Design, synthesis of celecoxib-tolmetin drug hybrids as selective and potent COX-2 inhibitors

Article abstract of DOI:10.1016/j.bioorg.2019.103029

Three novel series of diarylpyrazole 10b-d and triarylpyrazole derivatives 11a-d &12a-d were synthesized through Vilsmier-Haack condition. The structures of prepared compounds were determined through IR, ¹H NMR, ¹³C NMR, Mass spectral and elemental analysis. Docking of the synthesized compounds over COX-2 active site ensure their selectivity. Moreover, the target compounds were evaluated for both in vitro and in vivo inhibitory activity. All compounds were more selective for COX-2 isozyme than COX-1 isozyme and with excellent anti-inflammatory activity. Compounds 11b, 11d and 12b showed the highest anti-inflammatory activity (67.4%, 62.7%, 61.4% respectively), lower ulcerogenic liability (UI = 2.00, 2.75, 3.25 respectively) than indomethacin (UI = 14) and comparable to celecoxib (UI = 1.75) which were confirmed from the histopatholgical study.

Full text of DOI:10.1016/j.bioorg.2019.103029

Accepted Manuscript
Design, synthesis of celecoxib-tolmetin drug hybrids as selective and potent
COX-2 inhibitors
Khaled R.A. Abdellatif, Eman K.A. Abdelall, MadlenB. Labib, Wael A.A.
Fadaly, Taha H. Zidan
PII:
S0045-2068(18)31518-9
https://doi.org/10.1016/j.bioorg.2019.103029
103029
DOI:
Article Number:
Reference:
YBIOO 103029
To appear in:
Bioorganic Chemistry
Received Date:
Revised Date:
Accepted Date:
23 December 2018
1 April 2019
1 June 2019
Please cite this article as: K.R.A. Abdellatif, E.K.A. Abdelall, MadlenB. Labib, W.A.A. Fadaly, T.H. Zidan, Design,
synthesis of celecoxib-tolmetin drug hybrids as selective and potent COX-2 inhibitors, Bioorganic Chemistry
(
2019), doi: https://doi.org/10.1016/j.bioorg.2019.103029
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Design, synthesis of celecoxib-tolmetin drug hybrids as selective and potent COX-2
inhibitors
Khaled R. A. Abdellatif, EmanK.A.Abdelall, MadlenB. Labib, WaelA.A.Fadaly and Taha H.
Zidan
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University,
Beni-Suef, Egypt .
Key words;Tolmetin analogues, triarylpyrazole, COX-2, Celecoxib, anti-inflammatory.
*
Corresponding author
Khaled R. A. Abdellatif, Ph.D.
Tel.: (002)-0100-2535444, 00966-566840201
Fax: (002)-082-2317958
E-mail address: khaled.ahmed@pharm.bsu.edu.eg
1

ABSTRACT
Three novel series of diarylpyrazole10b-d and triarylpyrazole derivatives 11a-d
12a-dwere synthesized through Vilsmier- Haack condition. The structures of prepared
&
1
13
compounds were determined through IR, H NMR, C NMR, Mass spectral and elemental
analysis. Docking of the synthesized compounds over COX-2 active site ensure their
selectivity. Moreover, the target compounds were evaluated for both in vitro and in vivo
inhibitory activity. All compounds were more selective for COX-2 isozyme than COX-1
isozyme and with excellent anti-inflammatory activity. Compounds 11b, 11d and 12b
showed the highest anti-inflammatory activity (67.4%, 62.7%, 61.4% respectively), lower
ulcerogenic liability (UI = 2.00, 2.75, 3.25respectively) than indomethacin (UI = 14) and
comparable to celecoxib (UI = 1.75) which were confirmed from the histopatholgical study.
2

1.Introduction:
Inflammation is a normal protective process of body system towardsvarious infectious
agents and traumatic process[1–4]. These causative agents cause stimulation of various
cyclooxygenase (COX) isozymes to produce inflammatory mediators like
prostaglandins(PGs)[5,6].Suppression of COX isozymes via the use of traditional Non
steroidal anti-inflammatory drugs (NASIDS) leads to reduction of inflammation[7,8]. There
are three different COX isozymes COX-1, COX-2 and COX-3[7]. COX-1 isozyme is
responsible for production of PGs important for some physiological process such as renal
function, gastric homeostasis and platelet aggregation[8–11]. COX-2 isozyme is produced
during inflammatory process to exert PGs inquired in inflammation and pain[12–15].COX-3
isozyme is mainly produced in brain and responsible for anti-pyretic action of drugs which
,
can penetrate blood brain barrier like paracetamol [7] [16]. Non selective COX inhibitors
such as indomethacin (1), tolmetin (2)which are COX isozymes treat inflammation and pain
and characterized by high potency[17–20](Fig.1).But also, they cause kidney dysfunctionand
serious gastrointestinal side effects like bleeding and ulcer[17–20].Tolmetin is a pyrrole
derivative used intreatment of rheumatoid arthritis but not used for a long term due to
undesirable side effects[21,22].Regarding tolmetin, gastric side effects results from non
selective inhibition of COX isozymes and direct effect of carboxylate group on gastric
mucosa[23–25].On the other hand, selective COX-2 inhibitors as coxibs alleviate
inflammation with minimal undesirable gastric side effects[26–28]. Structure features of
coxibs showed that they have common central rings with vicinal diarylsubstituents, in
addition to the aminosulphonyl or methane sulfonylmoities that proved to be amajor definite
of COX -2 selectivity asin celecoxib(3)[29–31].Certain coxibs have been synthesized and
withdrawn from the market due to their cardiovascular side effects as rofecoxib (4) and
valdecoxib (5)[32]. Due to side effects of both traditional NSAIDs & coxibs drugs, until
3

now, the necessity for safe NSAIDs is directly attached to pyrazole ring but separated by
polar methylene hydrazino spacer to increase flexibility of the molecules, increase hydrogen
bond and fitting with receptor. Also, trifluroromethyl group is replaced by phenyl ring
carrying sulfamoyl moiety. Additionally, methyl group of tolyl moiety is replaced by variant
substituents such as methoxy, dimethoxy, ethoxy and isobutyl groups to explore their
electronic effects. Tolmetin pyrrole ring is replaced by pyrazole ring to increase selectivity.
Furthermore, removal of acetic acid group to decrease the gastric side effect. The designed
hybrids have been docked on COX-2 isozyme using molecular operating environment (MOE)
to show the binding interaction between designed molecules and COX-2 active site. Also,
novel compounds have been evaluated for their in vitro, in vivo anti inflammatory activity.
Moreover, the most active in vivo anti inflammatory activities have been evaluated for their
effective dose 50%, ulcerogenic liability and histopathological study.
[
Please insert figure 2 about here]
2
2
. Results and discussion.
.1 Chemistry.
The synthetic route used to synthesize the key intermediates 8a-d, 9a-d, the target
compoundsdiarylpyrazole10a-d and pyrazole4-hydrazino derivatives11a-d and 12a-d is
outlined in Scheme 1.Reaction of hydrazones8a-dapplying Vilsmier-Haack condition yields
4-formyl pyrazole9a-dendowed with 4-dimethyl aminomethylene moiety that was removed
adopting basic condition via the use of NaOH methanolic solution and tetrahydrofuran as a co
solvent to give diarylpyrazoles 10a-d.IR spectra of new pyrazoles 9b-d and 10 b-d displayed
the presence of CHO moiety by two stretching vibration bands of aldehydic C-H at δ 2835–
-
1
-1
870 cm and C=O at δ 1662 – 1678 cm .While, NMR spectral analysis of 9b-d and 10b-d
2
confirmed the formation of pyrazole ring via the presence of signal at δ 9.40 – 9.43 ppm due
4

1
to pyrazole proton at C-5 in H NMR and three peaks at δ 153.3 –154.1, 118.2 – 123.2, 129.9
1
136.1ppm in C NMR indicating C-3, C-4, C-5 of pyrazole ring respectively. Also, the
3
–
1 13
presence of signal at δ9.24 – 10.01 ppm in H NMR and at δ 185.1–185.2 ppm in C NMR
1
of compounds 9b-d & 10b-d confirmed the presence of aldehyde moiety. Additionally, H
NMR of compounds 9b-d displayed the presence of signals due to protecting
3 2
dimethylaminomethylene moiety at 2.93 – 3.17 ppm and 8.26 – 8.27 ppm due to N(CH ) and
1
N=CH respectively. Disappearance of these signals in H NMR of pyrazoles 10b-d and
presence of D
2
O exchangeable signal at 7.49 – 7.53 ppm due to SO
of 4-formyl pyrazoles 10a-d
2
NH
2
confirmed the
either 4-
structure. Condensation
with
hydrazinobenzenesulfonamide hydrochloride (6) or 4-methylsufonylbenzene hydrochloride
gave target compounds 11a-d and 12a-d respectively.IR spectra of triarylpyrazoles11a-
-
d&12a-d showed two characteristic stretching bands at 1311–1276 and 1157–1143 cm
1
2
indicating SO groups. Also, The structure of new compounds 11a-d and 12a-dwas proved
using NMR spectra through the absence of signals due aldehydic protons and presence of
others at δ 7.99 – 8.35 ppm and δ 10.71 – 11.24 ppm due to olefinic (N=CH)and NH protons
1
respectively. Additionally, HNMR spectra of compounds 12a-d showed signals due to
1
3
SO
2 3 2 3
CH in the range of δ 3.10 – 3.11 ppm. While C NMR showed peaks of SO CH at
44.71– 44.85ppm. Finally, mass spectroscopy support structure elucidation by the presence of
+
molecular ion peaks of different derivatives such as, 11a (M , 527), 12b (M , 540),12d (M ,
+
+
552) respectively.
[
Please insert Scheme 1 about here]
5

