Synthesis, analgesic, anti-inflammatory and anti-ulcerogenic activities of certain novel Schiff's bases as fenamate isosteres

Article abstract of DOI:10.1016/j.bmcl.2014.11.088

A series of certain novel Schiff bases as fenamate isosteres (VI:a-k) were synthesized to locate analgesic, anti-inflammatory agent with minimal ulcerogenic potential. The structures of the newly synthesized compounds were elucidated on the basis of their

Full text of DOI:10.1016/j.bmcl.2014.11.088

Accepted Manuscript
Synthesis, analgesic, anti-inflammatory and anti-ulcerogenic activities of cer-
tain novel Schiff’s bases as fenamate isosteres
Ahmed M. Alafeefy, Mohammed A. Bakht, Majid A. Ganie, Nazam Ansari,
Nahed N. El-Sayed, Amani S. Awaad
PII:
S0960-894X(14)01295-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.11.088
BMCL 22243
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Accepted Date:
26 October 2014
28 November 2014
Please cite this article as: Alafeefy, A.M., Bakht, M.A., Ganie, M.A., Ansari, N., El-Sayed, N.N., Awaad, A.S.,
Synthesis, analgesic, anti-inflammatory and anti-ulcerogenic activities of certain novel Schiff’s bases as fenamate
isosteres, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.11.088
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Synthesis, analgesic, anti-inflammatory and anti-ulcerogenic activities of
certain novel Schiff’s bases as fenamate isosteres
a
a
b
b
Ahmed M. Alafeefy *, Mohammed A. Bakht , Majid A. Ganie , Nazam Ansari , Nahed N.
c,d
e
El-Sayed , Amani S. Awaad
a
Department of Pharmaceutical Chemistry, College of Pharmacy, Salman Bin Abdulaziz
University, P.O. Box 173, Alkharj 11942, Saudi Arabia
b
Department of Pharmacology and Toxicology, College of Pharmacy, Salman Bin Abdulaziz
University, P.O. Box 173, Alkharj 11942, Saudi Arabia
c
Department of Chemistry, College of Science, King Saud University, P.O. Box 22452,
Riyadh 11495, Saudi Arabia
d
Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622,
Egypt
e
Department of Pharmacognosy, College of Pharmacy “Girls section”, Salman Bin Abdulaziz
University, P.O. Box 173, Alkharj 11942, Saudi Arabia
Abstract: A series of certain novel Schiff bases as fenamate isosteres (VI:a-k) were synthesized to locate
analgesic, anti-inflammatory agent with minimal ulcerogenic potential. The structures of the newly synthesized
compounds were elucidated on the basis of their elemental analysis as well as IR, and NMR and mass
spectroscopic data. All the compounds were evaluated for their anti-inflammatory activity by carrageenan
induced paw oedema method. The compounds possessing good anti-inflammatory activity were further tested
for analgesic, ulcerogenic, lipid peroxidation potentials and liver toxicity. Compounds (VI-c), (VI-f), (VI-h) and
(
VI-i) showed the best anti-inflammatory and significant analgesic activities at doses comparable to that of the
standard drug Indomethacin. However, compounds (VI-c) and (VI-f) could be considered the most potent anti-
inflammatory and analgesic molecules with maximum reduction in gastro-intestinal ulceration with no
hepatocyte necrosis or liver degeneration.
Keywords: Fenamate isostere. Schiff‟s bases. Synthesis. Analgesic. Anti-inflammatory. Anti-
ulcerogenic.
*
Corresponding authors.
a.alafeefy@sau.edu.sa Cell: + 966 50706 9896.
1

