Synthesis, characterization, thermal degradation and urease inhibitory studies of the new hydrazide based Schiff base ligand 2-(2-hydroxyphenyl)-3-{[(E)-(2-hydroxyphenyl)methylidene]amino}-2,3-dihydroquinazolin-4(1H)-one

Article abstract of DOI:10.1515/chem-2017-0035

The novel Schiff base ligand 2-(2-hydroxyphenyl)-3-{[(E)-(2-hydroxyphenyl)methylidene]amino}-2,3-dihydroquinazolin-4(1H)-one (H-HHAQ) derived from 2-aminobenzhydrazide was synthesized and characterized by elemental analyses, ES⁺-MS, ¹

Full text of DOI:10.1515/chem-2017-0035

Open Chem., 2017; 15: 308–319
Research Article
Open Access
Muhammad Ikram*, Sadia Rehman, Fazle Subhan, Muhammad Nadeem Akhtar,
Mutasem Omar Sinnokrot
Synthesis, characterization, thermal degradation
and urease inhibitory studies of the new hydrazide
based Schiff base ligand 2-(2-hydroxyphenyl)-3-
{
[(E)-(2-hydroxyphenyl)methylidene]amino}-2,3-
dihydroquinazolin-4(1H)-one
https://doi.org/10.1515/chem-2017-0035
Keywords: Schiff base hydrazide ligand, coordination
compounds, crystal structure, urease inhibition, kinetic
Abstract:ThenovelSchiffbaseligand2-(2-hydroxyphenyl)- and thermodynamic studies
-{[(E)-(2-hydroxyphenyl)methylidene]amino}-2,3-
received August 20, 2017; accepted October 9, 2017.
3
dihydroquinazolin-4(1H)-one (H-HHAQ) derived from
2
-aminobenzhydrazide was synthesized and characterized 1 Introduction
+
1
13
1
by elemental analyses, ES -MS, H and C{ H}-NMR, and
IR studies. The characterization of the ligand was further Urea amidohydrolases (EC 3.5.1.5), a class of enzymes
confirmed by single crystal analysis. The Schiff base ligand widespread among all types of organisms ranging
was complexed with metal ions like Co(II), Ni(II), Cu(II) from unicellular to higher multicellular organisms, are
and Zn(II) to obtain the bis-octahedral complexes. The generally termed as ureases. They are actively involved
ligand and its metal complexes were also studied for their in the hydrolysis of urea to ammonia and carbamate. The
ureaseinhibitoryactivities. Allthetestedcompoundsshow carbamate is divided further to produce another molecule
medium to moderate activities for the enzyme, whereas the of ammonia. The general reaction catalyzed by urease is
copper based complex was found to be much more active shown in scheme 1.
against urease with an IC50 = 0.3 ± 0.1 µM±SEM, which is
The enzymatic activity can be seen in all forms of
even more potent than the standard thiourea. The IC50 of organisms like bacteria, fungi, algae and even in man
the cobalt complex was 43.4±1.2 µM±SEM, whereas that causing elevation in blood pH due to the accumulation of
of the nickel complex was 294.2±5.0 µM±SEM. The ligand ammonia that leads to the appearance of various effects
H-HHAQ and the zinc complex were inactive against the like cell death, kidney failure, severe ulcer, urolithiasis,
tested enzyme.
pyelonephritis and hepatic encephalopathy, hepatic coma
and urinary catheter encrustation [1–14].
Structurally, the enzyme is comprised of two nickel (II)
centers each coordinated by two nitrogens from histidines,
one water molecule, and a bridging carbamylated lysine
through the O atom. The Ni (2) is further coordinated
by O-atom from aspartic acid. Therefore, one of the
nickels is penta-coordinated whereas the other is hexa-
coordinated with pseudo square pyramidal geometry for
*
Corresponding author: Muhammad Ikram, Sadia Rehman:
Department of Chemistry, Abdul Wali Khan University, Mardan
Pakistan, E-mail: ikram@awkum.edu.pk; sadia@awkum.edu.pk
Fazle Subhan: Department of Chemistry, Abdul Wali Khan University,
Mardan Pakistan
Muhammad Nadeem Akhtar: Department of Chemistry, University of
Agriculture, Faisalabad, Pakistan
Mutasem Omar Sinnokrot: Department of Chemistry, The Petroleum
Institute, Khalifa University of Science and Technology, Abu Dhabi,
2
O
O
H N
Urease
H O
2
2
H O
OH+ NH
+ 2NH3
+
2
3
H CO
3
2
NH2
H N
2
Scheme 1: Urease catalyzed hydrolysis of urea.
533 United Arab Emirates
Open Access. © 2017 Muhammad Ikram et al., published by De Gruyter Open.
Attribution-NonCommercial-NoDerivatives 4.0 License.
This work is licensed under the Creative Commons
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Synthesis, characterization, thermal degradation and urease inhibitory studies of the new...ꢀ
ꢀ309
(Lys)HN
(Lys)HN
Ligand
N(His)
N(His)
O
O
O
O
N(His)
N(His)
N(His)
N(His)
-H O
N(His)
N(His)
2
Ni(2) (1)Ni
HO
(
1)Ni
Ni(2)
HO
(Asp)O
(Asp)O
OH2
H O
H O
2
2
Ligand
Scheme 2: Mechanism of interaction of inhibitors with urease.