2
2
.2 Anti-inflammatory activity
.2.1 In vitro anti-inflammatory activity
The target of in vitro testing is to define the ability of synthesized compounds to
inhibit ovine COX-1 and human recombinant COX-2 using an enzyme immunoassay (EIA)
kit. The efficacy of the tested compounds was expressed as the concentration cause 50%
inhibition (IC50). The obtained (IC50) values were listed in Table 1.All tested compounds are
weak inhibitors of COX-1 inhibition (IC50 = 3.74–11.21 μM). Compounds 11a,
11band12dshowed the lowest COX-1 (IC50 = 9.88, 10.32, 11.21 μM) in comparison with
reference drug celecoxib (IC50 = 8.97 μM). In contrast, all compoundsshowed good COX-2
isozyme inhibitory activities (IC50 = 0.023– 0.125 μM) and selectivity index (SI) values (SI =
85.3 – 185.2 μM) comparable to reference drug celecoxib (IC50 = 0.063 μM, SI = 142.2
μM).The bisaminosulfonyl derivatives11a-d showed higher inhibitory activity against COX-
2
1
0
isozyme (IC50= 0.055 - 0.09 μM) range and accordingly higher SI(SI = 128.3, 185.2, 115.3,
53.5 μM respectively) than aminosulphonyl-methylsulphonyl compound 12a-d with (IC50
.037 – 0.125 μM) range and SI (SI = 85.3 - 134.5 μM).The ethoxy11b and isobutyl 11d
=
showed have higher SI values (SI = 185.2, 153.5 μM respectively) than methoxy 11a and
dimethoxy 11c analogues (SI = 128.3, 115.3 μM respectively). Compounds 10c, 10d, 11b,
11d and 12a exhibited the highest COX-2 selectivity (SI = 173.9, 162.6, 185.2, 153.5, 134.5
μM respectively).
[
Please insert Table 1 about here]
6

2.2.2 In vivo anti-inflammatory activity.
The diarylpyrazoles 10b-d and triarylpyrazoles11a-d and 12a-d were evaluated for
the in vivo anti-inflammatory activity (AI). The AI was determined using carrageenan -
induced rat paw edema assay using 100 mg/kg of the tested compounds and the% edema
inhibition after 1 h, 3 h and 6 h of carrageenan injection was expressed in Table 2.Generally,
all compounds showed good AI activity at all time intervals. After 1 h, they showed moderate
AI activity with % inhibition range (AI =10.87 – 63.04%) in comparison with reference drug
celecoxib (AI = 45.65%). After 3 h and 6 h the activity increased gradually. After 6 h,
diarylpyrazoles 10b-d showed moderate (AI = 27.9 – 48.5%) activity compared to celecoxib
(
AI = 72.0%). Within diarylpyrazoles the ethoxy 10b (AI = 37.2%) and isobutyl 10d (AI =
8.5%) derivatives showed higher AI activity than dimethoxy analogues 10c (AI = 27.9%).
Triarylpyrazoles11a-d and 12a-d showed better AI activity in range of (AI = 34.8 - 67.4%) at
h than non vicinal diarylpyrazole 10b-d (AI = 27.9 – 48.8%). The bisaminosulphonyl
4
6
derivatives 11a-d displayed better anti-inflammatory range (AI = 37.2 – 67.4%) than
aminosulphonyl-methylsulphonyl derivatives 12a-d (AI= 39.5 – 61.4%) range in comparison
with reference drug celecoxib (AI = 72.0%).Within bisaminosulphonyl11a-d derivatives, the
ethoxy11b derivative (AI = 67.4%) and isobutyl derivative11d(AI = 62.7%) showed higher
AI activity than methxoy derivative11a (AI = 37.2%) and dimethoxyderivative11c (AI =
34.8%).Compounds 11b, 11dand12b showed good (AI= 67.4, 62.7, 67.4%) in sequence to
standard drug celecoxib (AI = 72.0%).
[
Please insert Table 2 about here]
Moreover, Effective dose (ED50) causing 50% edema inhibition was determined for
the most potent AI agents11b, 11d, 12b and celecoxib. Compounds11b, 11d and12b were
more potent (ED50 = 101, 59, 77 µMol/kg respectively) than celecoxib (ED50 = 123 µMol/kg).
The isobutyl derivative 11d was the most potent compound possessing twice potency of
7

celecoxib ED50 = 123 µMol/kg). Furthermore, the most active compounds were subjected for
determination of ulcer index and histopathlogical study.
[
Please insert Table 3 about here]
2.2.3 Ulcerogenic liability.
The most potent AI compounds 11b, 11d and 12b were subjected to further
examination to determine their ulcerogenic effect (Ulcer Index). The results are expressed in
Table 4. The results revealed that the three compounds were less ulcerogenic (Ulcer Index)
(
UI) = 2.75, 2.00, 3.25 respectively) than indomethacin (UI = 14) and comparable to
celecoxib (UI = 1.75). The isobutyl derivative 11d that showed superior COX-2 selectivity
was the least ulcerogenic compound.
[
Please insert Table 4 about here]
2.2.4. Docking study.
Molecular Docking is one of the most important techniques in drug discovery[33].
The crystal structure of COX-2 isozyme with its selective inhibitor celecoxib was obtained
from PDB (ID.3LN1). Docking calculations were carried out using molecular operating
environment (MOE, version 2008). From docking study, it was observed that celecoxib
interact with COX-2 active site through sulfamoyl moiety NH- to form hydrogen bonds with
amino acid ser339, Glu178, Leu338. While the most active compounds 11b, 11d and 12b
showed multiple bond formation with receptor site. The triarylpyrazole derivative 11b
interacts with COX-2 receptor through formation of hydrogen bond with Glu510, Tyr371
through sulfamoyl moiety N-H. Also, it form H-bond and hydrophobic interaction with
Arg106 indicate the observed potent activity. Moreover, triarylpyrazole11d forms multiple
hydrogen bond through both aminosulphamoyl moieties through both nitrogen and oxygen
atoms which may potentiate the high potency due to presence of two sulfamoyl moieties.
8

Furthermore, triaryl pyrazole 12b compounds forms hydrogen bond through SO
2
2
NH with
Leu338, Gln178, His175 and another hydrogen bond with Leu82 through SO
atom.
2
CH oxygen
3
[
[
Please insert Fig.3 about here]
Please insert Table 5 about here]
2.2.5. Histopathologicalgical examination results.
Histopathological examination was carried out to explore the effect of the most potent
compounds (11b, 11d and 12b), celecoxib, indomethacin and control group.
Control group showed normal histological structure of stomach (fundic region) with intact
mucosahaving normal glandular epithelium, submucosa, muscular coat and serosal
membrane (Fig.4.Ia and Ib for control). In contrast, indomethacin group showed multiple
degenerative changes inculding necrosis in some areas and ulceration in mucosal layer (stars)
and submucosal edema with inflammatory cells infiltration like leucocytes, blood vessels
were dilated and coagulative necrosis of muscular layer were found.(Fig.4. IIa, IIbfor
indomethacin). For Celecoxib treated group showed apparent normal histological structure of
stomach with intactglandular mucosa, submucosa, muscular coat and serosal membrane.
(
Fig.4.IIIa and IIIb for celecoxib).Furthermore, Compound 11btreated group have an intact
mucosal epithelium with sever inflammatory cells infiltrations indeep mucosal and
submucosal tissue.(Fig.4. IVa, IVb for 11b). Additionally, compound11dexamination group
has apparent intact mucosal epithelium with congested mucosalCapillaries, submucosal
inflammatory cells infiltrations and congested blood vessels. (Fig.4.Va and Vb for 11d).
Furthermore, compound12b has apparent normal histological structure of mucosal,
submucosal,muscular and serosal layer without detected alteration.(Fig.4.VIa and VIb for
12b).
[
Please insert Figure 4 about here]
9

3. Conculsion:
Three novel diarylpyrazoles and eight novel triarylpyrazoles were synthesized and
evaluated for in vitro and in vivo anti-inflammatory activity. The docking study assured
COX-2 selectivity of all synthesized compounds. The in vitro testing authenticate that
allcompounds are more selective forCOX-2 isozyme than COX-1 isozyme. Also, the in vivo
study corroborate that test compounds have good AI activity. Moreover, compounds 11b,
11d and 12b are more potent than celecoxib and have approximate ulcerogenic liability to
celecoxib as obtained from the histopathological examination.The bisaminosulphonyl
compounds showed better anti-inflammatory activity than aminosulfonyl-methylsulfonyl
compounds and comparable to celecoxib.
4
4
. Experimental
.1 Chemistry
All Melting points were determined using aThomas-Hoover capillary apparatus and
were uncorrected. Infrared (IR) spectra were recorded as films on KBr plates using Nicolet
1
13
5
50 seriesII Magna FT-IR spectrometer. H NMR, C NMR were performed on a
BurkerAvence III 400 MHz Spectrophotometer, Faculty of Pharmacy, Beni-Suef University,
Egypt in CDCl or DMSO-d , where J (coupling constant) values are estimated in Hertz (Hz).
3
6
Microanalyses for C, H and N were carried out on Perkin–Elmer 2400 analyzer (Perkin–
Elmer, Norwalk, CT, USA) at the regional center for mycology and Bio-technology, Al-azhar
University, Egypt. All data were within ± 0.4% of the theoretical values and were corrected.
General procedure for synthesis of hydrazones8a-d:
To a solution of the appropriate acetophenones 6a-d (0.04 mol) in absolute ethanol
(
20 mL), p-sulfamoyl phenyl hydrazine hydrochloride (7) (8.9gm, 0.04 mol) and glacial
10

