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Transition metal complexes of 1 2-dihydroquinazolinone derivative an emerging class of analgesic and anti-inflammatory agents.

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Full Paper
Received: 6 September 2011
Revised: 23 September 2011
Accepted: 6 October 2011
Published online in Wiley Online Library: 29 November 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1855
Transition metal complexes of 1,2dihydroquinazolinone derivative, an emerging
class of analgesic and anti-inflammatory agents
Dayananda S. Badiger,a Ramesh B. Nidavani,b Rekha S. Hunoor,a
Basavaraj R. Patil,a Ramesh S. Vadavi,a V. M. Chandrashekhar,b
Iranna S. Muchchandib and Kalagouda B. Gudasia*
A new 1,2-dihydroquinazolinone, 2-(2-hydroxy-phenyl)-3-[1-(2-oxo-2H-chromen-3-yl)-ethylideneamino]-2,3-dihydro-1H-quinazolin4-one (L) and its Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes have been prepared. These were characterized by elemental,
spectral [UV–visible, IR, NMR (1H, 13C and 2D heteronuclear correlation) and mass], conductance, magnetic susceptibility and
thermal studies. The physicochemical data indicate that the ligand behaves as tridentate with ONO donor sequence towards
the metal ions, and trigonal bipyramidal geometry was assigned for complexes. The ligand and its metal complexes were evaluated for their in vivo anti-inflammatory and analgesic activity. The tested compounds have shown excellent activity, which are
almost equipotent to the standard used in the study. Copyright © 2011 John Wiley & Sons, Ltd.
Keywords: dihydroquinazolinone; trigonal bipyramidal; metal complex; analgesic activity; anti-inflammatory activity
Introduction
876
Quinazolinone is an exciting motif as regards its pharmacological
importance and is a building block for about 150 naturally occurring alkaloids.[1] They have been studied as an effective anticonvulsant,[2] anti-inflammatory, analgesic and cyclooxygenase-2 (COX-2)
inhibitor.[3–6] Proquazone, 1-isopropyl-7-methyl-4-phenylquinazoline2(1H)-one,[7] fluoroquazone, 4-(4-fluorophenyl)-7-methyl-1-propan-2yl-quinazoline-2-one,[8] and tryptanthrin, indolo[2,1-b]quinazoline
alkaloid,[9] are well-known anti-inflammatory drugs bearing an
quinazolinone nucleus. These came to notice as third-generation
non-steroidal anti-inflammatory agents (NSAIDs) that are superior
in protection and effectiveness and are comparable with indomethacin, which is already in use as a drug.
Quinazolin-4(3H)-ones with 2,3-disubstitution are reported to
possess remarkable analgesic, anti-inflammatory and anticonvulsant activities. It has also been reported that substitution by
different aryl or heteroaryl moieties at the second or third position
of the quinazolinone nucleus markedly influences the antiinflammatory activity.[10] Subsequently, 1,2-dihydroquinazolinones
were reported to possess greater potent activity compared to fully
aromatic quinazolinones.[11]
Quinazoline-4(3H)-ones have also drawn the attention of
coordination chemists, as they adopt various binding modes with
transition and main group metal ions which have a positive effect
on their activity. These bioactive molecules can act as monodentate or bidentate ligands,[12,13] and their coordination capacity
can be further increased if aldehydes or ketones that contain
additional functional group(s) in position(s) suitable for chelating
are used for their preparation.
Several coumarins isolated from plants or of synthetic origin possess significant anti-inflammatory and analgesic activities.[14–18]
Moreover, coumarin and related derivatives have been used as
Appl. Organometal. Chem. 2011, 25, 876–882
inhibitors of lipoxygenase (LOX) and COX pathways of arachidonic
acid metabolism.[17] One of the most well-studied coumarin-based
anti-inflammatory drugs is cloricromene (8-monochloro-3-bdiethylaminoethyl-4-methyl-7-ethoxy-carbonylmethoxy coumarin)
and several synthetic analogues of this compound have been
recently reported and tested for their anti-inflammatory and antioxidant activities.[19]
Earlier we have documented transition metal complexes of 1,
2-dihydroquinazoline-4-(3H)-ones exhibited comparatively good
analgesic and anti-inflammatory activities.[20–22] In view of these
facts and in continuation of our earlier work on coordination
chemistry, we have substituted coumarin as heteroaryl moiety
and 2-hydroxybenzaldehyde as aryl moiety at the second and third
position of the quinazoline nucleus to obtain 2-(2-hydroxyphenyl)3-[1-(2-oxo-2H-chromen-3-yl)-ethylideneamino]-2,3-dihydro11H-quinazolin-4-one (L). Here we report the synthesis and
characterization of transition metal complexes of L and their
comparative in-vivo anti-inflammatory and analgesic activities.