Non-steroidal anti-inflammatory drugs (NSAIDs) are successfully used to treat pain, fever
1
-3
and inflammation, particularly arthritis. They exert their beneficial effects mainly through
inhibition of cyclooxygenases (COXs), the key enzyme in prostaglandin (PG) biosynthesis
from arachidonic acid (AA). Two such isoforms, COX-1 and COX-2, are involved and are
4
-7
regulated differently. COX-1 is the constitutive enzyme which provides cytoprotection in
7
,8
the gastrointestinal (GI) tract whereas the inducible COX-2 mediates inflammation.
In spite of the successful application of NSAIDs by millions of patients worldwide, there are
serious problems in their medication, since most of them show greater selectivity for COX-1
9
than COX-2. This preferential selectivity leads to grave GI effects, such as mucosal lesions,
1
0,11
hemorrhage, and ulceration.
The incidence of such clinically significant GI problems is
alarming in addition to more complex adverse effect especially in patients with risk
1
2,13
factors.
N-substituted anthranilic acid derivatives, commonly known as fenamates, are interesting
class of NSAIDs, they are considered as nitrogen isosteres of salicylic acid. Moreover, they
are important classes of compounds in the medical field and their biological activities have
attracted considerable attention towards biomedical applications. They are well-known for
1
4,15
16
their importance as anticancer agents
antimicrobial, anti-inflammatory and immune
1
7-19
20
modulators
as well as analgesic agents. However, they also suffer the same general
untoward effects characteristic of this class of drugs. Conversion of the carboxylic acid
moiety to hydrazide and/or Schiff base is a suitable alternative to overcome such deleterious
effects.
In the present context a newly synthesized N-4-toluoyl anthranilic acid hydrazide was reacted
with different substituted aromatic aldehydes to produce novel Schiff‟s bases as fenamate
isosteres (VI:a-k). The structures of these newly synthesized compounds were confirmed by
IR, NMR, Mass spectrometry and their purity was ascertained by elemental analysis. The
synthesized compounds were evaluated for their anti-inflammatory, analgesic activities, acute
ulcerogenicity in addition to liver enzyme and lipid peroxidation.
Molecular properties, mainly hydrophobicity, molecular size, flexibility and the presence of
various pharmacophoric features influence the behaviour of molecules in the living organism,
mainly bioavailability. Thus, in order to achieve orally available drugs we have subjected the
newly developed Schiff bases (VI:a-k) for the prediction of some basic pharmacokinetic
properties under the Lipinski „„Rule of Five‟‟ to filtered compounds for anti-inflammatory
and analgesic properties.
2

The current compounds were subjected to computational study in order to filter the candidate
compounds for biological screening. For good membrane permeability logP value should be
2
1
≤
5. All the title compounds (VI:a-k) have logP value 4.02–6.12.
High oral bioavailability is an important factor for the development of bioactive molecules as
therapeutic agents. Good intestinal absorption, reduced molecular flexibility (measured by the
number of rotatable bonds), low polar surface area or total hydrogen bond count (sum of
2
4
donors and acceptors), are important predictors of good oral bioavailability. Molecular
properties such as membrane permeability and bioavailability is always associated with some
basic molecular descriptors such as logP (partition coefficient), molecular weight (MW), or
2
3
21
hydrogen bond acceptors and donors counts in a molecule. Lipinski used these molecular
properties in formulating his „„Rule of Five”. The rule states that most molecules with good
membrane permeability have logP ≤ 5, molecular weight ≤500, number of hydrogen bond
acceptors ≤10, and number of hydrogen bond donors ≤ 5. This rule is widely used as a filter
for drug-like properties. Table 1 contains calculated percentage of absorption (% ABS),
molecular polar surface area (TPSA) and Lipinski parameters of the investigated compounds
under test. Magnitude of absorption is expressed by the percentage of absorption. Absorption
2
4
percent was calculated using the expression: %ABS =109 - 0.345 PSA. Polar surface area
2
5,26
(PSA) was determined by the fragment-based method of Ertl and coworkers.
A poor
permeation or absorption is more likely when there are more than 5 H-bond donors, 10 H-
bond acceptors. Hydrogen-bonding capacity has been also identified as an important
2
7
parameter for describing drug permeability. The results in our hands proved that
compounds (VI:a-k) have hydrogen bond donor and acceptor in considerable range as shown
in Table 1.
The number of rotatable bonds is important for conformational changes of molecules under
study and ultimately for the binding of receptors or channels. It is revealed that for passing
2
2
oral bioavailability criteria no of rotatable bond should be ≤10. The compounds in this
series (VI:a-k) in general possess acceptable of rotatable bonds (5–8) and therefore, exhibit
low conformational flexibility.
Molecular polar surface area (TPSA) is a very useful parameter for the prediction of drug
transport properties. TPSA is a sum of surfaces of polar atoms (usually oxygen, nitrogen and
attached hydrogen) in a molecule. TPSA and volume is inversely proportional to % ABS,
compounds (VI-a) and (VI-e) had maximum absorption (88.98%) as their corresponding
polar surface area and volume are least among the series (Table 1). All the title compounds
3