acetic acid (1 mL) were added. The reaction mixture was heated under reflux for 12 h. The
solidprecipitated was filtered, washed with ethanol, dried and recrystalized to give 8a[34] and
8b-d compounds.
1-[4-(Ethoxyphenyl)ethylidene]-2-(4-sulfamoylphenyl)hydrazine (8b): Yield (2.29gm, 69%);
o
white solid; mp 220 - 222 C;IR (KBr): 3318, 3195 (NH
2
), 3062 (C H aromatic), 2975 (C–H
) cm . HNMR (DMSO-d , 400 MHz, δ ppm): 1.34
), 2.26 (s, 3H, CH ), 4.04 (q, J = 6.8 Hz, 2H, CH CH ), 6.93 (d, J
8.0 Hz, 2H, sulfamoylphenyl H-2, H-6),7.06 (s, 2H, SO NH , D O exchangeable), 7.30 (d, J
8.0 Hz, 2H, ethoxyphenyl H-3,H-5), 7.66 (d, J = 8.0 Hz, 2H,ethoxyphenyl H-2, H-6), 7.75
-1 1
aliphatic), 1599 (C=N), 1312, 1145 (SO
t,J = 6.8 Hz, 3H, CH CH
2
6
(
2
3
3
2
3
=
=
2
2
2
1
O exchngeable). C NMR
3
(
(
d, J = 8.0 Hz, 2H, sulfamoylphenylH-3, H-5), 9.60 (s, 1H, NH, D
2
DMSO-d ,100MHz, δ ppm): 13.5 (CH CH ), 15.0 (CH ), 63.5 (CH
6
2
3
3
2
CH ), 112.2 (CH,
3
ethoxyphenyl C-3, C-5), 114.6 (CH, sulfamoylphenyl C-2, C-6), 127.3 (CH, sulfamoylphenyl
C-3, C-5), 127.7 (CH, ethoxyphenyl C-2, C-6), 131.6 (C, ethoxyphenyl C-1), 133.6 (C,
sulfamoylphenyl C-4), 143.8 (C, sulfamoylphenyl C-1), 149.2 (C, ethoxyphenyl C-4), 159.1
+
C, C=N). MS m/z (ES ), 334 (M +1, 20%), 333 (M , 100%), Anal. Calcd. for:
+.
+.
(
16 19 3 3
C H N O S;C, 57.64; H, 5.74; N, 12.60; Found; C, 57.43; H, 5.83; N, 12.87.
1
-[(3,4-Dimethoxyphenyl)ethylidene]-2-(4-sulfamophenyl)hydrazine (8c):Yield (2.51gm,
o
7
2%); white solid; mp 208 - 210 C; ;IR (KBr): 3323, 3204 (NH
2
), 3082 (C H aromatic),
) cm . HNMR (DMSO-d , 400 MHz, δ
), 3.83 (s, 3H, OCH ), 6.96 (d, J = 8.4 Hz, 1H,
dimethoxyphenyl H-5), 7.07 (s, 2H, SO NH , D O exchangeable), 7.31 (m, 3H,
dimethoxyphenyl H-6 & sulfamoylphenyl H-2, H-6), 7.45 (d, J = 2.0 Hz,
-1 1
2
963 (C–H aliphatic), 1598 (C=N), 1318, 1143 (SO
), 3.78 (s, 3H, OCH
2
6
ppm): 2.27 (s, 3H, CH
3
3
3
2
2
2
1
H,dimethoxyphenylH-2), 7.67 (d, J = 8.4 Hz, 2H, sulfamoylphenyl H-3, H-5), 9.62 (s, 1H,
1
3
O exchangeable). C NMR (DMSO-d
NH, D
2
6 3 3
100MHz, δ, ppm):13.6 (CH ), 55.94 (OCH ),
5
5.98 (OCH ), 109.2 (CH, dimethoxyphenyl C-2), 111.7 (CH, dimethoxyphenyl C-5), 112.3
3
11

(
CH, sulfamoylphenyl C-2, C-6), 119.0 (CH, dimethoxyphenyl C-6), 127.7 (CH,
sulfamoylphenyl C-3, C-5), 132.1 (C, dimethoxyphenyl C-1), 133.7 (C, sulfamoylphenyl C-
), 143.8 (C, sulfamoylphenyl C-1), 149.0 (C, dimethoxyphenyl C-3), 149.1 (C,
4
+
+
dimethoxyphenyl C-4), 149.7 (C, C=N). MS m/z (ES ) 350 (M+1, 21%), 349 (M , 100%).
Anal. Calcd. for: C16 S;C, 55.00; H, 5.48; N, 12.03; Found; C, 54.89; H, 5.64; N,
19 3 4
H N O
12.25
1-[(4-Isobutylphenyl)ethylidene]-2-(4-sulfamoylphenyl)hydrazine (8d): Yield (2.58gm,75%);
o
white solid; mp 214 - 216 C; ;IR (KBr): 3326, 3225 (NH
2
), 3098 (C H aromatic), 2954 (C–
-
1 1
H aliphatic), 1597 (C=N), 1316, 1145, (SO
ppm): 0.87 (d, J = 6.4 Hz, 6H, 2CH ,CH CH(CH
s,3H, CH ), 2.47 (d, J = 6.8 Hz, 2H,CH CH(CH
exchangeable), 7.18 (d, J = 7.6 Hz, 2H, sulfamoylphenylH-2, H-6), 7.32 (d, J = 8.4 Hz,
2
NH
2
) cm . HNMR (DMSO-d
), 1.84 (m, 1H,CH CH(CH
), 7.08 (s, 2H, SO NH
6
, 400 MHz, δ
), 2.27
2
, D O
3
2
3
)
2
2
3 2
)
(
3
2
3
)
2
2
2
2
H,isobutylphenylH-3, H-5), 7.67 (d, J = 8.4 Hz, 2H,isobutylphenylH-2, H-6), 7.73 (d, J =7.6
1
3
Hz, 2H,sulfamoylphenyl H-3, H-5), 9.68 (s, 1H, NH, D
2
O exchangeable). C NMR (DMSO-
), 30.0 (CH CH(CH ), 44.7
), 112.3 (CH, sulfamoylphenylC-2, C-6), 125.7 (CH, sulfamoylphenyl C-3, C-
), 127.7 (CH, isobutylphenyl C-2, C-6), 129.4 (CH, isobutylphenylC-3, C-5), 133.8 (C,
sulfamoylphenyl C-4), 136.8 (C, isobutylphenyl C-1), 141.6 (C, isobutylphenyl C-4), 143.8
d
6
100MHz, δ ppm): 13.6 (CH
3
), 22.5 (CH
2
CH(CH
3
)
2
2
3 2
)
(
CH CH(CH
2
3 2
)
5
+
+
(
C, sulfamoylphenylC-1), 149.1 (C, C=N).MS m/z (ES ), 346 (M+1, 24%), 345 (M , 100%),
Anal. Calcd. for: C18 S;C, 62.58; H, 6.71; N, 12.16; Found; C, 62.75; H, 6.89; N,
2.40
23 3 2
H N O
1
General procedure for synthesis of pyrazole-4-carbaldehydes9a-d:
Phosphorusoxycholride (9gm, 0.06mol) was added dropwise to awell stirred ice-
cooled solution of the appropriate hydrazone8a-d(0.02mol) in dry DMF (15 mL). After
3
complete addition ofPOCl , the mixture was allowed to attain room temperature and then
12