Experimental Protocols
Chemistry
Methyl anthranilate, hydrazine hydrate, 2-hydroxybenzaldehyde
and hydrated metal chloride salts (S.D. Fine Chemicals, India),
* Correspondence to: Kalagouda B. Gudasi, Department of Chemistry, Karnatak
University, Pavate Nagar, Dharwad-580 003, Karnataka, India. E-mail: kbgudasi@gmail.com
a Department of Chemistry, Karnatak University, Dharwad-580003, Karnataka,
India
b H. S. K. College of Pharmacy, Bagalkot-587101, Karnataka, India
Copyright © 2011 John Wiley & Sons, Ltd.
Quinazolinones as analgesic and anti-inflammatory agents
were of analytical reagent grade and used as received. Solvents
were distilled before use.[23] Reaction progress was monitored
by thin-layer chromatography (TLC) on pre-coated silica gel
plates. A precursor, 3-acetylcoumarin-o-aminobenzoylhydrazone
(I) was prepared by the reaction of 2-aminobenzoyl hydrazide
and 3-acetylcoumarin in absolute ethanol as described earlier.[24]
Elemental analyses were carried out on a Thermoquest CHN
analyzer and metal complexes were analyzed for their metal
content gravimetrically and volumetrically through ethylenediaminetetraacetic acid titration after decomposition with a mixture
of HCl and HClO4. The chloride content of the complexes was
determined gravimetrically as AgCl after decomposing the
complexes with HNO3. The IR spectra were recorded on a Nicolet
170 SX FT-IR spectrometer in the 4000–400 cm1 region using
KBr discs. The NMR spectra were recorded on a Bruker Avance
400 MHz spectrometer operating at 400.23 MHz. The mass
spectrum was recorded on a quadrupole time-of-flight mass
spectrometer. Electronic spectra were recorded on a CARY 50
Bio UV–visible spectrophotometer in the 200–1100 nm range in
DMF solution. Magnetic susceptibility measurements were
carried out on a Gouy balance using Hg[Co(SCN)4] as the
calibrant. Conductance measurements were made in DMF
(103 M) solution using an ELICO-CM-82 conductivity bridge with
cell type CC-01 and cell constant 0.53. Thermal studies were
carried out in the temperature range 25–1000 C using a PerkinElmer
TGA7 analyzer with a heating rate of 10 C min1. Melting points
were determined in an open capillary on a Gallenkamp melting point
apparatus and are uncorrected.
Synthesis of 2-(2-hydroxyphenyl)-3-[1-(2-oxo-2H-chromen-3-yl)ethylideneamino]-2,3-dihydro-1H-quinazolin-4-one (L) (III)
2-Hydroxybenzaldehyde (II) (1.2 ml, 10 mmol) was added to an
ethanol solution (50 ml) of 3-acetylcoumarin-o-aminobenzoylhydrazone (I) (3.21 g, 10 mmol). The mixture was refluxed on a
water bath for 4 h, whereupon a bright-yellow solid was
obtained. Completion of the reaction was checked by TLC. The
residue was filtered, washed with cold ethanol and dried in air.
Recrystallization from hot ethanol yielded a yellow solid.
Attempts to grow single crystals were unsuccessful.