(Lys)HN
(Lys)HN
N(His)
O
O
N(His)
N(His)
N(His)
N(His)
O
O
Ni(1)
O
N(His)
N(His)
Ni(2)
Ni(1)
O
OH
Ni(2)
N(His)
O
(Asp)O
O
(Asp)O
P
HN
CH3
OH
a)
b)
(Lys)HN
N(His)
N(His)
O
O
N(His)
N(His)
Ni(1)
O
Ni(2)
OH
(Asp)O
O
B
OH
c)
Figure 1: Mechanism of action by different inhibitors (a) by acetohydroxamic acid, (b) by phosphate based molecule, and (c) by boric acid.
the former and pseudo octahedral geometry for the latter
Urease inhibition by metal complexes has been
respectively. Inhibition of the enzyme is achieved by studied extensively over the last decade [14,15]. The metal
various methods. One of these include the displacement of complexes bearing the active sites for attachment of –OH
the water molecule by the interacting inhibitor as shown in group have in particular been found to be very useful in
scheme 2.
inhibitory studies [14-16]. Recently we studied the Schiff
The mechanism of inhibition of urease for the base metal complexes for their inhibitory activities against
acetohydroxamic acid, phosphate based compounds and the human urease enzyme. It has been found that nickel
boric acid may be seen in Figure 1.
based complexes of 2-[(E)-(quinolin-3-ylimino)methyl]
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3
10ꢀ
ꢀ Muhammad Ikram et al.
phenol (H-QMP) [14] were even more potent (IC50 = 9.9 ± with freshly prepared solutions. Magnetic susceptibilities
0
.124 µM ± SEM) than the standard thiourea. In another were measured on a Sherwood Gouy Balance at room
study, we found out that copper based complexes of Schiff temperature calibrated with Hg[Co(SCN) ]. Mass spectra
4
baseligands2-{(E)-[(4-Chlorophenyl)imino]methyl}phenol were recorded on a LCT Orthogonal Acceleration TOF
(
[Cu(CIMP) ]) have IC = 10.66 ± 0.19 µM ± SEM) and 2-{(E)- Electrospray mass spectrometer.
2
50
[
(4-bromophenyl)imino]methyl}phenol
([Cu(BIMP) ])
2
have IC = 5 ± 0.047 µM ± SEM, respectively [15]. Changing
50
the environment around the metal center changes the 2.3 Crystal structure
inhibitory activity [16]. The mechanisms of action of metal
complexes against urease in these two instances have been Single crystal analyses were carried out using an
explored, and involve either hydrophobic interactions Oxford diffractometer. Suitable single crystals for X-ray
or hydrogen bond formation in the active pocket of the structural analyses of H-HHAQ were each mounted on
enzyme. Here, in this study we have synthesized a new a glass fibre, and the respective data were collected on
type of Schiff base ligand bearing both features such as a Oxford diffractometer (graphite-monochromated Mo
nitrogen in the cyclic ring and a free hydroxyl group af er Kα radiation, λ = 0.71073 Å) at 108(2) K. The structure
complexation in order to explore the effect of these groups was solved with the olex2.solve [19] structure solution
in the inhibition of the urease enzyme.
program using Charge Flipping and refined with the
olex2.refine [20] refinement package using Gauss-Newton
minimisation. Crystallographic details are given in the
supplementary information file. CCDC-1036707 (H-HHAQ)
data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
2
Experimental
2
.1 Materials and Methods
All chemicals, and solvents used were of analytical grade.
Metal(II) acetates (where metal(II) = Co, Ni, Cu and Zn) 2.4 Synthesis of 2-(2-hydroxyphenyl)-3-{[(E)-
were obtained from Riedel-de-Haen, and were partially
(
2-hydroxyphenyl)methylidene]amino}-2,3-
dehydrated by drying the hydrated salts in a vacuum oven
dihydroquinazolin-4(1H)-one (H-HHAQ)
o
for several hours at 80 – 100 C. 2-aminobenzohydrazine
was prepared using the previously reported procedure Benzohydrazide was prepared by condensing 25 mmol of
[
17,18]. Salicylaldehyde was obtained from Acros Organics. hydrazine hydrate with 20 mmol of methyl anthranilate in
3
Solvents were distilled at least twice before use. Unless 20 cm of distilled methanol [17,18]. The resulting mixture
o
and otherwise stated, all reactions were carried out under was stirred and refluxed at 80 C for 3 hrs and the solution
a dinitrogen atmosphere.
was lef overnight. Beautiful glassy crystals were isolated
af er one day. 10 mmol of the benzohydrazide ligand was
3
dissolved in 10 cm of distilled methanol and 20 mmol
2
.2 Instrumentation
salicyldehyde was added to it. The mixture was stirred for
1hr at room temperature. It was concentrated on a rotary
Elemental analyses were carried out using a Varian evaporator, af er which a yellow Schiff base ligand was
Elementar II. Melting points were recorded on a obtained, which was washed with copious amounts of
Gallenkamp apparatus. IR spectra were recorded using 5% n-hexane containing methanol and was recrystallised
1
a Shimadzo FTIR Spectrophotometer Prestige-21. H-NMR from THF.
o
were measured with a Bruker DPX 400MHz (400.23 MHz)
Yield: 76%, D. pt: 223 C, IR: 3500(s), 3387(s), 3155,
spectrometer whereas 1 C{ H}NMR were recorded on a 3020, 1620(s), 1573(s), 1548, 1514(s), 1450(s), 1367(s),
3
1
Bruker AV 400MHz (150.9 MHz) spectrometer, in CDCl at 1325(s), 1280(s), 1257(s), 1172(s), 1132(s), 1060(s), 1035(s),
3
roomtemperature. Chemicalshif sarereportedinppmand 960(s), 902(s), 866(s), 812(s), 786(s), 740(s), 698(s), 621(s)
-1 1
standardized by observing signals for residual protons. cm , H-NMR (400.23 MHz, CD OD, 303k): δ = 11.45 (s, 1H,
3
UV-Visible spectra were recorded on a BMS UV-1602. Molar Ar-OH, H27), 9.54 (s, 1H, Ar-OH, H7), 8.27(s, 1H, NH, H19),
3
conductance of the solutions of the metal complexes 7.54 (d, J = 8, aromatic), 7.29 (s, 1H, N-CH-N, H20) 7.19 (t,
HH
3
3
was determined with a conductivity meter type HI-8333. 2H, J = 7.5, H5 & H24), 7.05(d, 2H, J = 7.5, H6 & H23),
HH
HH
3
3
All measurements were carried out at room temperature 6.83 (d, 4H, J = 7.5, H4, H16, H17 & H25), 6.74 (d, 4H, J
HH
HH
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Synthesis, characterization, thermal degradation and urease inhibitory studies of the new...ꢀ
ꢀ311
3
=
8.5, H3, H12, H15 & H26), 6.56 (t, 2H, J = 7.5, H4 & H25), = 2.88 B.M. Elemental Analysis (C H N NiO ), Calc. C:
HH
42 32
6
6
13
1
6
.35 (s, 1H, CH=N, H8), C{ H}-NMR (150.9 MHz, CD OD, 65.05%, H: 4.16%, N: 10.84%, Ni: 7.57%, Exp. C: 65.12%,
3
3
1
03k), δ = 165 (C=O, C11), 160.3 (HC=N-, C8), 153(C, C22), H: 4.32%, N: 9.96%, Ni: 7.12%, EI-MS: m/z (%): 774.1731
+
49.8(CH, C20) , 148.7 (CH, C26), 147.9 (CH, C15), 147.5 (C, [C H N NiO ] , Ʌ = 4.3 µS.
