 23:2596–2607
Fig. 5 The chemical structures
of tetracycline and trimethoprim
Table 2 MIC values (lM) of compound and reference antibiotic against tested microorganisms
1
2
3
4
5
6
Trimetoprim
(lM)
Tetracycline
(lM)
P. fluorescens ATCC 49838
0.1194 0.0260
0.0496
[6.20.10-3 [0.0917
0.0229
0.0518
0.0260
0.0172
0.0172
–
1.406.10-3
1.406.10-3
8.437.10-4
1.687.10-3
1.687.10-3
0.01125
P. aeruginosa ATCC 27853 [0.2389 [0.1041
[0.1036
0.0518
[0.1041
0.0520
E. coli ATCC 25922
0.1194 0.0260
0.0597 0.0520
0.0496
0.0248
0.0458
0.0458
K. pneumonia ATCC 13883
0.0518
0.0260
0.0172
0.0172
–
E. aerogenes ATCC 13048 [0.2389 [0.1041
[0.0993
0.0496
[0.0917
0.0458
[0.1036
6.46.10-3 0.0260
6.46.10-3 0.0260
[0.1041
S. aureus ATCCT 25923
B. cereus ATCC 11778
0.1194 0.0260
0.0149 0.0260
0.0496
0.0229
–
–
S. epidermidis ATCC 12228 0.1194 0.0260
0.0496
0.0458
0.0129
0.0129
0.0129
0.0520
–
1.406.10-3
7.031.10-3
8.437.10-4
0.01125
E. faecalis ATCC 29212
B. subtilis ATCC 6633
M. luteus ATCC 10240
0.0597 0.0520
0.0993
0.0458
8.61.10-3
[0.2389 [0.1041
[0.0993
[0.0917
[0.1036
[0.1041
0.0172
0.0149 6.493.10-3 6.200.10-3 5.73.10-3 6.46.10-3 6.49.10-3 0.0344
L. monocytogenes ATCC
19115
0.1194 0.0260
0.0496
0.0229
6.46.10-3 0.0260
8.61.10-3
5.625.10-4
P. mirabilis ATCC 25933
C. renale ATCC 19412
0.1194 0.0520
0.0149 6.493.10-3 0.0496
0.0496
0.0458
0.0458
6.46.10-3 6.49.10-3 8.61.10-4
6.46.10-3 6.49.10-3
–
–
–
K ¼ 1000 ꢁ c=c
Conductometric measurements are performed at 25 °C
in 10–3 M DMSO solutions using a conductivity meter.
The nickel, cobalt, and copper complexes dissociate in
DMSO to give a total one ion and these complexes are not
found to have an electrolytic nature. The molar conduc-
tivity results of Ni(II), Cu(II) and Co(II) complexes are 46,
29 and 74.6 S/M, respectively.
DMSO
!
½M(1)2Cl2ꢂ
½Mð1Þ Cl2ꢂþ
2
The platinum and palladium complexes are found to
have an electrolytic nature. The molar conductivity results
of Pd(II) and Pt(II) complexes are 260, 248 S/M,
respectively.
Fig. 6 The molecular electrostatic potential maps for the Cu(II) and
Pd(II) complexes
These complexes dissociate in DMSO to give a total of
three ions.
Conductometric measurements
The molar conductivity K is defined as the ratio between
the specific conductivity c and the concentration c [mol/L]
of the dissolved substance:
DMSO
!
½M(1)2Cl2ꢂ
½Mð1Þ2ꢂþ + 2Clꢃ2
The ligands molar conductivity result is 29.4 S/M.
123

Med Chem Res (2014) 23:2596–2607
QSAR analysis
2605
where R2: 0.983, F: 237.66, s: 0.000, SPRESS: 0.005
Standard error of estimate: 0.00459
In order to identify the substituent effect on antimicrobial
activity, QSAR studies are performed using linear regression
analysis.
The resulting QSAR model for antimicrobial activity
against P.fluorescens
The parameters of the synthesized compounds are selec-
ted and those considered as consistent included molar
refractivity (MR), volume (V), mass (M), participation
coefficient (logP), polarisability (P), hydration energy (HE),
HOMO and LUMO energies.
MIC: 0.254( 0.008) ? volume (0.000) ( 0.000)
where R2: 0.994, F: 698.161, s: 0.000, SPRESS: 0.007
Standard error of estimate: 0.00309
The chemical structures of the compounds are set up with
˙
the GAUSSIAN 3.0 programme and optimised with the
The resulting QSAR model for antimicrobial activity
against E.aerogenes
semi-empirical method. HOMO and LUMO are calculated
˙
by the GAUSSIAN G03 software, and the other parameters
MIC: 0.396( 0.012) ? Mass (0.000) ( 0.000)
where R2: 0.993, F: 567685, s: 0.000, SPRESS: 0.016
Standard error of estimate: 0.00530
are calculated by HyperChem 7.5 software (HyperChem 7.5,
2002). The statistical analyses are performed with SPSS
software (version 13, 2002).