heated under reflux to 60-70 °C for 12 h. The resulting mixture was poured onto crushed ice,
neutralizedwith 10% sodium carbonate solution. The precipitate obtained was filtered,
washed withwater and recrystalized from aqueous ethanol to give compounds 9a[34] and 9b-
d.
3-(4-Ethoxyphenyl)-1-(4-N-dimethylamino-methylenebenzenesulfonamide)-1H-pyrazole-4-
o
carbaldehyde (9b): Yield (3.32gm, 78%);pale yellow solid; mp 170 -172 C;IR (KBr: 3078
(
C H aromatic), 2978 (C-H aliphatic), 2870 (C-H aldehyde),1678 (C=O), 1577 (C=N), 1342,
-
1 1
1
2
149 (SO
2
) cm . HNMR (DMSO-d
6
, 400 MHz, δ ppm): 1.36 (t, J = 6.8 Hz, 3H, CH
2 3
CH ),
.93 (s, 3H, NCH
3
), 3.17 (s, 3H, NCH
3
), 4.11 (q, J = 6.8 Hz, 2H, CH CH ), 7.06 (d, J = 8.4
2
3
Hz, 2H, ethoxyphenyl H-3, H-5), 7.90 (d, J = 8.4 Hz, 2H, ethoxyphenyl H-2, H-6), 7.95 (d, J
8.0 Hz, 2H ,sulfamoylphenyl H-2, H-6), 8.15 (d, J = 8.0 Hz, 2H, sulfamoylphenyl H-3, H-
=
1
), 8.27 (s, 1H, N=CH), 9.41 (s, 1H, pyrazole H-5), 9.99 (s, 1H, CHO). C NMR (DMSO-d
3
5
6
1
00MHz, δ ppm): 15.0 (CH CH ), 35.5 (NCH ), 41.4 (NCH ), 63.6 (CH CH ), 114.9 (CH,
3
2
3
3
3
2
ethoxyphenylC-3, C-5), 119.7 (CH, sulfamoylphenyl C-2, C-6), 122.8 (C, ethoxyphenyl C-1),
1
3
23.6 (C, pyrazole C-4), 128.1 (CH, ethoxyphenyl C-2, C-6), 130.5 (CH, sulfamoylphenyl C-
, C-5,), 136.1 (CH, pyrazole C-5), 141.1 (C, sulfamoylphenyl C-4), 142.1 (C,
sulfamoylphenyl C-1), 153.3 (C, pyrazole C-3), 159.9 (C, ethoxyphenyl C-4), 160.1 (N=CH),
+
+
85.1 (CHO).MS m/z (ES ) 329 (M+3, 9%), 426 (M , 3%), 352 (100%). Anal. Calcd. for:
1
21 22 4 4
C H N O S; C, 59.14, H, 5.20, N, 13.14; Found; C, 59.39; H, 5.37; N, 13.50.
3
-(3,4-Dimethoxyphenyl)-1-(4-N-dimethylamino-methylenebenzenesulfonamide)-1H-
o
pyrazole-4-carbaldehyde (9c):Yield (3.1gm, 69%);brown solid; mp 285 –287 C;IR (KBr):
3
1
3
074 (C H aromatic), 2935 (C–H aliphatic), 2835 (C-H aldehyde), 1662(C=O), 1573 (C=N),
-
1
1
)cm . HNMR (DMSO-d
346, 1153, (SO
2
6
, 400 MHz, δ ppm): 2.93 (s, 3H, NCH
3
), 3.16 (s,
H, NCH ), 3.82 (s, 3H, OCH
3
3
), 3.84 (s, 3H, OCH
3
), 7.08 (d, J = 8.4 Hz,1H,
dimethoxyphenyl H-5), 7.53 (dd, J = 8.4, 2.0 Hz, 1H, dimethoxyphenyl H-6), 7.56 (d, J = 2.0
13

Hz, 1H, dimethoxyphenyl H-2), 7.95 (d, J = 8.4 Hz, 2H, sulfamoylphenyl H-2, H-6), 8.15 (d,
J = 8.4 Hz, 2H, sulfamoylphenyl H-3,H-5), 8.26 (s, 1H, N=CH),9.42 (s, 1H, pyrazole H-5),
1
3
1
0.00 (s, 1H, CHO). C NMR (DMSO-d
OCH ), 56.0 (OCH ), 112.0 (CH, dimethoxyphenyl C-2), 112.5 (CH, dimethoxyphenyl C-5),
19.8 (CH, dimethoxyphenyl C-6), 122.0 (CH, sulfamoylphenyl C-2, C-6), 123.0 (C,
6 3 3
100MHz, δ ppm):35.3 (NCH ), 40.5 (NCH ), 56.0
(
3
3
1
pyrazole C-4), 123.8 (C, dimethoxyphenyl C-1), 128.1 (CH, sulfamoylphenyl C-3, C-
5
4
3
),136.3 (CH, pyrazole C-5), 141.0(C, sulfamoylphenyl C-4), 142.1(C, sulfamoylphenyl C-
), 149.0 (C, dimethoxyphenyl C-3), 150.3(C, dimethoxyphenyl C-4), 153.4 (C, pyrazole C-
+
+.
), 160.3 (N=CH), 185.2 (CHO).MS m/z (ES ), M+1 (443, 23%),442 (M , 100%). Anal.
S: C, 57.00, H, 5.01, N, 12.66; Found; C, 56.58; H, 5.13; N, 13.02.
-(4-Isobutylphenyl)-1-(4-N-dimethylamino-methylenebenzenesulfonamide)-1H-pyrazole-4-
22 4 5
Calcd. for: C21H N O
3
o
carbaldehyde(9d):Yield(2.4gm, 55%); light yellow solid; mp 170 -172 C;IR (KBr): 3062 (C
H aromatic), 2954 (C–H aliphatic), 2870 (C-H aldehyde), 1678 (C=O), 1597 (C=N), 1338,
-
1
1
1
6
2
7
145 (SO
H,CH CH(CH
.93 (s, 3H, NCH
.85 (d, J = 8.0 Hz, 2H, isobutylphenyl H-2, H-6), 7.95 (d, J = 8.4 Hz, 2H, sulfamoylphenyl
2
) cm . HNMR (DMSO-d
), 1.91 (m, 1H, CH CH(CH
), 3.17 (s, 3H, NCH ), 7.30 (d, J = 8.0 Hz, 2H, isobutylphenylH-3, H-5),
6
, 400 MHz, δ ppm): 0.90 (d, J = 6.4 Hz,
2
3
)
2
2
3
)
2
), 2.53 (d, J = 6.8 Hz, 2H, CH CH(CH ),
2
3 2
)
3
3
H-2, H-6), 8.16 (d, J = 8.4 Hz, 2H, sulfamoylphenyl H-3, H-5), 8.27(s, 1H, N=CH), 9.44 (s,
1
3
1
H, pyrazole H-5), 10.00 (s, 1H, CHO). C NMR (DMSO-d
CH CH(CH ), 30.0 (CH CH(CH ), 35.6 (NCH ), 41.4 (NCH
19.8 (CH, sulfamoylphenylC-2, C-6), 123.0 (C, Pyrazole C-4), 128.1 (CH, isobutylphenyl
6
100MHz, δ ppm): 22.6
(
2
3
)
2
2
3
)
2
3
3
), 44.8 (CH CH(CH ),
2
3 2
)
1
C-2, C-6), 128.9 (C, isobutylphenyl C-1), 128.9 (CH, sulfamoylphenyl C-3, C-5), 129.6 (CH,
isobutylphenyl, C-3, C-5), 135.8 (CH, pyrazole C-5), 141.1 (C, isobutylphenyl C-4), 142.1
(
C, sulfamoylphenyl C-4), 143.1 (C, sulfamoylphenyl C-1), 153.6 (C, pyrazole C-3), 160.3 (
14

+
N=CH), 185.1 (CHO). MS m/z (ES ) 439 (M+1, 26%), 438 (M , 1%), 348 (100%) Anal.
+
26 4 3
Calcd. for: C23H N O S: C, 62.99; H, 5.98; N, 12.78; Found; C, 62.64; H, 6.04; N, 12.85.
General procedure for synthesis of diarylpyrazole10a-d.
To asolution of the appropriate pyrazole 4-carbaldehyde9a-d (0.01
mol)intetrahydrofuran (50 mL),methanolic solution of sodium hydroxide (0.4gm, 0.01 mol,
5
mL) was added and the reaction mixture wasstirred at room temperature for 24h. The
mixture was then concentrated and neutralized by drop wise addition of concHCl.The formed
precipitated was filtered, dried andcrystallized from aqueous ethanol to give compound
10a[34] and 10b-d.
3-(4-Ethoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-4-carbaldehyde
(10b):Yield
o
2.52gm, 68%); pale yellow solid; mp 135-137 C;IR (KBr): 3329, 3255 (NH
(
2
), 3078 (C-H
aromatic), 2978 (C-H aliphatic), 2881 (C-H aldehyde), 1670 (C=O), 1577 (C=N), 1311,
-
1 1
1
4
2
161, (SO
.11 (q, J = 6.0 Hz, 2H, CH
H, SO NH , D O exchangeable), 7.91 (d, J = 7.6 Hz, 2H, ethoxyphenyl H-2, H-6), 8.00(d, J
8.0 Hz, 2H, sulfamoylphenylH-2, H-6), 8.20 (d, J = 8.0 Hz, 2H, sulfamoylphenyl H-3, H-
2
) cm . HNMR (DMSO-d
6 2 3
, 400 MHz, δ ppm): 1.36 (t, J = 6.0 Hz, 3H, CH CH ),
2
CH ), 7.06 (d, J = 7.6 Hz, 2H, ethoxyphenylH-3, H-5), 7.49 (s,
3
2
2
2
=
1
3
5
), 9.42 (s, pyrazole H-5), 10.00(s, 1H, CHO). C NMR (DMSO-d
6
100MHz, δ ppm): 15.0
(
CH CH ), 63.6 (CH CH ), 114.9 (CH, ethoxyphenyl C-3, C-5), 119.7 (CH, sulfamoylphenyl
2
2
3
3
C-2, C-6), 122.8 (C, pyrazole C-4), 123.6 (C, ethoxyphenyl C-1), 127.8 (CH,
sulfamoylphenyl C-3, C-5), 130.5 (CH, ethoxyphenyl C-2, C-6), 136.1 (CH, pyrazole C-5),
1
1
41.1 (C, sulfamoylphenyl C-4), 143.1 (C, sulfamoylphenyl C-1), 153.3 (C, pyrazole C-3),
+
59.9 (C, ethoxyphenyl C-4), 185.2 (CH, CHO).MS m/z (ES ) 373 (M+2, 100%). (M ).
+
17 3 4
Anal. Calcd. for: C18H N O
S;C, 58.21, H, 4.61, N, 11.31; Found; C, 58.47; H, 4.79; N,
11.46.
3-(3,4-Dimethoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-4-carbaldehyde(10c):
15