42
32
6
6
m
C1), 133.8 (C, C14), 132 (CH, C23), 128.1 (C, C13), 127.8 (C,
C2), 125.9 (CH, C6), 121.9 (CH, C12), 116.2 (CH, C23), 115.3
(
CH, C3) , 115.4 (C, C21), 113.8 (CH, C5, C4, C24, & C25), 108.7 2.5.3 bis(2-(2-hydroxyphenyl)-3-{[(E)-(2-hydroxyphenyl)
(
CH, C16 & C17), Elemental analyses (C H N O ) Calc. C: methylidene]amino}-2,3-dihydroquinazolin-4(1H)-one)
2
1
17
3
3
7
0.18%, H: 4.77%, N: 11.69%, EI-MS m/z (%): 382.1168 copper(II) (Cu-HHAQ)
+
(
88%) [C H N O +Na] , Ʌ = 0.10 µS.
21 17 3 3 m
o
Yield: 37%, D. pt: 310 C, IR: 3196(bd), 3066(bd), 2972(bd),
2
870(w), 1640(s), 1608(s), 1585(w), 1544(s), 1512(s),
2
.5 Synthesis of [M(HHAQ) ] where M= Co,
1460(w), 1429(s), 1382(bd), 1278(s), 1201(s), 1155(s), 1124(s),
053(s), 1028(s), 975(s), 893(s), 856(s), 819(s), 781(s),
2
1
7
Ni, Cu and Zn (II) acetates
-1
50(s), 690(s), 665(s), 615(s), 563(s) cm , λmax= 820 nm (ε
-
1
-1
0
.011 mol of metal(II) acetates was stirred in a minimum = 34.7 M cm , T g→eg), µ = 1.67 B.M. Elemental Analysis
2 eff
volume of dried methanol and 0.024 mol of H-HHAQ (C H CuN O ), Calc. C: 65.65%, H: 4.13%, N: 10.77%, Cu:
42
32
6
6
in a minimum volume of dried methanol was added to 7.57%, Exp. C: 65.12%, H: 4.32%, N: 9.96%, Ni: 7.12%, EI-
the metal solution. The mixture was stirred for 2-3hrs at MS: m/z (%): 779.167934 [C H CuN O ] , Ʌ = 87 µS.
+
42
32
6
6
m
room temperature. The metal complex was collected af er
filtration and copiously washed several times with 5%
n-hexane containing methanol.
2.5.4 bis(2-(2-hydroxyphenyl)-3-{[(E)-(2-hydroxyphenyl)
methylidene]amino}-2,3-dihydroquinazolin-4(1H)-one)
zinc(II) (Zn-HHAQ)
2
.5.1 Bis(2-(2-hydroxyphenyl)-3-{[(E)-(2-hydroxyphenyl)
o
methylidene]amino}-2,3-dihydroquinazolin-4(1H)-one)
Yield: 32%, D. pt: 210 C, IR: 3251(bd), 2968(w), 2870(w),
cobalt(II) (Co-HHAQ)
2366(w), 1687(w), 1614(s), 1585(s), 1564(s), 1510(s), 1427(s),
1384(s), 1334(w), 1278(w), 1253(s), 1205(s), 1155(s), 1124(s),
o
Yield: 38%, D. pt: 201 C, IR: 3240(bd), 3126(bd), 2970(w), 1028(s), 970(s), 896(s), 858(s), 821(s), 783(s), 748(s), 692(s),
-1
2
872(w), 1640(s), 1614(s), 1562(s), 1555(s), 1510(s), 1454(s), 665(s), 615(s), 582(s), 543(s) cm , Elemental Analysis
1
1
427(s), 1377(s), 1338(s), 1253(s), 1207(s), 1155(s), 1124(s), (C H N O Zn), Calc. C: 64.50%, H: 4.12%, N: 10.74%, Zn:
42
32
6
6
028(s), 970(s), 893(s), 860(s), 783(s), 750(s), 692(s), 8.36%, Exp. C: 64.67%, H: 4.82%, N: 10.44%, Zn: 8.12%,
-1
-1
-1
+
6
21(s) cm , λ = 480, 590, 640 nm (ε = 67.4, 12.7 M cm , EI-MS: m/z (%): 780.1669(23) [C H N O Zn] , Ʌ = 54 µS.
max
4
42 32
6
6
m
4
4
4
4
4
T g(F)→ A g, T g(F)→ T g(P), T g(F)→ T g), µ = 4.98
1
2
1
1
1
2
eff
B.M. Elemental Analysis (C H CoN O ), Calc. C: 65.03%,
42
32
6
6
H: 4.16%, N: 10.83%, Co: 7.60%, Exp. C: 66.30%, H: 4.60%, 2.6 Urease inhibition assay
N: 9.59%, Co: 8.12%, EI-MS: m/z (%): 775.1709(67%)
+
[C H CoN O ] , Ʌ = 10.0µS.