L: yield: 90%; m.p 203–205 C; 1H NMR (400 MHz, DMSO-d6,
d ppm); s, singlet; d, doublet; dd, doublet of doublet; t, triplet;
td, triplet of doublet: 10.18 (s, O4H, 1H), 8.45 (s, C18H, 1H),
7.78 (dd, J = 9.2/1.2 Hz, C4H, 1H), 7.44 (s, N1H, 1H), 7.37 (dd,
J = 9.2/1.6 Hz, C14H, 1H), 7.27 (m, C12H, C22H, 2H), 7.11
(td, J = 9.2/1.6 Hz, C6H, 1H), 6.97 (dd, J = 8.8/1.2 Hz, C23H, 1H),
6.88 (m, C13H, C20H, 2H), 6.84 (s, C1H, 1H), 6.81 (m, C7H, C11H,
2H), 6.74 (t, J = 7.2 Hz, C21H, 1H), 6.67 (t, J = 7.2 Hz, C5H, 1H), 1.71
(s, C16H, 3H); 13C NMR (DMSO-d6, d ppm): 160.25 (C2), 157.55
(C25), 154.67 (C15), 149.66 (C18), 146.32 (C8), 134.18 (C22),
131.54 (C14), 130.42 (C6), 129.82 (C4), 128.04 (C12), 125.94 (C23),
124.12 (C17), 119.16 (C5), 118.97 (C21), 118.28 (C13), 117.58
(C3), 116.52 (C20), 115.79 (C11), 114.84 (C7), 113.15 (C19), 65.68
(C1), 19.26 (C16).
General procedure for the synthesis of Mn(II), Co(II), Ni(II), Cu(II) and
Zn(II) (C1, C2, C3, C4, and C5) complexes
Appl. Organometal. Chem. 2011, 25, 876–882
Pharmacology
The prepared compounds were evaluated for their in vivo antiinflammatory and analgesic activities by the carrageenaninduced rat paw edema method[25] and Eddy’s hot plate method
in mice[26] respectively.
Female Sprague Dawley rats (150–200 g) and Swiss albino mice
(25–30 g) were obtained from the central animal house of H. S. K.
College of Pharmacy and Research Centre, Bagalkot. All animals
were kept under standard husbandry conditions (temperature
22–28 C; relative humidity 65% 10%) for 12 h dark and 12 h
light cycle in standard propylene cages. The animals were fed
with standard food (Pranav Agro Industries, Sangli, Maharashtra,
India) and water ad libitum. All the experiments were conducted
in accordance with the direction of the Institutional Animals
Ethics Committee (HSKCP/IAEC,Clear/2009-10/1-11). The compounds were administered orally using feeding tube as a suspension in 10% v/v Tween 80; only 10% v/v Tween 80 used as vehicle
for control.
Anti-inflammatory activity
The anti-inflammatory activity of the test compounds was
evaluated as described by Winter et al..[25] One hour after the
administration of test compounds, rats in all groups were challenged with carrageenan (1% prepared in 0.4% NaCl) in the
sub-plantar region of the right hind paw. The paw volume was
measured at different intervals of time (at 0.5, 1, 3 and 5 h.) using a
digital plethysmometer (UGO Basil, Italy). The percentage inhibition
of paw volume for each test group is calculated using the following
equation:
Percentage inhibitionð%Þ ¼ Vc Vt =ðVc Þ 100
where Vt and Vc are mean paw volume of test and control groups
respectively.
Analgesic activity
The Eddy and Leimback[26] hot plate test was carried out in mice
for evaluating analgesic activity. Swiss albino mice of either sex
were divided into 12 groups, containing six animals each.
Animals were administered with control (0.4% NaCl), test
compounds (3 and 10 mg kg1) and standard pentazocine
(5 mg kg1) as an aqueous suspension of Tween 80. One hour
after the administration of compounds, mice were kept on a
hot plate pre-heated to 50 C for 15 s. Reaction time between
the moment when the mouse reached the hot plate and when
the animal licked its hind paw was noted at different time intervals (60, 120 and 180 min). The cut-off time was fixed for 15 s to
Copyright © 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc
877
The hydrated metal chloride (1 mmol) was dissolved in ethanol
(10 ml) and added to an ethanol solution (15 ml) of L (0.425 g,
1 mmol) with constant stirring. The reaction mixture was then
boiled under reflux on a water bath for 2 h. The precipitate
obtained was filtered, washed with ethanol and dried in air.
Attempts to grow single crystals of complexes were unsuccessful.
Yield: 55–70%.