o
Yield (2.9gm, 75%); brown solid; mp 275 - 277 C;IR (KBr): 3340, 3244 (NH
2
), 3082 (C H
aromatic), 2935 (C–H aliphatic), 2831 (C-H aldehyde), 1674 (C=O), 1597 (C=N), 1330,
-
1 1
1
161(SO
Hz, 1H, dimethoxyphenyl H-5), 7.29 (d, J = 7.6 Hz, 1H, dimethoxyphenyl H-6), 7.43 (s, 1H,
dimethoxyphenyl H-2), 7.51 (s, 2H, SO NH , D O exchangeable), 8.00 (d, J = 7.6 Hz, 2H,
sulfamoylphenyl H-2, H-6), 8.22 (d, J = 8.0 Hz, 2H, sulfamoylphenyl H-3, H-5), 8.70 (s, 1H,
2 6 3
) cm . HNMR (DMSO-d , 400 MHz, δ ppm): 3.85 (s, 6H, 2OCH ), 7.11 (d, J = 8.0
2
2
2
1
3
pyrazole H-5), 9.24 (s, 1H, CHO). C NMR (DMSO-d
OCH ), 112.2 (CH, dimethoxyphenyl C-2), 112.6 (CH, dimethoxyphenyl C-5), 118.2 (C,
Pyrazole C-4), 119.3 (CH, sulfamoylphenyl C-2, C-6), 121.8 (CH, dimethoxyphenyl C-
),124.5 (C, dimethoxyphenyl C-1), 127.8 (CH, sulfamoylphenyl C-3, C-5), 129.9 (CH,
6 3
100MHz, δ ppm): 55.9 (OCH ), 56.0
(
3
6
pyrazole C-5), 141.4 (C, sulfamoylphenyl C-4), 142.6 (C, sulfamoylphenyl C-1), 149.2 (C,
dimethoxyphenyl C-4), 151.1 (C, dimethoxyphenyl C-3), 153.7 (C, pyrazole C-3) 154.1
+
CHO).MS m/z (ES ), 389 (M+2, 4%), 387 (M , 2%), 93 (100%). Anal. Calcd. for:
+
(
18 17 3 5
C H N O S: C, 55.80, H, 4.40, N, 10.85; Found; C, 55.62; H, 4.69; N, 10.98.
3
-(4-Isobutylphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-4-carbaldehyde
(10d):Yield
o
2.83gm, 74%); pale yellow solid; mp 140-142 C; IR (KBr): 3356, 3259 (NH
(
2
), 3078 (C H
aromatic), 2954 (C–H aliphatic), 2846 (C-H aldehyde),1678 (C=O), 1597 (C=N), 1338, 1161,
-
1 1
(
SO
.89 (m, 1H CH
isobutylphenylH-3, H-5), 7.53 (s, 2H, SO
isobutylphenylH-2, H-6), 8.02 (d, J = 8.8 Hz, 2H, sulfamoylphenyl H-2, H-6), 8.21 (d, J =8.8
2
) cm . HNMR (DMSO-d
CH(CH ), 2.51 (d, J = 7.2 Hz, 2H, CH
NH , D O exchangeable), 7.86 (d, J = 8.0 Hz, 2H,
6
, 400 MHz, δ ppm): 0.88 (d, J = 6.8 Hz, 6H, CH
2 3 2
CH(CH ) ),
1
2
3
)
2
2
CH(CH ), 7.30 (d, J = 8.0Hz, 2H,
3 2
)
2
2
2
1
Hz, 2H, sulfamoylphenylH-3, H-5), 9.45 (s, 1H, pyrazole H-5), 10.01 (s, 1H, CHO). C NMR
3
(
(
DMSO-d
6
, 100MHz, δ, ppm): 22.6 (CH
2 3 2 2 3 2
CH(CH ) ), 30.0 (CH CH(CH ) ), 44.8
CH CH(CH )
2
3 2
), 119.7 (CH, sulfamoylphenyl C-2, C-6), 123.0 (C, Pyrazole C-4), 127.8 (CH,
isobutylphenyl C-2, C-6), 128.9 (C, isobutylphenylC-1), 128.9(CH, sulfamoylphenylC-3, C-
16

5), 129.6 (CH, isobutylphenyl C-3, C-5), 135.9 (CH, pyrazole C-5), 141.1 (C,
sulfamoylphenyl C-4), 143.0 (C, isobutylphenyl C-4), 143.2 (C, sulfamoylphenyl C-1), 153.6
+
C, pyrazole C-3), 185.1 (CH, CHO).MS m/z (ES ) 384 (M+1, 10%), 383 (M , 20%), 340
+
(
(
21 3 3
100%). Anal. Calcd. for: C20H N O S: C, 62.64; H, 5.52; N,
General procedure for synthesis of triarylpyrazoles 11a-d and 12a-d.
To asolution of 3-(substituted phenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-4-
carbaldehydes10a-d (0.01 mol) in absolute ethanol (15mL), p-sulfamoylphenylhydrazine
hydrochloride (7), (0.01mol, 2.23 gm) or p-methylsulfonylphenylhydrazine hydrochloride
(
0.01mol, 2.24gm) was added. The reaction mixture was heated under reflux for 24h.The
formed precipitated was filtered, dried and recrystalized from ethanol to give
triarylpyrazoles11a-d or 12a-d respectively.
1-[3-(4-Methoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-4-yl-methylene]-2-(4-
o
sulfamoylphenyl)hydrazine (11a);Yield (3.78gm, 72%); pale yellow solid; mp 206 -208 C
;
IR (KBr): 3363, 3278 (NH
2
), 3116 (C H aromatic), 2974 (C–H aliphatic), 1597 (C=N),
) cm . HNMR (DMSO-d , 400 MHz, δ ppm):3.84 (s, 3H, OCH ), 7.01 (s,
O exchangeable), 7.07-7.12 (m, 4H, sulfamoylphenylhydrazine H-2, H-
&methoxyphenyl H-3, H-5), 7.45 (s, 2H, SO NH , D O exchangeable), 7.60 (d, J = 8.0 Hz,
H, methoxyphenyl H-2, H-6), 7.70 (d, J = 7.6 Hz, 2H, sulfamoylphenyl H-2, H-6), 7.93 (d, J
7.6 Hz, 2H, sulfamoylphenylhydrazine H-3, H-5), 8.35 (s, 1H, N=CH), 8.20 (d, J = 7.6 Hz,
H, sulfamoylphenyl H-3, H-5), 9.06 (s, 1H, pyrazole H-5), 10.71 (s, 1H, NH, D
-1 1
1
2
6
2
311, 1149 (SO
2
6
3
H, SO NH , D
2
2
2
2
2
2
=
2
2
O
1
exchangeable). C NMR (DMSO-d
3
6
3
100MHz, δ ppm): 55.7 (OCH ), 111.3 (CH,
methoxyphenyl C-3, C-5), 114.5 (CH, sulfamoylphenylhydrazine C-2, C-6), 118.81 (CH,
sulfamoylphenyl C-2, C-6), 118.89 (C, pyrazole C-4), 124.9 (C, methoxyphenyl C-1), 127.3
(
CH, pyrazole C-5), 127.7 (CH, sulfamoylphenyl C-3, C-5), 127.8 (CH,
sulfamoylphenylhydrazineC-3, C-5), 130.4 (CH, methoxyphenyl C-2, C-6), 132.0 (N=CH),
17

133.6 (C, sulfamoylphenylhydrazine C-4), 141.6 (C, sulfamoylphenylC-4), 142.0 (C,
sulfamoylphenyl C-1), 148.2 (C, sulfamoylphenylhydrazineC-1), 151.8 (C, pyrazole C-3),
+
60.1 (C, methoxyphenyl C-4).MS m/z (ES ) 526, 373 (100%). Anal. Calcd. For
1
23 22 6 5 2
C H N O S C, 52.46; H, 4.21; N, 15.96;Found; C, 52.79; H, 4.08; N, 16.28.
1-[3-(4-Ethoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-4-yl-methylene]-2-(4-
sulfamoylphenyl)hydrazine (11b);Yield (4.05gm, 75%); pale yellow solid; mp 220 - 222
o
C;IR (KBr): 3371, 3282 (NH
2
), 3074 (C-H aromatic), 2935 (C–H aliphatic), 1597 (C=N),
) cm . HNMR (DMSO-d , 400 MHz, δ ppm): 1.37 (t, J = 6.8 Hz, 3H,
), 4.11 (q, J = 6.8 Hz, 2H, CH CH ), 7.07-7.14 (m, 6H, sulfamoylphenylhydrazine
H-2, H-6, ethoxyphenyl H-3, H-5 & SO NH , D O exchangeable), 7.48 (s, 2H, SO NH ),
.67 (d, J = 8.0 Hz, 2H, ethoxyphenyl H-2, H-6), 7.71 (d, J = 8.0 Hz, 2H, sulfamoylphenyl
H-2, H-6), 7.98 (d, J = 8.0 Hz, 2H,sulfamoylphenylhydrazine H-3, H-5), 8.10 (s, 1H, N=CH),
-1 1
1
311, 1149 (SO
2
NH
2
6
CH CH
2
3
2
3
2
2
2
2
2
7
8.19 (d, J = 8.0 Hz, 2H, sulfamoylphenylH-3, H-5), 9.05 (s, 1H, pyrazole H-5), 10.97 (s, 1H,
1
3
2 6 2 3 2 3
NH, D O). C NMR (DMSO-d , 100MHz, δ, ppm): 15.1 (CH CH ), 63.6 (CH CH ), 111.3
(
CH, ethoxyphenyl C-3, C-5), 114.9 (CH, sulfamoylphenylhydrazine C-2, C-6), 118.7 (CH,
sulfamoylphenyl C-2, C-6), 118.9 (C, pyrazole C-4), 124.8 (C, ethoxyphenyl C-1), 127.4
CH, pyrazole C-5), 127.8 (CH, sulfamoylphenyl C-3, C-5), 127.8 (CH, ethoxyphenyl C-2,
(
C-6), 130.1 (CH, sulfamoylphenylhydrazine C-3, C-5), 132.0 (N=CH), 133.4 (C,
sulfamoylphenylhydrazine C-4), 141.6 (C, sulfamoylphenyl C-4), 141.9 (C, sulfamoylphenyl
C-1), 148.2 (C, sulfamoylphenylhydrazine C-1), 151.8 (C, pyrazole C-3), 159.3 (C,
24 6 5 2
ethoxyphenyl C-4).Anal. Calcd. For C24H N O S : C, 53.32; H, 4.47; N, 15.55; Found; C,
53.64; H, 4.59; N, 15.90.
1-[3-(3,4-Dimethoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-4-yl-methylene]-2-(4-
o
sulfamoylphenyl)hydrazine (11c): Yield (3.94gm, 71%); brown solid; mp 213 -215 C ;IR
18