Exactly 25 µL of enzyme (jack bean urease) solution
and 5 μL of test compound (0.5 mM concentration) were
incubated with 55 μL of buffer containing 100 mM urea for
15 min at 30 °C in each well of a 96-well plate. Ammonia
production was measured as a measure of urease activity
bytheindophenolmethod.Finalvolumesweremaintained
as 200 µL by adding 45 µL of a phenol reagent (1% w/v
42
32
6
6
m
2
.5.2 Bis(2-(2-hydroxyphenyl)-3-{[(E)-(2-hydroxyphenyl)
methylidene]amino}-2,3-dihydroquinazolin-4(1H)-one)
nickel(II) (Ni-HHAQ)
o
Yield: 47%, D. pt: 278 C, IR: 3224(bd), 1635(w), 1612(s), phenol and 0.005% w/v sodium nitroprussside), and 70
1
1
550(s), 1506(s), 1490(s), 1425(w), 1382(w), 1338(w), μL of an alkali reagent (0.5% w/v NaOH and 0.1% active
280(s), 1255(s), 1213(w), 1155(s), 1126(s), 1028(s), 972(s), chloride NaOCl) to each well. Using a microplate reader
9
31(w), 860(w), 825(w), 792(w), 750(s), 692(s), 615(s), (Molecular Devices, CA, USA), the increase in absorbance
-
1
-1
-1
5
86(w), 553(w) cm , λ = 780(bd) nm [ε = 12.7 M cm , was measured at 630 nm af er 50 min at pH 6.8 [21,22].
max
3
3
3
3
3
3
A g (F) → T g (P), A g (F)→ T g (F), A g (F) → T g (F)], µ
2
1
2
1
2
2
eff
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12ꢀ
ꢀ Muhammad Ikram et al.
2
.7 TG-DTA analysis
aromatic protons are in the same environment, therefore
1
the H-NMR spectrum of the ligand show four doublets and
The TG-DTA analyses were carried out using TG/DTA two triplets in the region 6.5-7.6 ppm. Five singlets were
Diamond model by Perkin Elmer at a heating rate of 10 C also observed along with these aromatic bands. Singlets at
º
-1
º
min in a temperature range of 30-1000 C under static air. 11.45 ppm and 6.34 ppm were assigned to the two hydroxyl
The specific mass of samples were contained in ceramic groups. The difference in the values was assigned to the
pan crucibles adjusted on a platform support giving a probable involvement of one of the hydroxyl groups in
proportional signal to recorder, observed by a computer hydrogen bonding with the nitrogen of the Schiff base
interface and the results were plotted in the form of mass linkage. The other hydroxyl group is considered to be
loss of sample vs. temperature for TG and microvolts vs. freely available as may also be seen in the crystal structure.
temperature for DTA. All the results were referenced to the The HC=N proton appears at 9.45 ppm as expected. A
thermaldecompositionofalumina. Theactivationenergies singlet at 8.25 ppm was assigned to the cyclic NH group.
of all of the samples were calculated using the Horowitz- A singlet at 7.29 ppm was assigned to the cyclic N-CH-N
1
3
1
Metzger method [23]. It was found that linear plots could proton. The C{ H}-NMR recorded also show similar peaks
f
f
be obtained while ln (Wo - W )/(W - W ) {where Wo = initial for the secondary and tertiary carbon atoms. The ketonic
t
t
mass taken, W = weight remaining at a given temperature, carbon was observed at 165 ppm, whereas the –CH=N was
f
W = final weight} were plotted against Ɵ {where Ɵ = T - observed at around 160 ppm. C1 and C22 were observed
t
c
Ts}. The slope of the straight line was used to calculate the at 147 and 153 ppm respectively which were assigned to
activation energy through the expression (1):
the carbon atoms with the hydroxyl groups. The rest of
1
3
the C-NMR spectrum was assigned unambiguously to the
(1) respective secondary and tertiary carbon atoms.
The ligand H-HHAQ was reacted with divalent metal
Slope = E*/RT 2
s
The order of decomposition was calculated from the ions like Co(II), Ni(II), Cu(II) and Zn(II) and bis-complexes
relationship between the reaction order and concentration were obtained as may be seen in scheme 3.
at maximum slope [23]. Thermodynamic parameters
All the complexes were characterized by elemental
+
of activation were evaluated by using the following analyses, ES -MS, UV-visible and IR spectroscopic
+
expressions (2), (3) and (4), respectively [24]:
techniques. The elemental analyses supported by the ES -
MS results confirmed the mentioned compositions.
The IR spectra were also recorded in the region 4000-
∆
∆
S* = 2.303 log[Ah/k T ]R
(2)
B
s
-1
6
00 cm , which show that the complex formation occurs
H* = ∆E*-RT
G* = ∆H*-T∆S*
(3) through coordination from Schiff base linkage, hydroxyl
group and the cyclic ketone group. In the free ligand
(4) and the complexes these linked groups were found to be
∆
-1
varying in the range of ∆ʋ= 40-60 cm . In the free ligand the
-1
Ethical approval: The conducted research is not related to –OH group was observed in the region 3500 cm which is
either human or animals use.
-1
further broadened and moved to 3200 cm af er formation
of the complexes. The cyclic ketone group was observed
-1
-1
around 1620 cm which was moved to 1640 cm in Co-
3
Results and discussion of H-HHAQ HHAQ, Ni-HHAQ and Cu-HHAQ whereas in Zn-HHAQ
-1
it is moved to 1680 cm . Similarly the Schiff base linkage
series
-1
was observed around 1573 cm as a strong peak which was
-1
found around 1620 cm in all of the complexes. Therefore
it was confirmed that these functional groups are involved
in the formation of the octahedral metal complexes.