[ZnLCl2] (C5): m.p. > 300 C; 1H NMR (400 MHz, DMSO-d6,
d ppm); 10.25 (s, O4H, 1H), 8.42 (s, C18H, 1H), 7.77 (d, J = 8 Hz,
C4H, 1H), 7.42 (s, N1H, 1H), 7.30 (m, C7H, C11H, 2H), 7.10
(t, J = 7.6 Hz, C6H, 1H), 7.03 (m, C12H, C13H, C14H, 3H), 6.94
(d, J = 7.6 Hz, C23H, 1H), 6.88 (m, C20H, C22H, 2H), 6.84 (s, C1H,
1H), 6.73 (t, J = 7.2 Hz, C21H, 1H), 6.66 (t, J = 7.6 Hz, C5H, 1H), 1.83
(s, C16H, 3H); 13C NMR (DMSO-d6, d ppm): 161.35 (C2),
158.42 (C25), 155.62 (C15), 154.62 (C10), 150.21 (C18), 146.38 (C8),
134.30 (C22), 131.68 (C14), 130.49 (C6), 129.93 (C4), 128.12
(C12), 125.98 (C23), 124.17 (C17), 119.33 (C21), 119.28 (C5), 118.35
(C13), 117.72 (C3), 116.61 (C20), 115.92 (C11), 114.93 (C7),
113.22 (C19), 65.74 (C1), 20.03 (C16).
lmax (nm)
wileyonlinelibrary.com/journal/aoc
Copyright © 2011 John Wiley & Sons, Ltd.
—
0.50
0.62
0.43
0.47
0.55
—
12.85 (12.86)
12.74 (12.77)
12.75 (12.77)
12.64 (12.66)
12.60 (12.62)
—
9.95 (9.97)
10.57 (10.61)
10.56 (10.57)
11.36 (11.35)
11.61 (11.64)
425.44
551.29
555.28
555.04
559.90
561.74
70.55 (70.58)
54.46 (54.47)
54.06 (54.08)
54.07 (54.10)
53.61 (53.63)
53.44 (53.45)
4.49 (4.50)
3.49 (3.47)
3.43 (3.45)
3.41 (3.45)
3.45 (3.42)
3.39 (3.41)
9.86 (9.88)
7.60 (7.62)
7.55 (7.57)
7.56 (7.57)
7.48 (7.51)
7.47 (7.48)
Cl
M
(Ω1 cm2 mol1); Dia, diamagnetic.
C
MW
Yield (%)
90
55
60
60
65
70
a
878
In order to authenticate the formation of 1,2-dihydroquinazolinone and to correlate the chemical shifts of directly attached
protons and carbon, we undertook 2D HETCOR NMR spectral
studies (Fig. 1). The numbering for the assignment of carbons
and the corresponding protons is given in Scheme 1. The 1H
and 13C assignments of the new derivatives presented in the
Experimental section were done by comparing corresponding
data of I and II.
The 1H NMR spectral data of both L and C5 are in good
agreement with the proposed structure and are given in the
Experimental section. The NMR spectrum of C5 is slightly modified with respect to the free ligand and shows variation in the
chemical shifts but with same multiplicity of signals. When the
1
H NMR spectrum of C5 was compared with that of free ligand,
few features could be observed: (i) the peak corresponding to
C16H has shifted downfield by 0.12 ppm, which provides
evidence for coordination of azomethine nitrogen to metal ion;
(ii) the signal at 10.18 ppm assignable to the OH group is present
Empirical formula
H, 13C and 2D HETCOR NMR Studies
Compound code
1
Table 1. Analytical and physicochemical data of L and its metal complexes (C1–C5)
The diagnostic IR bands of L and its complexes are presented in
Table 2. The sharp-intensity band at 3326 cm1 in L was assigned
to n(N-H). A medium-intensity band around 3246 cm1 is due to
n(OH) stretching and it is present in the spectra of all complexes,
suggesting its non-involvement in coordination. The characteristic
frequencies of n(C = O) of the quinazolinone ring and n(C O) of
lactone in free L appearing at 1646 and 1693 cm1 respectively
have shifted to a lower frequency by 19–34 and 16–35 cm1 in all
complexes, providing an evidence for involvement of carbonyl
oxygen and lactone oxygen in complexation. A band at
1608 cm1 in the spectrum of free L is attributed to n(C = N) stretch,
which also shifted to lower frequency by 9–25 cm1 in all
complexes, as a result of coordination through the azomethine
nitrogen. Thus from IR data it is clear that L behaves in tridentate
fashion with ONO as donor atoms.