The resulting QSAR model for antimicrobial activity
against B.subtilis
The resulting QSAR model for antimicrobial activity
against E.coli
MIC: 0.012 ( 0.010)—LUMO (39.761) ( 3.344)
MIC: 0.016 ( 0.001)—LUMO (17.342) ( 1.125)
Table 3 Correlation matrix for E. coli
MIC
Surface area
Volume
Mass
log P
Refractivity
Polarizability
HOMO
LUMO
MIC
1
6
-0.917*
0.010
6
-0.939*,
0.005
6
-1
Surface Area
Volume
Mass
6
0.922**
0.009
6
1
6
-0.898*
0.015
6
0.907*
0.012
6
0.986**
0.000
6
1
6
-0.672
0.144
6
0.745
0.090
6
0.822*
0.045
6
0.898*
1
6
log P
0.015
6
-0.911*
0.012
6
0.879*
0.021
6
0.989**
0.000
6
0.980**
0.001
6
0.859*
1
Refractivity
Polarizability
HOMO
0.028
6
6
-0.932**
0.007
6
0.913*
0.011
6
0.993**
0.000
6
0.983**
0.000
6
0.853*
0.031
6
0.997**
0.000
6
1
6
0.877*
0.022
6
-0.930**
0.007
6
-0.963**
0.002
6
-0.940**
0.005
6
-0.799
0.057
6
-0.960**
0.002
6
-0.968*
0.001
6
1
6
-0.992**
0.000
6
0.865*
0.026
6
0.902*
0.014
6
0.859*
0.028
6
0.638
0.173
6
0.881*
0.020
6
0.901*
0.014
6
-0.822*
0.045
6
1
6
LUMO
123

2606
Med Chem Res (2014) 23:2596–2607
where R2: 0.972, F: 141.377, s: 0.000, SPRESS: 0.027
sulfonylhydrazone (Hsalbsmh)and its Nickel(II), Palladium(II),
Platinum(II), Copper(II), Cobalt(II) complexes. Inorg Chem Com-
mun 14:1550–1553
Standard error of estimate: 0.01364
¨
Aslan HG, Ozcan S, Karacan N (2012) The antibacterial activity of
The resulting QSAR model for antimicrobial activity
against M.luteus
some hydrazones, and 2D-QSAR study of a series of sulfonyl
hydrazones. Spectrochimica Acta Part A 98:329–336
Bellamy LJ (1978) The infrared spectra of complex molecules.
Chapman and Hall, London
Berber I, Cokmus C, Atalan E (2003) Characterization of staphylo-
coccus species by SDS-PAGE of whole-cell and extracellular
proteins. Microbiology 72:54–59
MIC: 0.031 ( 0.001)—logP (1.500) ( 0.000)
where R2: 0.981, F: 201.722, s: 0.000, SPRESS: 0.000
Standard error of estimate: 0.00055
Boss C, Bolli M, Weller T (2002) Endothelin receptor antagonists:
structures, synthesis, selectivity and therapeutic applications.
Curr Med Chem 9:349–383
Burdge EL (2000) The mode of action of RH-1965: a new
phenylpyrimidinone bleaching herbicide. Pest Manag Sci
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Harbart S, Aldrich W, Goldman DA, Huebner J (2001) Control of
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Hardtmann GEF (1978) G. U. S. Patent 1997, 4, 053, 600, Chem
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Kappe CO (1993) X-ray structure, conformational analysis, enantio-
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Kappe CO, Fabian WMF, Semones MA (1997) Conformational
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The treatment of the HOMO and LUMO is based on the
general principles governing the nature of reactions. LUMO
energy is related to the electron affinity susceptibility of the
molecule against attack by nucleophiles. Also, hard and soft
nucleophiles are directly related to the energy of HOMO–
LUMO; hard electrophiles have a high-energy LUMO and soft
electrophiles have a low-energy LUMO. Our molecules have a
low-energy LUMO. In other words our molecules have soft
electrophiles. The correlation of each one of the descriptors with
each other and with MIC is calculated. The resulting correlation
matrix for E. coli is represented in Table 3. All the parameters
show significant correlations with biological activity.
Conclusion
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4-aryldihydropyrimidines by direct enantioselective HPLC A critical
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In conclusion, 1-(2-hydroxyphenylmethylenamino)-5-(4-
methylbenzoyl)-4-(4-methylphenylpyrimidine)-2(1H)-
thione and its complexes are synthesized. An octahedral
geometry is observed around the Ni(II), Cu(II) and Co(II)
complexes and a square planar geometry is observed
around the Pd(II) and Pt(II) complexes. Hsalmmp and its
Ni(II) complex are indexed in orthorhombic crystal sys-
tems. The Pd(II) complex is indexed in tetragonal system
and the Pd(II) complex is indexed in a hexagonal crystal
systems. Cu(II) and Co(II) complexes did not have any
peaks with CuKa radiation. The thermal decomposition of
Hsalmmp and its Pd(II) and Pt(II) complexes took place in
three stages. Cu(II), Ni(II) and Co(II) complexes take place
in four stages. In addition to spectroscopic studies, the
ligand and its complexes are evaluated by the microdilution
procedure for their in vitro antimicrobial activity. In order
to identify the substituent effect on antimicrobial activity,
QSAR studies are performed using linear regression ana-
lysis. Further research on this ligand and its complexes is in
progress in our laboratory.
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Acknowledgments The authors are grateful to Erciyes University’s
Research Foundation for financial support under Project Number
Roy S, Westmaas JA, Buda F, Reedijk J (2009) Platinum(II)
compounds with chelating ligands based on pyridine and pyrim-
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