(
KBr): 3294, 3224 (NH
2
), 3082 (C H aromatic), 2931 (C-H aliphatic), 1593 (C=N),
) cm . HNMR (DMSO-d , 400 MHz, δppm): 3.86 (s, 3H, OCH ), 3.86 (s,
), 7.08 (s, 2H, SO NH exchangeable), 7.11-7.13 (m, 3H,
-1 1
1
3
311,1153, (SO
H, OCH
2
6
3
3
2
2
,
2
D O
sulfamoylphenylhydrazine H-2, H-6 & dimethoxyphenyl H-5), 7.27 (d, J = 8.4 Hz, 1H,
2
dimethoxyphenyl H-6) 7.31 (s, 1H, dimethoxyphenyl H-2), 7.46 (s, 2H, SO NH , D O
2
2
exchangeable), 7.66 (d, J = 8.4 Hz, 2H, sulfamoylpheny H-2, H-6), 7.98 (d, J = 8.8 Hz, 2H,
sulfamoylphenylhydrazine H-3, H-5), 8.03 (s, 1H, N=CH), 8.21 (d, J = 8.8 Hz, 2H,
2
sulfamoylphenyl H-3, H-5), 9.06 (s, 1H, pyrazole H-3), 10.71 (s, 1H, NH, D O
1
exchangeable). C NMR (DMSO-d
3
6
100MHz, δ, ppm): 56.1 (2OCH
(CH, dimethoxyphenyl C-5),
3
), 111.6 (CH,
112.4 (CH,
dimethoxyphenyl C-2), 112.2
sulfamoylphenylhydrazine C-2, C-6), 118.8 (CH, sulfamoylphenyl C-2, C-6), 119.2 (C,
pyrazole C-4), 121.5 (CH, dimethoxyphenyl C-6), 125.1 (C , dimethoxyphenyl C-1), 127.2
(
CH, pyrazole C-5), 127.7 (CH, sulfamoylphenyl C-3, C-5), 127.8 (CH,
sulfamoylphenylhydrazine C-3, C-5), 132.1 (N=CH), 133.6 (C, sulfamoylphenyhydrazine C-
), 141.6 (C, sulfamoylphenyl C-4), 142.0 (C, sulfamoylphenyl C-1), 148.2 (C,
sulfamoylphenylhydrazine C-1), 149.2 (C, dimethoxyphenyl C-4), 149,8(C, dimethoxyphenyl
4
+
+
C-3 ), 152.0 (C, pyrazole, C-3) MS m/z (ES ) 559 (M+2, 4%), 557 (M , 2%), 417 (100%).
24 6 6 2
Anal. Calcd. For: C24H N O S : C, 51.79; H, 4.35; N, 15.10; Found; C, 51.92; H, 4.43; N,
1
4.89.
1
-[3-(4-Isobutylphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-4-yl-methylene]-2-(4-
sulfamoylphenyl )hydrazine (11d) ; Yield (4.02gm, 73%); light yellow solid; mp 260 - 262
o
C;IR (KBr): 3363, 3267 (NH
2
), 3074 (C H aromatic), 2924 (C–H aliphatic), 1597 (C=N),
) cm . HNMR (DMSO-d , 400 MHz, δ, ppm): 0.92 (d, J = 6.4 Hz, , 6H,
), 1.90 (m, 1H, CH CH(CH ), 2.54 (d, J = 6.4 Hz, 2H, CH CH(CH ), 7.07
NH , D O exchangeable), 7.10 (d, J = 8.8 Hz, 2H, sulfamoylphenylhydrazineH-2,
-1 1
1
311, 1149 (SO
CH CH(CH
s, 2H, SO
2
6
2
3
)
2
2
3
)
2
2
3 2
)
(
2
2
2
19

H-6 ), 7.33 (d, J = 7.6 Hz, 2H, isobutylphenyl H-3, H-5), 7.45 (s, 2H, SO
exchangeable), 7.68 - 7.73 (m, 2H, isobutylphenyl H-2, H-6 & sulfamoylphenyl H-2, H-6),
.98 (d, J = 8.4 Hz, 2H, sulfamoylphenylhydrazineH-3, H-5), 8.05 (s, 1H, N=CH), 8.20 (d, J
2 2 2
NH , D O
7
=
2
8.4 Hz, 2H, sulfamoylphenyl H-3, H-5), 9.08 (s, 1H, pyrazole H-5), 10.74 (s, 1H, NH, D O
1
3
Exchangeable)
C NMR (DMSO-d
), 44.8 (CH CH(CH ), 111.3 (CH, sulfamoylphenylhydrazineC-2, C-6),
18.8 (CH, sulfamoylphenyl C-2, C-6), 119.0 (C, pyrazole C-4), 127.4 (CH, pyrazole C-5),
27.8 (CH, isobutylphenyl C-2, C-6), 128.6 (CH, sulfamoylphenyl C-3, C-5), 128.9 (CH,
6 2 3 2
100MHz, δ ppm): 22.6 (CH CH(CH ) ), 30.1
(
CH
2
CH(CH
3
)
2
2
3 2
)
1
1
sulfamoylphenylhydrazine C-3, C-5), 129.6 (CH, isobutylphenyl C-3, C-5), 130.1
isobutylphenyl C-4), 131.9 (C, sulfamoylphenylhydrazine C-4), 133.6 (N=CH), 141.6 (C,
(
isobutylphenyl C-1), 142.1 (C, sulfamoylphenyl C-4), 142.2 (C, sulfamoylphenyl C-1),
+
48.2(C, sulfamoylphenylhydrazine C-1) 152.0 (C, pyrazole C-3). MS m/z (ES ), 554 (M+1,
1
8
1
+
,
%), 552(M 12%), 349(100%). Anal. Calcd. For C26
28 6 4 2
H N O S : C, 56.50; H, 5.11; N,
5.21; Found; C, 56.79; H, 5.18; N, 15.38.
1-[3-(4-Methoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-4-yl-methylene]-2-(4-
o
methylsulfonylphenyl)hydrazine(12a): Yield (3.46gm, 66%); yellow solid; mp 195-197 C;IR
(
KBr): 3275–3113(NH ), 3074 (C-H aromatic), 2927 (C–H aliphatic), 1597 (C=N), 1315,
2
-
1 1
1
3
3
157; 1276, 1134, (2SO
.84 (s, 3H, OCH ), 7.10–7.19 (m, 4H, methylsulfonylphenyl H-2, H-6 & methoxyphenyl H-
, H-5), 7.50 (s, 2H, SO NH , D O exchangeable) 7.70 - 7.74 (m, 4H, methoxyphenyl H-2,
2 6 2 3
) cm . HNMR (DMSO-d , 400 MHz, δ ppm): 3.11 (s, 3H, SO CH ),
3
2
2
2
H-6 & sulfamoylphenyl H-2, H-6), 8.00 (d, 2H, J = 8.4 Hz, methylsulfonylphenylH-2,H-6),
8.08 (m, 3H, sulfamoylphenyl H-3, H-5 & N=C-H), 9.07 (s, 1H, pyrazole H-5), 11.26 (s, 1H,
1
3
2 6 2 3 3
NH, D O exchangeable). C NMR (DMSO-d 100MHz, δ ppm):44.7 (SO CH ), 55.9 (OCH ),
111.7 (CH, methoxyphenyl C-3, C-5), 114.5 (CH, methylsulfonylphenyl C-2, C-6),118.7 (C,
pyrazole C-4), 118.8 (CH, sulfamoylphenyl C-2, C-6), 124.9 (C, methoxyphenyl C-1), 127.6
20