H
IR Spectral Studies
N
Found (calc.) (%)
ΛM a
The elemental analyses of prepared compounds are in good
agreement with the proposed formula (Table 1). All the prepared
complexes are insoluble in common organic solvents but soluble
in DMF and DMSO. The peak at 65.56 ppm in 13C NMR [2D heteronuclear correlation (HETCOR), Fig. 1] of L is assigned to sp3
hybridized carbon (C1), which confirms the formation of 1,2-dihydroquinazolinone. The liquid chromatographic electrospray
ionization mass spectrum (Fig. 2) of the ligand shows a molecular
ion peak at 448 (M+Na+), supporting the proposed structure for
the ligand. Elemental and thermal analyses of the complexes
C1–C5 reveal 1:1 metal-to-ligand stoichiometry. The lower
molar conductance values in DMF solution indicates the nonelectrolytic nature of the complexes. Magnetic susceptibility
and electronic spectral studies indicate that the complexes have
trigonal bipyramidal geometry.
C25H19N3O4
[MnC25H19N3O4Cl2]
[CoC25H19N3O4Cl2]
[NiC25H19N3O4Cl2]
[CuC25H19N3O4Cl2]
[ZnC25H19N3O4Cl2]
Chemistry
—
4.82
3.72
2.23
1.47
Dia
meff (BM)
Results and Discussion
L
C1
C2
C3
C4
C5
prevent injury to the paw. Increase in reaction time (time interval
taken by the animal to lick its paw) was considered as
proportional to analgesic activity.
314, 348
—
560, 441
510, 437, 329
620, 442
—
D. S. Badiger et al.
Appl. Organometal. Chem. 2011, 25, 876–882
Quinazolinones as analgesic and anti-inflammatory agents
through azomethine nitrogen. Hence the changes in chemical
shifts with respect to carbonyl oxygen, lactone oxygen and
azomethine nitrogen of C5 clearly support their involvement in
coordination.
Electronic Spectra and Magnetic Susceptibility Studies
Figure 1. Expanded 2D HETCOR spectrum of L.
in both L and C5 and reveals the non-participation of OH in coordination; (iii) changes in chemical shift observed for aromatic
protons of quinazoline and coumarin moieties can be interpreted
as a sign of the participation of carbonyl oxygen of the respective
ring in coordination.
Likewise, with respect to the 13C NMR spectrum, this is consistent with 1H NMR analysis in demonstrating the architecture of
the new compounds. C2 and C25 signals observed at 160.25 and
157.55 ppm respectively in the ligand have shifted downfield in
the complex spectrum, indicating the participation of the
carbonyl oxygen of the quinazoline ring and lactone carbonyl
oxygen in coordination with the metal ion. The C15 and C16
signals undergo changes that could be due to coordination
The electronic absorption spectrum of L exhibits a strong peak at
314 nm with a shoulder at 348 nm assignable to p!p* and n!p*
transitions respectively.[27] The electronic spectrum of Co(II) complex (C2) shows a transition at 441 nm assignable to 4AI2!4EII
transition, indicating the trigonal bipyramidal geometry, which
is also supported by its meff value of 3.72 BM. In the electronic
spectrum of Ni(II) complex (C3), absorption at 510, 437 and
329 nm is assigned to 3EI!3AII2, 3EI!3AII1 and 3EI!3EII transitions
respectively, along with its magnetic moment of 2.23 BM,
suggesting a trigonal bipyramidal geometry around the Ni(II)
ion.[28] The electronic spectrum of the Cu(II) complex (C4) shows
broad absorption at 620 nm attributed to the 2AI1!2EII, which
illustrates the trigonal bipyramidal geometry around the Cu(II)
ion with D3h symmetry and is further supplemented by its
magnetic moment value of 1.47 BM.[28,29] The effective magnetic
moment of 4.82 BM observed for Mn(II) complex (C1) shows the
high spin state of the metal ion. Zn(II) complex (C5) is diamagnetic,
as expected for the d10 configuration, and has not shown any d-d
transitions.
Thermal Studies
In order to study the thermal stability and as supportive data for
the proposed molecular formulae, we have undertaken the
Figure 2. Mass spectrum of L.
Table 2. Diagnostic IR bands (cm1) of L and its metal complexes (C1–C5)
Compound
n(O-H)
n(N-H)
n(C¼O) lactone
n(C¼O) quin. ring
L
C1
C2
C3
C4
C5
3246m
3243w
3244m
3240m
3238br
3241br
3326s
3338m
3342s
3335s
3340s
3363s
1693s
1671s
1677s
1663s
1658s
1661s
1646s
1623s
1616s
1627m
1612s
1619m
n(C¼N)
n(C-O)
1608m
1594m
1583s
1599s
1586m
1589s
1368m
1366m
1365m
1367m
1369m
1370m
Appl. Organometal. Chem. 2011, 25, 876–882
Copyright © 2011 John Wiley & Sons, Ltd.
