Synthesis of amidine and amide derivatives and their evaluation for anti-inflammatory and analgesic activities

Article abstract of DOI:10.1016/j.ejmech.2008.06.029

A number of amidine derivatives (2a-i) have been synthesized by condensation of 2-cyanopyridine with various 3,4-diaryl-2-imino-4-thiazolines. Various amide derivatives (3a-h) were synthesized by condensation of orotic acid and hydantoin-5-acetic acid wit

Full text of DOI:10.1016/j.ejmech.2008.06.029

European Journal of Medicinal Chemistry 44 (2009) 1010–1015
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of amidine and amide derivatives and their evaluation for
anti-inflammatory and analgesic activities
,
a
b
c
c
Sham M. Sondhi a , Jaiveer Singh , Ashok Kumar , Hyder Jamal , P.P. Gupta
*
a Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India
b Department of Pharmacology, LLRM Medical College, Meerut 250004, Uttar Pradesh, India
c Department of Pharmacology, BRD Medical College, Gorakhpur 273013, Uttar Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of amidine derivatives (2a–i) have been synthesized by condensation of 2-cyanopyridine with
various 3,4-diaryl-2-imino-4-thiazolines. Various amide derivatives (3a–h) were synthesized by
condensation of orotic acid and hydantoin-5-acetic acid with a number of 3,4-diaryl-2-imino-4-thia-
zolines using microwave irradiation. All the compounds i.e. (2a–i) and (3a–h) synthesized were char-
acterized by spectroscopic means and elemental analysis. Compounds (2a–i) and (3a–h) at 50 mg/kg p.o.
were screened for anti-inflammatory activity whereas 2a–d, f, g, i and 3a, b, d, f at 50 mg/kg p.o. were
evaluated for analgesic activity. Compounds 2e and 3g exhibited good anti-inflammatory activity (49%
and 34%, respectively) and 2f, g showed interesting (50% in each case) analgesic activity.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Received 1 February 2008
Received in revised form 23 May 2008
Accepted 30 June 2008
Available online 4 July 2008
Keywords:
Amidine
Amide
Anti-inflammatory
Analgesic
Microwave irradiation
1. Introduction
2. Results and discussion
Arthritis, asthma, allergy, multiple sclerosis and other diseases
which cause inflammation and pain are widely prevalent
throughout the world. For the treatment of pain and inflammation
various drugs such as indomethacin, ibuprofen, dichlofenac,
aspirin, nimisulide, celecoxib, rofecoxib, etc. are available in the
market [1,2]. Long term use of these drugs causes various side
effects such as ulceration, gastrointestinal bleeding and heart
stroke [3,4] All these indicate that there is a need for safer anti-
inflammatory drugs.
Amidine derivatives exhibiting anti-inflammatory [5], anti-
degenerative [6], antiplatelet [7], anticancer [8,9], antimicrobial
[10], urokinase inhibitor [11] and amide derivatives possessing
anti-inflammatory [12–15] antimicrobial [16] antitubercular [17]
activities have been reported in the literature. Tempted by wide
variety of biological activities shown by amidine and amide
derivatives and in continuation [18–22] of our efforts in search of
potent, molecules exhibiting anti-inflammatory and analgesic
activities we report herewith synthesis, anti-inflammatory and
analgesic activity evaluation of various amidine and amide
derivatives.
2.1. Chemistry
Various 3,4-diaryl-2-imino-4-thiazolines (1a–i, Scheme 1) were
synthesized by condensation of amine hydrochlorides with
phenacylthiocyanates as reported in the literature [23]. 2-Cyano-
pyridine on refluxing with 3-(4-methoxyphenyl)-4-phenyl-2-
imino-4-thiazoline (1a; Scheme 1) in methanol for 8 h gave
condensed product 2a (Scheme 1) after usual workup. Compound
2a was purified by crystallization from methanol to give pure N-[3-
(4-methoxyphenyl)-4-phenyl thiazol-2-(3H)-ylidene] picolinami-
dine (2a, Scheme 1) in 91% yield. 1H NMR (500 MHz; DMSO-d6) of
2a shows signals at d 3.77 (s, 3H, OCH3), 6.97–6.99 (d, 3H, Ar), 7.22–
7.23 (t, 4H, Ar), 7.27–7.29 (t,3H, Ar), 7.40–7.43 (m, 1H, py), 7.73–7.74
(d,1H, py), 7.82–7.85 (m,1H, py), 8.64–8.65 (d,1H, py),10.11 (br s,1H,
NH, exch). FAB-MS m/z 387 (MH,þ 100%). FT-IR spectra show
absorption band at 3239 (NH), 1632 (C]N), 1543 and 1513 (Ar)
cmꢀ1 Spectral data of 2a fully support the structure assigned to it.
Similarly other amidine derivatives i.e. 2b–i (Scheme 1) were
synthesized and purified by crystallization. Spectral and analytical
data of compounds 2a–i reported in Section 4 of this paper fully
support the structures assigned to them.
Various amide derivatives (3a–h; Scheme 1) were synthesized
by using microwave irradiation under solvent free reaction condi-
tion. Thus equimolar ratio of 3-(4-methoxyphenyl)-4-phenyl-2-
imino-4-thiazoline (1a, Scheme 1) and orotic acid were taken
* Corresponding author. Tel.: þ91 1332 285811; fax: þ91 1332 273650.
E-mail address: sondifcy@iitr.ernet.in (S.M. Sondhi).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.06.029