(
CH, pyrazole C-5), 127.8 (CH, sulfamoylphenyl C-3, C-5), 129.2 (CH, methoxyphenyl C-2,
C-6), 129.3 (C, methylsulfonylphenyl C-4), 130.2 (CH, methylsulfonylphenyl C-3, C-5),
33.0 (N=CH), 141.6 (C, sulfamoylphenyl C-4),142.0 (C, sulfamoylphenyl C-1), 149.6 (C,
methylsulfonylphenyl C-1), 151.8 (C, pyrazole C-3),160.1 (C, methoxyphenyl C-4). MS m/z
1
+
+
(
23 5 5 2
ES ), 525 (M ) . Anal. Calcd. For C24H N O S : C, 54.84; H, 4.41; N, 13.32; Found; C,
54.76; H, 4.50; N, 13.59
1-[3-(4-Ethoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-4-yl-methylene]-2-(4-
methylsulfonylphenyl)hydrazine (12b);Yield (3.93gm,73%); pale yellow solid; mp 208-210
o
C;IR (KBr): 3336, 3275 (NH
276, 1149; 1149 ,1138 (2SO ) cm . HNMR (DMSO-d
Hz,3H, CH CH ), 3.10 (s, 3H, SO CH ), 4.13 (q, J = 6.8 Hz, 2H,CH
Hz, 2H,methylsulfonylphenyl H-2, H-6 ), 7.16 (d, J = 8.4 Hz, 2H,ethoxyphenyl H-3, H-5),
2
), 3074 (C H aromatic), 2927 (C–H aliphatic), 1597 (C=N),
-1 1
1
2
6
, 400 MHz, δ, ppm): 1.38 (t, J = 6.8
CH ), 7.08 (d, J = 8.4
2
3
2
3
2
3
7
2 2 2
.39 (s, 2H, SO NH , D O exchangeable), 7.70 - 7.72 (m, 4H, ethoxyphenyl H-2, H-
6
&sulfamoylphenyl H-2, H-6), 7.98 (d, J = 8.4 Hz, 2H, methylsulfonylphenyl H-2, H-6),
8
.09 (s, 1H, N=CH), 8.18 (d, J = 8.4 Hz, 2H, sulfamoylphenyl H-3, H-5), 9.03 (s, 1H,
1
3
pyrazole H-5), 10.85 (s, 1H, NH, D
2
O exchangeable). C NMR (DMSO-d
), 63.7 (CH CH ), 111.7 (CH, ethoxyphenyl C-3, C-5),
15.0 (CH, methylsulfonylphenyl C-2, C-6), 118.7 (C,pyrazole C-4), 118.8 (CH,
sulfamoylphenyl C-2, C-6), 124.7 (C, ethoxyphenyl C-1), 127.2 (CH, pyrazole C-5), 127.3
CH, ethoxyphenyl C-2, C-6), 129.1 (CH, sulfamoylphenyl C-3, C-5), 129.7 (C,
methylsulfonylphenyl C-4), 130.2 (CH, methylsulfonylphenyl C-3, C-5), 133.0
N=CH),141.6 (C, sulfamoylphenyl, C-4), 142.0 (C, sulfamoylphenyl C-1), 149.5 (C,
methylsulfonylphenyl C-1), 151.9 (C, pyrazole C-3), 159.4 (C, ethoxyphenyl C-4).MS m/z
6
100MHz, δ
ppm):15.1 (CH
2
CH
3
), 44.7 (SO
2
CH
3
2
3
1
(
(
+
ES ),541 (M+1, 3%), 540 (M , 2%), 367 (100%). Anal. Calcd. For C25
+
(
25 5 5 2
H N O S , C, 55.64;
H, 4.67; N, 12.98; Found; C, 55.96; H, 4.60; N, 13.21
21

1-[3-(3,4-Dimethoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-4-yl-methylene]-2-(4-
methylsulfonylphenyl)hydrazine (12c);Yield (3.50gm, 63%); pale yellow solid; mp 250 - 252
o
C ;IR (KBr): 3336, 3232 (NH
346,1288, 1165,1134 (2SO ) cm . HNMR (DMSO-d
SO CH ), 3.86 (s, 3H, OCH ), 3.87 (s, 3H, OCH ), 7.12 (d, J = 7.4 Hz, 1H, dimethoxyphenyl
H-5), 7.19 (d, J = 6.8 Hz, 2H, methylsulfonylphenyl H-2, H-6), 7.31 (m, 2H,
dimethoxyphenyl H-6, H-2),7.43 (s, 2H, SO NH , D O exchangeable ), 7.70 (d, J = 6.8 Hz,
H, methylsulfonylphenyl H-3, H-5), 7.98 (d, J = 6.4 Hz, 2H, sulfamoylphenyl H-2, H-6),
.10-8.19 (m, 3H, N=CH & sulfamoylphenyl H-3, H-5), 9.03 (s, 1H, pyrazole H-5), 11.12 (s,
2
), 3086 (C H aromatic), 2993 (C–H aliphatic), 1589 (C=N),
-1 1
1
2
6
, 400 MHz, δ ppm): 3.10 (s, 3H,
2
3
3
3
2
2
2
2
8
1
1
3
H, NH, D
), 56.15 (OCH
), 112.3 (CH, methylsulfonylphenyl C-2, C-6), 118.8 (C, pyrazole C-4), 118.9 (CH,
2
O exchangeable). C NMR (DMSO-d
6 2 3
100MHz, δ ppm): 44.7 (SO CH ), 56.12
(
OCH
3
3
), 111.7 (CH, dimethoxyphenyl C-2), 112.2 (CH, dimethoxyphenyl C-
5
sulfamoylphenyl, C-2, C-6), 121.5 (CH, dimethoxyphenyl C-6), 125.0 (C, dimethoxyphenyl
C-1), 127.4(CH, pyrazole C-5), 127.7 (CH, sulfamoylphenyl C-3, C-5), 129.2 (CH,
methylsulfonylphenyl C-3, C-5), 129.3 (C, methylsulfonylphenylC-4), 133.0 (N=CH), 141.6
(
C, sulfamoylphenyl C-4), 142.1 (C, sulfamoylphenyl C-1), 149.2 (C, methylsulfonylphenyl
C-1), 149.6 (C, dimethoxyphenyl C-4), 149.8 (C, dimethoxyphenyl C-3), 152.0 (C, pyrazole
+
+
C-3).MS m/z (ES ), 557 (M+2, 6%), 556 (M , 13%), 358 (100%). Anal. Calcd. For:
; C, 54.04; H, 4.54; N, 12.60: Found; C, 54.28; H, 4.67; N, 12.37
-[3-(4-Isobutylphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-4-yl-methylene]-2-(4-
methylsulfonylphenyl) hydrazine (12d):Yield (3.20gm,58%); brown solid; mp 216-218 C;IR
KBr): 3383, 3275 (NH ), 3074 (C H aromatic), 2943 (C–H aliphatic), 1589 (C=N), 1311,
25 25 5 6 2
C H N O S
1
o
(
2
-
1 1
1
6
3
161; 1276, ,1134 (2SO
H, CH CH(CH ), 1.9 (m, 1H, CH
.11 (s, 3H, SO CH ), 7.18 (d, J = 6.4 Hz, 2H, methylsulfonylphenyl H-2, H-6), 7.32 (d, J =
2
) cm . HNMR (DMSO-d
6
, 400 MHz, δ, ppm): 0.92 (d, J = 4 Hz,
2
3
)
2
2
CH(CH ), 2.53 (d, J = 6.8 Hz, 2H, CH
3
)
2
2
CH(CH ),
3 2
)
2
3
22

5
.2 Hz, 2H, isobutylphenyl H-3, H-5), 7.49 (s, 2H, SO
m, 4H, isobutylphenyl H-2, H-6 & sulfamoylphenyl H-2, H-6), 8.00 (d, J = 6.4 Hz, 2H,
methylsulfonylphenyl H-3, H-5), 8.14 - 8.21 (m, 3H, sulfamoylphenyl H-3, H-5 & N=CH),
2 2 2
NH , D O exchangeable), 7.48 –7.71
(
1
3
9
.10 (s, 1H, pyrazole H-5), 11.24 (s, 1H, NH, D
00MHz, δ ppm): 22.6 (CH CH(CH ), 30.1 (CH
(CH ), 111.6 (CH, methylsulfonylphenyl C-2, C-6), 118.8 (CH, sulfamoylphenyl
2
O exchangeable). C NMR (DMSO-d
6
1
2
3
)
2
2
CH(CH ), 44.81 (SO CH ), 44.84
3
)
2
2
3
(
CHCH
2
3 2
)
C-2, C-6), 118.9 (C, pyrazole C-4), 127.8 (CH, isobutylphenyl C-2, C-6), 128.6 (CH,
sulfamoylphenyl C-3, C-5), 129.2 (CH, methylsulfonylphenyl C-3, C-5), 129.3 (C,
methylsulfonylphenyl C-4), 129.6 (CH, isobutylphenyl C-3, C-5), 130.1 (C, isobutylphenyl
C-1), 132.9 (N=CH), 141.6 (C, sulfamoylphenyl C-4), 142.1 (C, isobutylphenyl C-4), 142.2
(
C, sulfamoylphenyl C-1), 149.6 (C, methylsulfonylphenyl C-1), 152.0 (C, pyrazole C-
+
).MS m/z (ES ).554 (M+2, 10%), 552 (M , 16%), 444 (100%). Anal. Calcd. For
+
3
27 29 5 4 2
C H N O S
: C, 58.78; H, 5.30; N, 12.69; Found; C, 59.01; H, 5.17; N, 13.02.
4
4
.2 Biological activity
.2.1 Cyclooxygenase inhibition assays
The designed compounds efficacy to inhibit ovineCOX-1 and human
recombinant COX-2 (IC50 value, µM) was measured using an enzyme immuno assay (EIA)
kit (catalog no. 560131, Cayman Chemical, Ann Arbor, MI, USA) according to the
previously reported method[35].
4.2.2 In vivo anti-inflammatory assay
The newly synthesized compounds10b-d, 11a-d and12a-d and lead drug
celecoxib were evaluated for their in vivo anti-inflammatory activity using carrageenan-
induced rat foot paw edema model using (100 mg/kg). Measurement of paw thickness was
23

performed at 1h, 3h and 6h after carrageenan injection according to previously reported
method.[36] Moreover, ED50values were determined for the most active compounds 11b, 11d
and12b in comparison with reference drug celecoxib.
4.2.3 Ulcerogenic liability
The ulcerogenic effect of indomethacin, celecoxib and (11b, 11d and 12b) that
showed superior in-vivo anti-inflammatory activity better than celecoxib, determined.
Rats were scarified at 4h after drug administration (150mg/kg) according to previously
described method.[17]
4.2.4. Histopathlogical study
Tissue samples were flushed and fixed in neutral buffered formalin 10% remain for
72 h. Samples were trimmed, processed and dehydrated by serial grades of alcohol,
clearing in Xylene, synthetic wax infiltration and blocking out into paraplast tissue
embedding media. 5µ sections were cut by rotatory microtome. The sections were stained
with Harris hematoxylin and Eosin as a general examination staining methodas outlined
by Bancroft and Stevens .[35]
4.2.5. Docking study
The crystal structure of COX-2 isozyme with celecoxib as lead drug was obtained
from protein data bank (PDB; ID: 3LN1). For the purpose of studying Scoring interaction,
binding interaction with different amino acid, docking of crystallized ligand should be done.
Docking was attained using London DG forces. The synthesized compounds were prepared
for docking through protonation, obtaining the lowest energy conformer of 3D structure build
by Molecular Operating Environment (MOE). The celecoxib was docked first then removed
from site of interaction. All molecules were docked using the same condition as standard
drug. The binding interaction and docking score was studied using 2D and 3D pictures.
24