879
s, strong; br, broad; w, weak; m, medium; quin, quinazoline.
wileyonlinelibrary.com/journal/aoc
D. S. Badiger et al.
O
O
O
4
N
C2H5OH
O
+
CH3
NH2
Reflux, 4 hrs
HO
25
3
O
23
24
22
3
2
3
5
N
17
7
N1
H
18
20
CH3
H
9
21
19
16
1
8
15
N2
6
II
I
O
O
H
N
H
2
1
4
OH
14
III (L)
10
13
11
12
C2H5OH
Reflux, 2 hrs
MCl2.nH2O
Cl
Cl
M
O
O
O
N
N
H CH3
N
H
OH
IV
M = Mn(II), Co(II), Ni(II), Cu(II) and Zn(II)
Scheme 1. Synthetic route for the preparation of L and its metal complexes.
thermal studies of C1 and C3 (Mn and Ni) as representative
complexes. The thermal decomposition was recorded in the
temperature range of 25–1000 C. The complexes are thermally
stable up to 215–237 C, which indicates the absence of lattice
held or coordinated water molecules. Both C1 and C3 have
followed the same decomposition pattern. In C1, the first weight
loss of 12.83% (calc. 12.86%) at 215–310 C and second weight
loss of 71.12% (calc. 71.17%) at 310–893 C correspond to the loss
of two coordinated chlorides and a ligand molecule respectively.
The plateau obtained above 893 C corresponds to the formation
of stable MnO. The metal content calculated (9.91%) from this
residue is in good agreement with the metal analysis (9.97%).
Table 3. Anti-inflammatory activity of L and its metal complexes (C1–C5)
Treatment
Normal
Control
Diclofenac (10 mg kg1)
L (3 mg kg1)
L (10 mg kg1)
C1 (3 mg kg1)
C1 (10 mg kg1)
C2 (3 mg kg1)
C2 (10 mg kg1)
C3 (3 mg kg1)
C3 (10 mg kg1)
C4 (3 mg kg1)
C4 (10 mg kg1)
C5 (3 mg kg1)
C5 (10 mg kg1)
0.5 h
1h
3h
5h
Paw volume (ml)
% EI
Paw volume (ml)
% EI
Paw volume (ml)
% EI
Paw volume (ml)
% EI
0.6625 0.01315
1.2523 0.45213c
0.2263 0.0149***
0.3200 0.09725*
0.3625 0.04941
0.2675 0.01414
0.2700 0.03475
0.3200 0.02462*
0.2975 0.03719*
0.3250 0.01931
0.2725 0.05485*
0.3500 0.02839
0.2825 0.01047*
0.3160 0.01911
0.2925 0.05465*
—
—
81.92
74.44
71.05
78.63
78.43
74.44
76.24
74.04
78.24
72.05
77.44
74.76
76.64
0.6225 0.06415
1.2950 0.64300c
0.2763 0.0239***
0.3570 0.08456
0.3835 0.04481
0.2876 0.01724*
0.3027 0.03318*
0.3350 0.02153*
0.3366 0.02549*
0.3620 0.01851*
0.3114 0.04985**
0.3810 0.02752*
0.3666 0.01248**
0.3510 0.01901*
0.3526 0.05435**
—
—
78.66
72.43
70.38
77.79
76.62
74.13
74.00
72.04
75.95
70.57
71.69
72.89
72.77
0.6675 0.01109
1.3520 0.07325c
0.2838 0.0171***
0.4705 0.03680
0.3875 0.02500
0.4075 0.01848
0.3975 0.05515*
0.4175 0.02630
0.3725 0.02739*
0.5305 0.02462
0.5005 0.02810
0.4825 0.02380
0.4375 0.03379
0.5208 0.02402
0.4910 0.02710
—
—
79.00
65.19
71.33
69.85
70.59
69.11
72.44
60.76
62.98
64.31
67.64
61.47
63.68
0.6675 0.01652
1.1983 0.02314c
0.2988 0.028***
0.3275 0.03058
0.4205 0.03449
0.3925 0.00912
0.3050 0.3902**
0.3825 0.02483*
0.3075 0.00492
0.4355 0.02898
0.4055 0.02175
0.4155 0.04308
0.3555 0.02287
0.4255 0.02800
0.3957 0.02375
—
—
75.09
72.66
64.90
67.24
74.54
68.07
74.33
63.65
66.16
65.32
70.33
64.49
66.97
880
All values are expressed as mean SEM, ANOVA followed by Dunnett’s test.