(
VI:a-k) followed the Lipinski „„Rule of Five‟‟. The pharmacokinetic parameters were
calculated Online from Molinspiration Chemoinformatics
http://www.molinspiration.com/cgi-bin/properties) and are given in Table 1.
(
Structure based drug design is now very routine work as many drug fail to reach clinical
phases because of the encountered ADME/TOX problem. Therefore prediction of these
problems before synthesis is rational approach to minimize the cost. The Osiris calculations
are tabulated in Table 2. Toxicity risks (mutagenicity, tumorogenicity, irritation,
reproduction) and physicochemical properties (miLogP, solubility, drug likeness and drug
score) of compounds (VI:a-k) were calculated by the methodology developed by Osiris. The
toxicity risk predictor locates fragments within a molecule, which indicates a potential
toxicity risk. Based on our data (Table 2), it is obvious that, all compounds, except compound
(VI-j), are supposed to be non-mutagenic, non-irritating, when run through the mutagenicity
assessment system in comparison with the standard drug. The logP value of a compound is a
well-established measure of the compound‟s hydrophilicity. Low hydrophilicities and
therefore high logP values may cause poor absorption or permeation. It has been shown that
for compounds to have a reasonable probability of good absorption, their logP value must not
be greater than 5.0. On this basis, the current compounds (VI:a-k) possessed logP values in
the acceptable range.
Further, Table 2 shows drug likeness of compounds (VI:a-k) which is in the comparable
zone with that of standard drug used for comparison. We have calculated overall drug score
(DS) for the compounds (VI:a-k) and compared with that of standard drug Indomethacin.
The drug score combines drug likeness, miLogP, logS, molecular weight and toxicity risks in
one handy value than may be used to judge the Compound‟s overall potential to qualify for a
drug. This value is calculated by multiplying contributions of the individual properties with
the equation (1): DS = ∏ (1/2+1/2Si) ∏ti, where S; (1/1+eap+b) DS is the drug score. Si is
the contributions calculated directly from miLogP; logS, molecular weight and drug likeness
(
pi) via the second equation, which describes a spline curve. Parameters a,b are (1,-5), (1, 5),
0.012, -6) and (1, 0) for miLogP, logS, molecular weight and drug likeness, respectively.
(
The ti is the contributions taken from the four toxicity risk types and the values are 1.0, 0.8
and 0.6 for no risk, medium risk and high risk, respectively. The reported compounds (VIa-k)
showed moderate to good drug score as compared with standard drug used.
4