The UV-Visible spectra of Co-HHAQ, Ni-HHAQ and
3
.1 Analytical and spectroscopic
characterization
The novel Schiff base ligand 2-(2-hydroxyphenyl)- Cu-HHAQ were recorded in the range 200-800 nm in a
3
-{[(E)-(2-hydroxyphenyl)methylidene]amino}-2,3- 1 cm matched quartz cuvette. The compound Co-HHAQ
dihydroquinazolin-4(1H)-one (H-HHAQ) and its first was found to absorb visible light and gave three peaks at
row divalent metal complexes were characterized using 480, 590 and 640 nm. These peaks were assigned to the
4
4
4
4
4
4
different spectroscopic and analytical methods. By looking
at the structure of the ligand, it becomes apparent that the transitions, respectively [25,26]. It means that carbonyl
T g (F) → A g and the T g (F) → T g (P), T g (F) → T g
1 2 1 1 1 2
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(A)
-
Scheme 3: Formation of Octahedral complexes of HHAQ with M(II)
ions where M = Co, Ni, Cu and Zn.
group,hydroxylionandtheSchiffbaselinkageareinvolved
in the formation of octahedral geometry. The ligand is
responsible for the high spin electronic configuration of
the complex as suggested by the magnetic susceptibility
value. The compound Ni-HHAQ was found to be
absorbing in the range of 780 nm as a broad peak which
might be encompassing the overlapping peaks. Therefore
this broad spectral line may be assigned to the possible
(B)
3
3
3
3
transition caused by A g (F) → T g (P), A g (F) → T g (F),
2
1
2
1
3
3
and A g (F) → T g (F). The magnetic susceptibility value of
2
2
the compound shows that the complex is high spin having
two unpaired electrons in the eg level. Similarly the copper
complex Cu-HHAQ of this ligand is absorbing in the form
of broad peak in the range of 820 nm. This transition may
be due to T g→eg [25,26]. The complex has µeff = 1.67 B.M.
2
representing the paramagnetic nature with one unpaired
electron in the eg level. The complex Zn-HHAQ was found
to be diamagnetic in nature, therefore did not correspond
to any magnetic effects.
Compounds Co-HHAQ and Ni-HHAQ were found to
be non-electrolytic in nature as depicted from their molar
conductance values, whereas compounds Cu-HHAQ and
Zn-HHAQ show small values for the conductance which
Figure 2: (A) Molecular structure of H-HHAQ. Thermal ellipsoids are
shown at 50% probability, and (B) Crystal packing diagram of H-HHAQ.
H atoms are omitted for reasons of clarity for both (A) and (B).
may be due to the free availability of the proton on the by C(12)-C(13)-C(14)-C(15)-C(16)-C(17) aromatic ring. C(20)
non-coordinating hydroxyl group.
º
was found to be 32.49 below the plane produced by C(12)-
C(13)-C(15)-C(16)-C(17) aromatic ring.
Therefore it can be concluded that C(20) is involved in
the distortion of both aromatic rings. Similarly the plane
3
.2 Crystal Structure of H-HHAQ
º
produced by N(10)-C(11)-C(13)-C(14)-N(19) is also 32.49
H-HHAQ was crystallised from THF with a C222 space above than C(20). The distance between C(8)-N(9) is 1.292 Å,
1
group af er keeping the solution for 12hrs at room whichisequaltothenormalbondlengthofiminelinkageas
temperature, af er which a yellow block single crystal was found in (E)-4-bromo-2-[(2-chloro-3-pyridyl)-iminomethyl]
isolated. The ORTEP plot (Figure 2) of H-HHAQ show a phenol (1.291 Å) [27]. The C(20)-N(10) and C(20)-N(19) bond
Schiff base linkage at C(8) and N(9). C(20), a chiral carbon, lengths are 1.458 Å and 1.452 Å respectively with a 0.006 Å
may be seen in the formation of distorted heterocyclic difference. These bond lengths may be compared with 1.437
ring system connecting both N(19) and N(10). Due to this Å in 2,2’,2’’,2’’’-(1,4-Phenylenedinitrilo)tetraacetic acid
unique linkage the three aromatic rings lie at angle less dehydrate [28]. The ligand H-HHAQ crystalizes in splits
º
than 180 , creating a three dimensional orientation. The for phenyl groups reasonably to greater extent that the
plane produced by the aromatic ring C(8)-C(1)-C(3)-C(4)- electron density for the carbon atoms can be justified only
º
C(5)-C(6) is therefore lying at 32.45 to the plane produced in sense that reflection of the two groups are considered.
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ꢀ Muhammad Ikram et al.
Table 1: Crystal data and structure refinement for H-HHAQ.
Table 3: Selected bond angles of H-HHAQ.
Identification code
H-HHAQ
Moiety
Bond angle (º) Moiety
Bond angle (º)
125.1(8)
115.5(7)
Empirical formula
C H N O
O7‘-C1‘-C2‘
O7‘-C1‘-C6‘
C2‘-C1‘-C6‘
O7-C1-C2
126(3)
O12-C11-C13
21
17
3
3
Formula weight
359.38
295(2)
orthorhombic
C2221
10.2571(9)
14.4341(12)
23.706(2)
90
90
90
3509.7(5)
8
1.360
114(3)
N10-C11-C13
C15-C14-N19
C13-C14-N19
C14-N19-C20
N19-C20-N10
N19-C20-C21
N10-C20-C21
C26-C21-C22
C26-C21-C20
C22-C21-C20
O27-C22-C23
O27-C22-C21
Temperature/K
120.0
122.3(8)
117.7(8)
115.7(7)
107.5(6)
113.6(6)
113.3(6)
118.1(6)
124.1(7)
117.8(7)
122.9(7)
116.4(6)
Crystal system
123.1(16)
116.8(16)
120.0
Space group
O7-C1-C6
C2-1-C6
C1-C2-C3
C3-C2-C8
N9-C8-C2
C8-N9-N10
N9-N10-C11
N9-N10-C20
C11-N10-C20
O12-C11-N10
a/Å
b/Å
c/Å
α/°
β/°
γ/°
120.0
124.1(9)
128.6(10)
121.9(7)
115.7(7)
123.5(6)
120.5(7)
119.4(8)
3
Volume/Å
Z
3
ρcalcg/cm
μ/mm-1
0.093
1504.0
MoKα (λ = 0.71073)
5.9 to 53.912
F(000)
Radiation
3.3 Enzyme inhibitory activities
2
Θ range for data
collection/°
Urease (urea amidohydrolase EC 3.5.15) is a nickel
containing metalloenzyme which catalyzes the hydrolysis
of urea to ammonia and carbon dioxide as may be seen in
scheme 1. Urease is involved in the function to use urea as
nitrogen source [1-16] and is known to be the major cause of
diseases induced by H. pylori, thus allow them to survive at
low pH inside the stomach and thereby play an important
role in the pathogenesis of gastric and peptic ulcer, apart
from cancer as well [1-16]. Urease is directly involved in
the formation of infection stones and contributes to the
pathogenesis of urolithiasis, pyelonephritis, and hepatic
encephalopathy, hepatic coma and urinary catheter
encrustation. Previously reported bismuth complexes
are one of the widely used compounds for the treatment
of peptic ulcers and Helicobacter pylori infections as
urease inhibitors [1-16]. Bismuth complexes exhibited
many side effects such as darkening of tongue, vomiting,
diarrhea, dizziness. To overcome these side effects we
have synthesized various metal complexes of Schiff-base
ligands [14-16] and were tested for their potential inhibition
against the urease enzyme. Here we extended our quest for
Index ranges
-12 ≤ h ≤ 6, -17 ≤ k ≤ 16, -28 ≤ l ≤ 29
5355
3037 [Rint = 0.0718, Rsigma = 0.1716]
Reflections collected
Independent reflections
Data/restraints/parameters 3037/55/255
2
Goodness-of-fit on F
Final R indexes [I>=2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole /
e Å-
0.998
R = 0.0820, wR = 0.0650
1
2
R = 0.1888, wR = 0.0886
1
2
0.18/-0.23
3
Flack parameter
0.5(10)
Table 2: Selected bond lengths of H-HHAQ.