* P < 0.05
** P < 0.01 and
*** P < 0.001 as comparison of test groups to control group
a
P < 0.05
b
P < 0.01 and
c
P < 0.001 as comparison of normal group to control group.
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Copyright © 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 876–882
Quinazolinones as analgesic and anti-inflammatory agents
The thermogram of C3 shows a similar two-step decomposition.
The first weight loss of 12.71% (calc. 12.77%) in the temperature
range of 237–325 C and second weight loss of 76.63% (calc.
76.65%) in the temperature range of 328–880 C correspond to
the loss of two coordinated chlorides and a ligand molecule
respectively. After 880 C a plateau was observed and corresponds to the formation of stable NiO. These values suggest that
the complexes are penta-coordinated with the [M(L)Cl2] as their
general composition.
Anti-inflammatory Activity
In the present investigation, the control group showed a significant increase of edema in the right hind paw of animals after
carrageenan induction in the plantar region. This is due to the
release of inflammatory mediators such as histamine, serotonin,
kinins, and prostaglandins (PGs). The edema developing after
carrageenan inflammation is a biphasic event. The first phase is
mediated by the release of histamine and serotonin for 1 h,
followed by the kinin-mediated increased vascular permeability
up to 2.5 h, while the second phase is mediated up to 6 h mainly
by the release of PGs and PG-associated leukocytes into the site
of edema.[30] Acute inflammation is a short-term process, which
is characterized by the typical signs of inflammation, such as
swelling, pain, and loss of function due to infiltration of the tissues
by plasma and leukocytes. Among them, edema is one fundamental action of acute inflammation and it is an essential parameter to
be considered when evaluating compounds with potential antiinflammatory activity.[31]
The anti-inflammatory activity of newly synthesized compounds
L and C1–C5 were evaluated by applying the carrageenan-induced
paw edema bioassay in rats using diclofenac as a reference
standard. Results were expressed as mean SEM (Table 3). Differences between vehicle control and treatment groups were tested
using analysis of variance (ANOVA), followed by Dunnett’s test.
Administration of tested compounds 60 min prior to carrageenan
injection at doses of 3 and 10 mg kg1 body weight caused different significant inhibition of paw edema response with respect to
dose and time duration. The ligand L showed a consistent and
significant decrease in paw edema at 0.5, 1, 3 and 5 h after drug
administration, while complexes at higher dose gave a good
response up to fifth hour but at lower dose the significant
response decreased as time progressed. The significant inhibition
of paw edema by tested compounds was almost equipotent
at 10 mg kg1 dose with the standard diclofenac drug but was
comparatively less at 3 mg kg1. In comparison with L, all the
complexes showed excellent effect at 0.5 and 1 h but only C1 and
C2 retained their activity up to fifth hour, while C3, C4 and C5
Table 4. Analgesic activity of L and its metal complexes (C1–C5)
Reaction time (X SE) in seconds (difference in reaction time compared to basal value)
Compound
Basal
Control
Pentazocine
(5 mg kg1)
L
(3 mg kg1)
L
(10 mg kg1)
C1
(3 mg kg1)
C1
(10 mg kg1)
C2
(3 mg kg1)
C2
(10 mg kg1)
C3
(3 mg kg1)
C3
(10 mg kg1)
C4
(3 mg kg1)
C4
(10 mg kg1)
C5
(3 mg kg1)
C5
(10 mg kg1)
4.60 0.23
4.93 1.33
8.30 1.20
9.88 0.96
7.29 0.67
8.67 0.89
7.81 0.22
9.61 0.56
6.82 0.72
8.44 1.23
8.61 1.82
9.68 0.87
7.30 0.67
8.61 0.89
60 min
10.01 1.20
11.21 1.23
(6.28 0.10 )
10.42 0.96
(2.12 0.24)
10.80 0.76*
(0.92 0.20)
12.23 0.62
(4.94 0.05)
14.32 0.88
(5.65 0.01)
10.21 1.81
(2.40 1.59)
13.92 2.31*
(4.31 1.75)
10.76 1.62
(3.94 0.90)
13.81 0.70*