Based on previous work and literature survey it was expected to obtain the corresponding
2
8-32
cyclic quinazolinone structure upon treating the oxazine (IV) with hydrazine hydrate.
However, the spectroscopic data of the isolated compound were in full agreement with the
proposed open structure corresponding to the formation of N-4-toluoyl anthranilic acid
3
01,32
hydrazide (V).
corresponding Schiff‟s bases. The identity of the formed fenamate derived Schiff‟s bases
VI:a-k) is fully supported by their elemental analysis as well as IR, and NMR spectroscopic
data. In general, the IR spectra showed absorption bands due to two NH groups around 3300
Condensing the later hydrazide with various aromatic aldehydes gave the
(
-1
-1
cm , in addition to other bands at 1540-1538 cm due to C=N group and absorption bands at
-1
1
1
700-1682 cm for two carbonyl groups. The H-NMR spectra of the current Schiff‟s bases
displayed in general multiplets at δ = 6.62-8.52 ppm due to the aromatic protons. The most
characteristics protons of azomethin groups (N=CH) of Schiff‟s bases appeared at δ = 8.72-
8
.84 ppm as singlets. Two broad singlets due to two amide protons appeared at δ around = 12
1
3
ppm. C-NMR spectra again proved the formation of the proposed open systems. The two
carbonyl, (N=CH) as well as other aromatic and aliphatic carbons appeared at the expected δ
values. Mass spectra of all the compounds revealed the parent ion peaks with a considerable
1
13
relative intensity. The spectral data (IR, H-NMR, C-NMR, MS) and C, H, N elemental
analysis of all the synthesized compounds are in accordance with the proposed structures.
The compounds were tested at an equimolar oral dose relative to 10mg/kg indomethacin. The
percentage inhibition was calculated both after 2 and 3h. The tested compounds showed
variable degrees of anti-inflammatory activity in comparison to standard drug indomethacin
after 3h (Table 3). The best activity was obtained from compounds (VI-f), (VI-h) and (VI-i),
it was found to be ranging from 61.84% to 64.31%. On examining the structure of these
compounds, one could conclude that compounds having more methoxy (-OCH ) functionality
3
produced maximum anti-inflammatory inhibitory effect. It can be deduced that compound
(VI-i) having 3,4,5-trimethoxy substituent exhibited more inhibitory activity than 2,4,5-
trimethoxy (VI-h) which is more active than monosubstituted methoxy compound (VI-f).
Therefore, the number and arrangement of methoxy substituted derivatives are important for
good anti-inflammatory activity. Compound (VI-c) having dihydroxy substituents exhibited
moderate activity. Rest of the compounds, possessing OH (VI-b), Cl (VI-e) and unsubstituted
(VI-a), were found to be weakly active as anti-inflammatory agents compared to the standard
drug indomethacin (78.80% after 3h).
5

Compounds (VI-c), (VI-f), (VI-h) and (VI-i) which showed almost comparable anti-
inflammatory to that of reference drug, were further tested for their analgesic activity at an
equimolar oral dose relative to 10 mg/kg indomethacin (Table 4). The tested compounds in
this series showed analgesic activity ranging from 34.2% to 77.8%, compared to 81.0%
inhibition displayed by the reference drug indomethacin. It was noticed that compound (VI-i)
having maximum anti-inflammatory activity displayed the least analgesic properties. On the
other hand, compound (VI-f) having the lowest anti-inflammatory activity (61.84%) showed
significant analgesic (67.8%) activities among the current series. Compound (VI-c) showed
the highest analgesic properties (77.8%) whereas compounds (VI-h) and (VI-i) showed
reduced analgesic activity (46.2% and 34.2%).
Consequently, compounds (VI-c and VI-f) were further screened for their acute ulcerogenic
activity. The compounds were tested at an equimolar oral dose relative to 10 mg/kg
indomethacin. Surprisingly, they showed significant reduction in ulcerogenic activity ranging
from 1.417±0.15 to 1.750±0.11, whereas standard drug indomethacin showed high severity
index of 2.750±0.44. The maximum reduction in ulcerogenic activity (1.417±0.15) was due
to compound (VI-c) having dihydroxy substituent. These results clearly indicated that we
succeeded to develop good anti-inflammatory and analgesic agents with reduced ulcerogenic
potential.
NSAIDs are associated with high incidence of GI ulceration; bleeding and kidney damage
which may be linked with lipid peroxidation. So, our study aimed to examine lipid
peroxidation (LP) induction capacity of compounds (VI-c and VI-f) which showed
remarkable analgesic and anti-inflammatory activity. LP was measured as nanomoles of
malondialdehyde (MDA)/100 mg of gastric tissue. We noticed that indomethacin exhibited
maximum lipid peroxidation 6.73±0.17, whereas (VI-c and VI-f) 4.02 and 4.39, respectively
(control group showed 3.14±0.14).
The most potent anti-inflammatory and analgesic agents with reduced ulcerogenic and lipid
peroxidation potential (VI-c and VI-f) were further examined for their hepatotoxic effects as
well as their effect on serum enzymes and total albumin. Both compounds exhibited
significant reduction in SGOT, SGPT and total albumin level in comparison to control as
shown in Table 5.
Because several studies reported that most NSAIDs induce liver damage, we studied the
histopathlogy of liver samples. The results revealed that there is no indication of any
6