Moiety
C1‘-O7‘
C1-O7
Bond length (Å)
1.359(18)
1.374(12)
1.471(11)
Moiety
Bond length (Å)
1.463(8)
1.240(9)
1.512(7)
1.385(9)
1.457(9)
N10-C20
C11-O12
C20-C21
C14-N19
N19-C20
C22-O27
C20-C21
C2-C8
C2‘-C8
C8-N9
N9-N10
N10-C11
1.447(15)
1.275(9)
1.362(8)
1.368(7)
1.512(7)
1.382(8)
This crystal structure is completely different from the one successful and selective urease inhibitor development.
reported earlier [29]. The electron density of phenolic ring The H-HHAQ and its complexes were studied for their
is duplicated upon refinement. The molecule bears intra inhibitory activities against the urease enzyme in
and intermolecular hydrogen bonding. The intramolecular optimum conditions and the results are shown in table
H-bond is found between two sets of atoms like O27… 4. Table 4 shows that the copper complex Cu-HHAQ, is
H19 = 2.466 Å and N9...H7 = 1.989 Å. The intermolecular acting as an inhibitor for the inhibition of urease activity.
H-bond is found between O12 and H27 of 1.939 Å length. Other complexes like Co-HHAQ and Ni-HHAQ, are active
The molecular packing diagram is shown in Figure 2B for inhibiting the activity of urease whereas Zn-HHAQ is
revealing the butterfly structure of the ligand. The crystal not active for the enzyme. Therefore, Cu-HHAQ may act
data, selected bond lengths and bond angles are shown in as drug for the treatment of diseases related to urease and
tables 1, 2 and 3 respectively.
butyrylcholinesterase adding to the metal based drugs.
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ꢀ315
It was found that all the metal containing derivatives inhibition. The active compounds may further be studied
-
of HHAQ are active except the zinc based derivative. in vivo for possible urease metal based drug.
The nickel containing compound Ni-HHAQ is also
moderately active. Previously, the Schiff base containing
metal complex Bis(2-[(E)-(quinolin-3-ylimino)methyl] 3.4 Thermodynamics and Thermal studies
phenolato)nickel(II) has been reported with the inhibitory
activity IC = 9.9 ± 0.124 μM ± SEM. Here in this work, the ThermaldegradationoftheligandH-HHAQanditsdivalent
50
compound Ni-HHAQ showed IC = 294.2 ±5 .0 μM ± SEM metal complexes were evaluated in the temperature range
5
0
o
which is higher in comparison to the above example. The 30-1000 C. The thermal pyrolysis in the form of TG curves,
activities of the metal complexes against urease enzyme is shown in Figure 3 and the corresponding DTA peaks
-
show that copper based metal complex of HHAQ are are shown in Figure 4. Based upon the Td temperatures
º
º
º
more active than the other counterparts. The activity the order of stability may vary viz; 220 C, 225 C, 230 C and
º
may be compared with reported examples like Bis(2-{(E)- 550 C for Co-HHAQ, Ni-HHAQ, Cu-HHAQ and Zn-HHAQ
[
(4-chlorophenyl)imino]methyl}phenolate)copper(II) respectively. For ligand H-HHAQ the Td temperature
º
with IC50 ± S.E.M. = 10.7 ± 0.2 µM whereas Bis(2-{(E)-[(4- is 245 C. TG and DTA curves are shown in Figure 3 and
bromophenyl)imino]methyl}phenolate)copper(II) shown 4 respectively for H-HHAQ and its metal complexes,
IC50 ±S.E.M. = 5.0±0.1 µM [14, 15]. The activities of these whereas the data obtained from TG and DTA are shown in
copper complexes are far less than the activity shown by table 5 and 6 respectively.
the copper complex with H-HHAQ ligand. The inhibitory
By comparing the data in Table 6, it is clear that the
activity of the compound Cu-HHAQ may be explained by ligand and all its metal complexes decompose in a two
geometric constraints created by the ligand around the step degradation process. The difference between the
central metal ion. The ligand in its coordinated form also ligand and the metal complexes lie in the final step, for the
offers coordinating sites for possible interaction with the ligand no residue is found whereas the decomposition of
Ni center of urease enzyme. There may be an interaction complexes lef behind metal or the corresponding oxides
with the OH bridge group in the enzyme which may lead to as residues. From Table 5 it is apparent that the ligand has
th
enzymatic activities. One or more than one effect may be 8.75 KJ/mol activation energy and follow 5 order kinetics
involved in enzyme inhibition therefore; some complexes for its decomposition. The negative entropy value and a
have shown moderate whereas others have shown strong high Gibbs free energy term represent that decomposition
is not favored for the parent compound.