(5.37 0.53)
13.21 1.24
(4.60 0.58)
14.21 1.32*
(4.53 0.45)
12.43 0.62
(5.13 0.05)
14.12 0.35
(5.51 0.54)
120 min
9.550 0.62
14.32 1.23***
(9.39 0.10)
11.00 0.00*
(2.70 1.20)
11.00 0.00*
(1.12 0.96)
14.50 0.88**
(7.21 0.21)
15.00 0.00***
(6.33 0.89)
13.81 0.89
(6.00 0.67)
14.92 1.12***
(5.25 0.56)
14.20 0.212
(7.38 0.51)
15.00 0.42***
(6.56 0.81)
14.81 0.64**
(6.20 1.18)
15.00 0.00***
(5.32 0.87)
14.10 0.88**
(6.80 0.21)
14.43 0.03**
(5.82 0.86)
180 min
10.35 1.24
15.00 0.00***
(10.07 1.33)
10.50 0.92
(2.20 0.28)
10.56 0.23**
(0.68 0.73)
14.12 0.43
(6.83 0.24)
14.45 0.22*
(5.78 0.67)
12.76 0.61
(4.95 0.39)
13.82 0.21**
(4.21 0.35)
14.31 0.125*
(7.49 0.60)
15.00 0.00***
(6.56 1.23)
14.21 0.61*
(5.60 1.21)
14.62 0.73**
(4.94 0.14)
14.17 0.43
(6.87 0.24)
14.55 0.20*
(5.94 0.69)
Appl. Organometal. Chem. 2011, 25, 876–882
Copyright © 2011 John Wiley & Sons, Ltd.
881
Results are expressed as mean SEM (n = 6); significance level:
* P < 0.5
** P < 0.01 and
*** P < 0.001 as comparison of test groups to control group.
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D. S. Badiger et al.
showed a gradual decrease in activity. Hence L and C1–C5 derivatives showed dose- and time-dependent anti-inflammatory activity.
This was probably a result of inhibiting synthesis and release of PGs,
proteases, lysosomal enzymes and other inflammatory mediators
such as NSAIDs.
Acknowledgments
Analgesic Activity
References
Analgesic activity was performed using Eddy’s hot plate method,
which involves the use of heat as the source to induce pain in
mice. The increase in reaction time compared to basal is proportional to analgesic activity of test compounds. The results are
summarized in Table 4.
Analgesic activity of synthesized compounds was assessed in
mice by using the Eddy’s hot plate test. The pain was induced
to mice by placing them on free heated hot plate, 1 h after administration of the test substances. The reaction time (time interval taken by animal to lick the paw) was recorded up to 180 min
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both 120 and 180 min. Both L and its complexes showed significant activity (p < 0.05) at higher doses and in shorter time duration (60 min). The activity was found to be dose-dependent and
may be mediated by inhibition of CNS mediated mechanisms
of analgesic activity.
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Conclusions
The present study depicts the synthesis, characterization and
biological evaluation of transition metal complexes of a new 1,2-dihydroquinazolinone derivative, 2-(2-hydroxy-phenyl)-3-[1-(2-oxo-2Hchromen-3-yl)-ethylideneamino]-2,3-dihydro-1H-quinazolin-4-one.
Physicochemical studies reveal that the ligand behaves as a neutral
tridentate donor (ONO) yielding five coordinated transition metal
complexes with trigonal bipyramidal geometry around the central
metal ion. A tentatively proposed structure for the complexes is
given in Scheme 1(IV).
Both ligand and its transition metal complexes exhibit excellent
activity as compared to the standard used in the anti-inflammatory
and analgesic activity studies, which is probably due to the synergistic effect of both coumarin and quinazoline moieties. In the analgesic study, complexes have shown better activity than the ligand
probably due to increased lipophilicity. In conclusion, the compounds have demonstrated dose- and time-dependent activity,
which are better even at lower dose level (3 mg kg1).
The authors thank USIC, Karnatak University, Dharwad, for spectral
analyses, and the NMR Research Centre, IISc, Bangalore, for NMR
studies. Thanks are due to the Department of Physics, Karnatak
University, Dharwad, for magnetic moment measurements.
882
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Appl. Organometal. Chem. 2011, 25, 876–882
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