Conflict of interest
The authors have declared no conflict of interest
5. References
[
1] R. Kumar, S. Bawa, G. Chawla, G. Singh, S. Kumar, V. Rathore, N. Mulakayala, A.
Rajaram, A.M. Kalle, O. Afzal, Eur. J. Med. Chem. 57 (2012) 176–184.
[
[
[
2] J.M. Pelletier, D. Lajeunesse, P. Reboul, J.P. Pelletier, 62 (2003) 501–509.
3] M. Parente, L. Perretti, Biochem. Pharmacol. 65 (2003) 153–159.
4] G. Kulkarni, R.G. Achaiah, G. Narahari sastry, Curr. Pharm. Des. 2 (2006) 2437–
2
454.
[
5] M.A. Abdelgawad, M.B. Labib, W.A.M. Ali, G. Kamel, A.A. Azouz, E. El-nahass,
Bioorg. Chem. 78 (2018) 103–114.
[
[
[
6] M.A. Abdelgawad, M.B. Labib, M. Abdel-latif, Bioorg. Chem. 74 (2017) 212–220.
7] K. Mahdi, M.Faisel, Mohammed, M. H. Abdul, A.J. Molecules. 17 (2012) 1751–1763.
8] A.R. Eweas, A.F. El-nezhawy, A. O. H. Abdel-rahman, R.F. Baiuomy, Med. Chem.
(
Los. Angeles). 5 (2015) 458–466.
[
[
[
9] I. Nasir, S. Bukhari, A. Zhang, X. Jantan, Chem Biol Drug Des 2015. 2 (2015) 729–
42.
7
10] K. Masferrer, J.L. Zweifel, B. S. Manning, P.T. Hauser, S.D. Leahy, K.M. Smith,
W.G. Isakson, P.C. Seibert, Proc. Natl. Acad. Sci. USA. 91 (1994) 3228–3232.
11] H.A.H. Elshemey, E.K.A. Abdellal, A.A. Azouz, A. Moawad, W.A.M. Ali, N.M.
25

Safwat., Eur. J. Med. Chem. 127 (2017) 10–21.
[
12] V. Migliara, O. Spanò, P. Parrino, B. Ciancimino, C. Diana, ARKIVOC. 2012 (2012)
4
1–49.
[
[
[
13] E.E. Rao, P. N .P Knaus, J Pharm Pharm. Sci. 11 (2008) 81–110.
14] E.K.A. Abdelall, P.F. Lamie, W.A.M. Ali, Bioorg. Med. Chem. Lett. (2016).
15] K.R.A. Abdellatif, E.K.A. Abdelall, W.A.A. Fadaly, G. Kamel, Med. Chem. Res. 7
(
2015) 1327–1334.
[
[
16] F. Howard S. S. MD, Arachidonic Acid Pathways in Nociception, 2006.
17] K.R.A. Abdellatif, M.A. Abdelgawad, M.B. Labib, T.H. Zidan, Bioorg. Med. Chem.
Lett. (2015) 6–10.
[
18] M.M. Mohy El-din, A.A. Senbel, A.M. Bistawroos, H.A. El-mallah, A. Nour El-din,
N. A. Bekhit, A. A. Abd ElRazik, Basic Clin. Pharmacol. Toxicol. 1742 (2010) 263–
273.
[
[
19] S.A.F. Faidallah, H.M. Rostom, Arch. Pharm. (Weinheim). 350 (2017) 1–17.
20] H.I. Gouda, A.M. Ali, A.H. Almalki, W.H. Azim, M.A. Abourehab, M.A S.
Abdelazeem, Molecules. 21 (2016) 1–21.
[
[
[
[
21] A. Corelli, F.Garofalo, J.Heterocyclic.Chem. 27 (1990) 1489.
22] J.J. Taylor, R.J. Salata, Biochem. Pharmacol. 25 (1976) 2479–2484.
23] S.N. Rao, P.P.N. Kabir, T. Mohamed, Pharmaceuticals. 3 (2010) 1530–1549.
24] M.M. Fahmy, H.H. Khalifa, N.M. Nossier, E.S. Abdalla, Acta Pol. Pharm. 69 (2012)
4
11–421.
26

[
[
25] D. Hussain, S. Kaushik, J. Saudi Chem. Soc. 19 (2015) 274–281.
26] K.R.A. Abdellatif, M.A. Abdelgawad, M.B. Labib, T.H. Zidan, Arch. Pharm.
(
Weinheim). 350 (2017) 1–10.
[
[
27] M. Jadhav, S. B.Fatema, S. Farooqui, Chem. Biol. Interface. 7 (2017) 154–165.
28] P. Seibert, K. Zhang, Y. Leahy, K. Hauser, S. Masferrer, J. Perkins, W. Lee, L.
Isakson, Proc. Nati. Acad. Sci. 91 (1994) 12013–12017.
[
29] J.M. Kurumbail, R.G. Stevens, A.M. Gierse, J. K. Mcdonald, J. J. Stegeman, R. A.
Pak, J.Y. Gildehaus, D. Miyashiro, T. D. Penning, K. Seibert, P.C. Isakson, W.C.
Stallings, Lett. TO Nat. 384 (1996) 400–402.
[
[
30] S.M. Billones, J.B., Buenaobra, Philipp. J. Sci. 140 (2011) 125–132.
31] S.N. Vandana, J.N.Ashok, K.S. Veerma, R. Jeeternda, J. Pharm. Res. 5 (2012) 5014–
5
017.
[
[
[
32] P. Singh, R. Kumar, S. Tiwari, S. Khanna, A. Ranjana, K. Tewar, H.D. Khanna, Clin.
Med. Biochem. 1 (2015) 2–5.
33] S.N. Dighe, G.S. Deora, E. De Mora, F. Nachon, S. Chan, M. Parat, Brazzolotto., J.
Med. Chem. 59 (2016) 7683–7689.
34] F.A. Ragab, N.M.A. Gawad, H.H. Georgey, M.F. Said, Eur. J. Med. Chem. 63 (2013)
645–654.
[
[
35] O.D. Bancroft, A. Stevens, Theory and Practice of Histological Technique., 2010.
36] G.W. (Winter, C. A.; Risley, E. A.; Nuss, Proc. Soc. Exp. Biol. Med. 111 (n.d.) 544.
27

Figures, Schemes and Table captions
Figure.1. Chemical structures of indomethacin (1), tolmetin (2), celecoxib (3), rofecoxib (4),
and valdecoxib(5).
Figure. 2. Designed compounds 11a-d and 12a-d as celecoxib-tolmetin drug hybrids
Figure.3. (3ia) 2D, (3ib) 3D interaction between celecoxib and COX-2 active site. (3iia) 2D
interaction, (3iib) 3D interaction between compounds 11b and COX-2 active. (3iii) 2D 3iii
(
B) 3D interaction between compounds 11d and COX-2 active site. (3iva) 2D, (3ivb) 3D
interaction between compounds 12b and COX-2 active site.
Figure.4. Gastric mucosa examination,Ia and Ib for control.IIa, IIb and IIc for
indomethacin. IIIa and IIIb for celecoxib, IVa, IVb andIVc for 11b.Va and Vb for 11d, VIa
and VIb for 12b.
Scheme1: Synthesis of the target compounds
Table 1: In vitro COX-1, COX-2, Selectivity Index (SI) of diarylpyrazoles (10b-d) and
triarypyrazoles (11a-d and 12a-d) and reference drug celecoxib.
Table 2: In vivo anti-inflammatory activity of diarylpyrazoles (10b-d) and triarypyrazoles
(
11a-d and 12a-d) and reference drug celecoxib.
Table 3: ED50 for the most active compound 11b, 11d, 12b and celecoxib.
Table 4: Ulcerogenic liability for the most active triarylpyrazoles11b, 11d, 12b indomethacin
and celecoxib.
Table 5: Docking scores and Number of H-bond of 10b-d, 11a-d and 12a-d compounds and
reference drug celecoxib.
28

Graphical abstract
SO R
2
R1
HN
N
R2
N
N
SO NH
2
2
R = CH , NH ;
2
3
R = O-CH , O-C H , CH CH(CH ) ;
1
3
2
5
2
3 2
R = H, OCH3
2
29