H-HHAQ follows the two step degradation, including
the formation of free radicals like phenol and benzene.
The two phenol free radicals combine together to produce
the fused biphenylenediol. Along with bipheneylenediol
one mole of carbon monoxide gas and one mole of
nitrogen gas are released in the first step. In the second
step the benzene free radical produces the cyclohexa-1,3-
diene-5-yne as a product along with one mole of acetylene
Table 4: Urease Inhibition by metal complexes of H-HHAQ.
Compound
Conc. (mM)
% Inhibition
18.6
IC50 (μM±SEM)
--
H-HHAQ
0.5
0.5
0.5
0.5
0.5
0.5
1
88.9
43.4±1.2
294.2±5.0
0.3±0.1
--
2
94.0
3
99.9
[
14], half a mole of dinitrogen and dihydrogen gases. The
4
38.5
degradation route is shown below in scheme 4.
Thiourea
96.9
21.8±1.26
Table 5: Kinetic and thermodynamic parameters of H-HHAQ and its metal complexes.
#
#
-1 -1
Compound
Ts in K
526.5
501.6
775.5
560
Ea, KJ/mol
8.75
∆H, KJ/mol
4.37
∆G , KJ/mol
136.30
138
∆S , Jmol K
-250.56
-243.03
-253.33
-247.5
Order of reaction, n
H-HHAQ
5
1
20.30
12.00
20.8
16.1
∞
2
2
3
4
5.5
202
16.2
154.76
248.74
5
855.7
31.65
24.53
-262.02
1/2
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ꢀ Muhammad Ikram et al.
Table 6: Thermo analytical results of H-HHAQ and its complexes.
Compound
H-HHAQ
TG Temp. range/ Stage
Mass loss
% Calc.
67.3
DTA
Moiety evolved
º
C
% Found
66.2
33.8
30-400
I
II
(+)5, (-)18,
(-)22, (-)25
N , CO, C H O
2
2
12 10
400-600
32.3
C H , C H , 1/2N , 1/2H
6 4 2 2 2
2
1
30-280
80-620
I
II
18.8
69.6
17.0
68.1
(-)2, (+)8
(+)32, (-)15
C H
12 8
2
2 C H O , 2CO, C H ,
12 10 2 2 2
3
/2N , H
2 2
˃
620
30-390
90-640
Res
9.6
11.3
---
CoO
2
3
4
I
II
39.9
47.9
39.2
47.2
(-)12, (-)9, (-)18
C H 3N2, C H , 2CO
1
2
8,
2
2
3
(-)38, (+)1, (-)14, 2 C H O
1
2
10
2
(
-)29
˃
640
Res
I
10.5
55.6
11.4
---
NiO
30-450
56.0
(-)5.8, (-)5.6,
C H 1/2N , 2CO, 2C H
12 8, 2 2
2,
(
-)15.3, (-)18
N O
2 4
4
50-600
600
30-380
II
48.2
48.2
(-)12.0
2 C H O
12 10 2
˃
Res
I
10.1
47.9
10.9
47.5
---
CuO
C H 3N , 2CO, 2C H
2
(-)0.5, (+)5.6,
1
2
8,
2
2
(
-)5.3
3
80-680
II
48.8
6.8
49.9
5.1
(-)5.0
2 C H O
12 10 2
˃
680
Res
---
Zn
Figure 3: Thermogravimetric plots of H-HHAQ and its metal complexes.
Figure 4: Differential thermogravimetric curves for H-HHAQ and its
metal complexes.
C H N O → C H O + CO + N + C H N
I Stage
II Stage
2
1
17
3
3
12 10
2
2
8
7
Co-HHAQ follows thermal degradation in two steps,
in the first step the two free radicals of benzene are
produced which combine together to produce bipheylene.
There are two exothermic DTA peaks for the first step of
pyrolysis. In the second stage two moles of acetylene, 3/2
moles of nitrogen, and two moles of biphenylenediol are
C H N → C H + C H + 1/2H + 1/2N
2
8
7
6
4
2
2
2
Scheme 4: Thermal degradation of H-HHAQ.
º
The decomposition of the Ni-HHAQ starts at 220 C
º
produced [15]. Cobalt oxide remains as a residue. There and ends at 650 C producing nickel oxide as a residue. It
are two exothermic DTA peaks observed for the second also follows a two step degradation; the first step is the
step of pyrolysis. It has a negative entropy of activation, same as for comp]ound Co-HHAQ, with the production
and a high value of Gibbs free energy of activation and of biphenylene. This step of degradation is represented
a reasonable enthalpy of activation. According to the by the production of two intermediate free radicals of
Horowitz method, compound Co-HHAQ follows an benzene moiety. Apart from this, two moles of carbon
infinite order of degradation. The degradation route is monoxide and acetylene and three moles of dinitrogen,
shown in scheme 5.
are also produced. Three DTA peaks are observed for this
stage, including one exothermic and two endothermic
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C H N O Co → C H + C H CoN O
ꢀ317
I Stage
II Stage
4
2
32
6
6
12
8
30 24
6
6
peaks. The fusion of two benzene free radicals to produce
biphenylene is an endothermic process. The second
stage of degradation is represented by the production
C H CoN O + O → 2C H O +2C H +3/2N + CoO
30
24
6
6
2
12 10
2
2
2
2
of the same phenol free radicals which may combine Scheme 5: Thermal degradation of Co-HHAQ.
together producing two moles of biphenol as whole in the
degradation process. Nickel oxide remains as a residue in
C H N NiO → C H + 3N + 2CO + 2C H + C H NiO
4
I Stage
II Stage
4
2
32
6
6
12
8
2
2
2
24 20
the whole degradation process of Ni-HHAQ. The second
stage is represented by a marked exothermic DTA peak
having the other two as shoulder counterparts. The
activation energy of Ni-HHAQ is lower than Co-HHAQ and
follows second order degradative kinetics. The entropy
value is more negative than Co-HHAQ and also the Gibbs
free energy of activation is also high depicting the stable
nature of the parent compounds. The degradative route is
shown in scheme 6.