pathological change. Neither necrosis nor degeneration was found in comparison to the
control group (Fig 1-3).
In conclusion, we have accomplished the synthesis of certain novel Schiff‟s bases. The new
compounds have been investigated for their anti-inflammatory and analgesic activities as well
as their ulcerogenic activity, liver toxicity and lipid peroxidation. Among the synthesized
Schiff‟s bases, compounds (VI-c) and (VI-f) were found to be the most potent as anti-
inflammatory and analgesic agents with maximum reduction in GI toxicity, no hepatocyte
necrosis or degeneration in liver samples. Indeed, these two compounds could be considered
as suitable candidates for bio-technologic application as anti-inflammatory and analgesic
agents.
Acknowledgments
This research was funded by National Plan of Science, Technology and Innovation (Grant
No. 12-MED2980-54), Salman bin Abdulaziz University, Alkharj, P.O.Box 173, 11942 (to
AF).
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9

Table 1 Pharmacokinetic Properties important for good oral bioavailability of titled
compounds (VI:a-k)
Lipiski’s
Violations
≤1
Compounds %ABS Volume (A3) TPSA(A2) NROTB HBA HBD LogP M W
Rule
VI-a
-
-
-
-
<10
3
<5
2
≤5
<500
357
8
8
7
8
8
8
8
8
8
8
8
8.98
355.88
58.05
5
4.61
0
0
0
0
1
0
0
0
0
0
0
VI-b
VI-c
VI-d
VI-e
VI-f
VI-g
VI-h
VI-i
VI-j
VI-k
3.02
6.91
0.23
8.98
6.23
6.09
0.61
0.59
7.96
0.68
366.42
377.94
399.32
387.81
386.46
387.72
451.16
451.63
405.38
449.92
75.31
93.04
83.42
58.05
66.01
66.43
82.30
82.36
61.01
82.11
5
5
6
5
6
6
8
8
6
8
4
5
5
3
4
4
6
6
3
6
3
4
3
2
2
2
2
2
2
2
4.14
4.02
4.10
6.12
4.59
4.66
4.23
4.63
4.87
4.41
373
389
403
425
387
387
447
447
400
447
%
ABS, percentage of absorption; TPSA, topological polar surface area; NROTB, number of rotatable bonds;
MW, molecular weight; LogP, logarithm of compound partition coefficient between n-octanol and water; HBA,
number of hydrogen bond donors; HBD, number of hydrogen bond acceptors.

Table 2 Osiris calculations of compounds (VI:a-k)
a
Toxicity Risks
MUT TUM IRRIT
b
Compd.
Bioavailability and Drug Score
RE
MW
CLP
S
DL
D-S
0.49
VI-a
3
3
3
4
4
3
3
4
4
4
4
57
73
89
05
25
87
87
47
47
00
47
4.72
-5.58
4.17
VI-b
VI-c
4.43
4.12
4.29
5.92
4.59
4.59
4.38
4.38
4.74
4.38
-5.28
-4.98
-5.36
-7.05
-5.66
-5.64
-5.63
-5.63
-5.61
-5.63
4.32
5.06
4.67
5.15
4.42
4.29
7.07
4.73
3.12
5.18
0.53
0.57
0.52
0.31
0.48
0.48
0.46
0.46
0.28
0.46
VI-d
VI-e
VI-f
VI-g
VI-h
VI-i
VI-j
VI-k
Indomethacin
3
57
3.83
-5.48
7.59
0.57
(Std)

Table 3 Anti-inflammatory activity of compounds (VI:a-k)
a
Increase in Paw Volume
% Inhibition ±SEM
Potency
Compound
After 2 h
After 3 h
After 2 h
15.25
After 3 h
15.90
VI-a
VI-b
0
.80±0.731
.76±0.118
0.79±0.077
0.20
0.30
0.70
0.30
0.01
0.78
0.29
0.79
0.82
0.18
0.28
1.00
-
0
0.72±0.088
0.42±0.129**
0.66±.055
19.50
55.32
19.50
0.35
23.32
55.12
23.32
1.06
VI-c
0
.42±0.143*
VI-d
0
.65±0.066
.94±0.114
VI-e
0
0.96±0.093
0.36±0.051**
0.70±0.053
0.36±0.128**
0.34±0.081**
0.81±0.124
0.73±0.158
0.20±0.013**
0.94±0.150
VI-f
0
0
0
0
.35±0.060**
.75±0.062**
.35±0.142**
.35±0.090**
62.41
19.31
62.41
62.77
13.12
22.34
78.37
-
61.84
22.55
62.19
64.31
14.49
22.26
78.80
-
VI-g
VI-h
VI-i
VI-j
0
0
.82±0.115
.73±0.165
VI-k
Indomethacin
0
.20±0.024**
.94±0.148
Control
0
a
Relative to control and data were analyzed by ANOVA followed by Dunnett’s multiple
comparison test for n = 6;*p<0.05, **p < 0.01.