C H NiO + O → 2C H O + NiO
2
4
20
4
2
12 10
2
Scheme 6: Thermal degradation of Ni-HHAQ.
C H CuN O → C H + 1/2N + 2CO + 2C H +
4
2
32
6
6
12
8
2
2
2
+
NO + 2N O + C H CuO
4
I Stage
II Stage
2
2
4
24 20
C H CuO + O → 2C H O + CuO
2
4
20
4
2
12 10
2
For compound Cu-HHAQ the oxidative degradation
º
Scheme 7: Thermal degradation of Cu-HHAQ.
starts at 450 C with the release of the same biphenylene
product af er the reaction between the two benzene free
radicals with each other [14,15]. It is accompanied by the C H N O Zn → C H + 3N + 2CO + 2C H + + C H O Zn
I Stage
II Stage
4
2
32
6
6
12
8
2
2
2
24 20
4
release of two moles each of the acetylene and carbon
monoxide gases. Apart from this, one mole each of nitrogen
dioxide and dinitrogen tetra oxide are also released,
the latter of which may undergo further decomposition
adding to the molar quantity of nitrogen dioxide. This
C H O Zn → 2C H O + Zn
2
4
20
4
12 10
2
Scheme 8: Thermal degradation of Zn-HHAQ.
stage of pyrolysis depicts four exothermic DTA peaks. The By comparing the data in table 5 it becomes clear that
second and final stage of pyrolysis is accompanied by the the values of activation energy, change in entropy of
release of a biphenol moiety leaving behind the copper activation, change in Gibbs free energy of activation,
oxide as the residue. This step has one huge exothermic change in enthalpy of activation are higher for Zn-HHAQ
DTA peak. If Table 5 is consulted for the thermodynamic than any other complex of the same ligand. Therefore zinc
parameters it can be seen that the entropy of activation produces the stable complex with H-HHAQ, representing
for Cu-HHAQ is more negative than Co-HHAQ and more that the degradation is less favored in this case.
positive than Ni-HHAQ. The same trend can be seen for
the Gibbs free energy of activation; while the enthalpy
change of activation is almost equal to Co-HHAQ. The 4 Conclusion
activation energy is higher than both Co-HHAQ and Ni-
th
HHAQ and follows 5 order kinetics. The decomposition The novel Schiff base ligand H-HHAQ was synthesized
of the compound may be seen in scheme 7.
from aminobenzohydrazin which is actually a heterocyclic
The decomposition for Zn-HHAQ starts at around derivative of salicyldehyde. It was complexed with divalent
º
º
2
30 C and completes at 680 C. The whole degradation of metal ions like Co(II), Ni(II), Cu(II) and Zn(II) to yield
the compound takes place in two steps. In the first step octahedral metal complexes. The ligand and its metal
biphenylene is produced by the fusion of benzene free complexes were completely characterized by different
radicals along with the release of three moles of dinitrogen, analytical and spectroscopic techniques and was assigned
two moles of acetylene and two moles of carbon monoxide. composition and structures. Apart from this, the ligand
The whole degradation is comprised of four DTA peaks, was also characterized by single crystal studies and it
all of them are exothermic. This includes three exothermic was determined that intermolecular and intramolecular
DTA peaks for the first stage of decomposition and one hydrogen bonding is responsible for the crystal packing
huge DTA peak for the second stage of decomposition. of the ligand. All the compounds were studied for their
The second stage of decomposition releases the biphenol inhibiting activities against urease enzyme. It was
moiety, whereas zinc remains as a residue in the metallic observed that copper based metal complex of H-HHAQ
state. The degradation is shown in the scheme 8.
ligand was active with an IC = 0.3 ± 0.1 µM±SEM which is
50
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18ꢀ
ꢀ Muhammad Ikram et al.
[
13] You Z.-L., Ni L.-L., Shi D.-H., Bai S., Synthesis, structures, and
urease inhibitory activities of three copper(II) and zinc(II)
complexes with 2-{[2-(2-hydroxyethylamino)ethylimino]
methyl}-4-nitrophenol, Eur. J. Med. Chem., 2010, 45, 3196-
even more potent than the standard thiourea. The cobalt
complex showed an IC of 43.4±1.2 µM±SEM, whereas for
5
0
the nickel complex, this was 294.2±5.0 µM±SEM. Therefore
it becomes apparent that the Cu-HHAQ based drug for
3
199.
the diseases related to urease enzyme can be designed. [14] Ikram M., Rehman S., Faridoon, Baker R.J., Rehman H.U., Khan
The thermal degradation of the compounds revealed that
the order of decreasing activation energies was E* <E*
A., Choudhary M.I., Rehman S.–U., Synthesis and distinct
urease enzyme inhibitory activities of metal complexes of
Schiff-base ligands: Kinetic and thermodynamic parameters
evaluation from TG-DTA analysis, Thermochim. Acta, 2013, 555,
Zn
Cu
<
E* <E* and the order of decreasing stability was Zn(II)
Ni Co
<
Cu(II) <Co(II) <Ni(II).
7
2– 80.
[
[
15] Ikram M., Rehman S., Ali M., Faridoon, Schulzke C., Baker
R.J., Blake A.J., Malook K., Wong H., Rehman S.-U-., Urease
and α-chymotrypsin inhibitory activities of transition
metal complexes of new Schiff base ligand: Kinetic and
thermodynamic studies of the synthesized complexes using TG
DTA pyrolysis, Thermochim. acta, 2013, 562C, 22-28.
16] Ikram M., Rehman S.-U., Rehman S., Baker R.J., Schulzke C.,
Synthesis, characterization and distinct butyrylcholinesterase
activities of transition metal [Co(II), Ni(II), Cu(II) and Zn(II)]
complexes of 2-[(E)-(quinolin-3-ylimino)methyl]phenol, Inorg.
Chim. Acta, 2012, 390, 210–216.
Conflict of interest: Authors state no conflict of interest.
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