Table 4 Analgesic, ulcerogenic and lipid peroxidation activities of selected compounds
a
Ulcerogenic
activity
Nanomoles of
MDA content ±
SEM/100 mg
Compound
Analgesic activity
Pretreatment/normal Post-treatment/
h (s) (normal) after 3 h (s)
%
(severity index
Potency
0.96
b
b
0
Inhibition
± SEM)
tissue
1
*
9
*
8
*
9
0
9
0
1.15 ± 1.212
**
.60 ± 0.759
**
.39 ± 0.502
**
.95 ±
.631***
.83 ±
.721***
VI c
VI-f
VI-h
VI-i
6.27±0.837
5.72 ±0.726
5.74 ± 0.565
7.41 ± 0.787
77.8
67.8
46.2
34.2
1.417 ± 0.15**
1.500 ± 0.26**
1.750 ± 0.11*
1.583 ± 0.20*
4.02 ± 0.24**
4.39 ± 0.14**
6.13 ± 0.17
0.84
0.57
0.42
6.05 ± 0.11*
Indomethacin 5.43 ± 0.365
81.0
-
1.00
-
2.750 ± 0.44
0.00
6.73 ± 0.17
Control
-
-
3.14 ± 0.14**
a
Relative to normal and data were analyzed by paired student’s t-test for n=6; ***p < 0.0001, **p <
0
.001.
b
Relative to standard and data were analyzed by ANOVA followed by Dunnett’s multiple
comparison test for n=6; **p < 0.01, *p <0.05.

Table 5 Effect of compounds (VI-c and VI-f) on serum enzymes and total albumin
Compound SGOT
Units/ml)
SGPT
(Units/ml)
Total Bilirubin
(mg/dl)
(
VI-c
VI-f
140.50 ± 7.10 16.96 ± 1.07 3.60 ± 0.29
137.67 ± 5.19 14.01 ± 1.23 3.37 ± 0.17
151.33 ± 2.55 19.68 ± 3.08 3.82 ± 0.13
Control
Relative to Control and data were analyzed by ANOVA followed by Dunnett’s multiple
comparison test for n=6

Fig 1. Compound VI-c; section of liver showing portal triad structures (400x).
Fig 2. Compound VI-f; showing section of liver showing portal triad structures (400x).

Fig 3. Control; section of liver showing portal triad structures (400x).

Scheme: Synthesis of target compounds VI:a-k
O
O
Cl
O
O
OH
NH
OH
(
AcO) O
O
TEA
2
+
NH2
N
O
CH3
CH3
I
II
III
CH3
IV
Ar
O
O
NH2
N
N H H O
N
N
2
4.
2
Ar-CHO
AcOH
H
H
NH
NH
O
O
V
VI:a-k
CH3
CH3
O
OH
OH
Ar =
OH
O
Cl
O
Cl
OH
a-
b-
c-
d-
e-
f-
O
O
O
O
O
O
O
O
N
O
g-
h-
i-
j-
k-

Graphical Abstract
Synthesis, analgesic, anti-inflammatory and anti-ulcerogenic activities of certain novel
Schiff’s bases as fenamate isosteres
Alafeefy et al.
College of Pharmacy, Salman bin Abdulaziz University, Saudi Arabia
Ar
O
O
N
N
O
N
N H H O
2
4. 2
X
N
IV
CH3
CH3
N H H O
2
4.
2
Ar
O
O
NH2
N
N
H
NH
N
H
NH
Ar-CHO
AcOH
O
O
V
VI:a-k
CH3
CH3