S.M. Sondhi et al. / European Journal of Medicinal Chemistry 44 (2009) 1010–1015
NH
1011
S
R1
N
R2
1a-i
O
N
RC
OH
CN
MWI
MeOH
O
C
NH
C
N
N
S
N
R
S
R1
N
R2
R1
N
R2
2a-i
3a-h
R1 & R2 are same for compounds 1a-i & 2a-i
R2 R1
R1
2a
2b
2c
2d
2e
2f
R2
R
O
NH
H
H
OMe
3a
3b
3c
3d
3e
3f
OMe
H
O
N
H
O
COCH3
NH
H
COCH3
O
N
H
O
H
H
H
Cl
NH
Cl
H
O
N
H
O
NH
OCH3
NO2
NO2
O
N
H
O
NH
H
H
H
H
O2N
Me
O
O2N
N
H
O
O
NH
Cl
OC2H5
H
H2C
H2C
O
O
N
H
NH
NO2
2g
2h
3g
3h
N
H
O
NH
H
H2C
O
N
H
O2N
MeO
Br
2i
Scheme 1.
together in a petri dish. Both the reactants were mixed thoroughly
and then subjected to microwave irradiation for 20 min at a power
level of 450 W. The reaction contents were taken in hot methanol
and filtered to remove any insoluble material. From the filtrate so
obtained solvent was removed under reduced pressure to give the
crude product. This crude product was washed thoroughly with
ethyl acetate and the solid product left behind was purified by
crystallization from methanol to give N-[3-(4-methoxyphenyl)-4-
phenyl thiazol-2(3H) ylidene]-2,6-dioxo-1,2,3,6-tetrahydropyr-
imidine-4-carboxamide (3a, Scheme 1) in 80% yield. 1H NMR
support the structure assigned to it. Following similar procedure of
other amide derivatives i.e. 3b–h (Scheme 1) were synthesized and
purified by crystallization. Spectral and analytical data of 3a–h
reported in Section 4 of this paper is in agreement with the
structures assigned to them. 1H NMR of compounds reported in this
paper was taken after six months from synthesizing them and no
change was observed in the 1H NMR, similarly 1H NMR (DMSO-d6)
of compounds solution in DMSO-d6 taken after keeping them for
ten days at room temperature did not show any change. From these
observations it is clear that the compounds reported in this paper
are very stable in solid as well in liquid phase.
(500 MHz, DMSO-d6) of 3a shows signals at
d 3.75 (s, 3H, OCH3),
5.74 (s, 1H, >C]CH–), 7.02–7.03 (d, 2H, Ar), 7.13 (s,1H, Ar), 7.18–7.20
(d, 2H, Ar), 7.21–7.34 (m, 3H, Ar), 7.39–7.41 (d, 2H, Ar), 9.27 (s, 1H,
NH, exch), 10.95 (s, 1H, NH, exch). GC–MS m/z 420 (Mþ, 43.26%). FT-
IR spectra show absorption bands at 3450 (NH), 1703 (>C]O), 1631
(>C]N–), 1532 and 1508 (Ar) cmꢀ1. Spectral data of 3a fully
2.2. Biological results
Anti-inflammatory activity [24] evaluation of 2a–i and 3a–h was
carried out using carrageenan induced paw oedema assay and

1012
S.M. Sondhi et al. / European Journal of Medicinal Chemistry 44 (2009) 1010–1015
results are summarized in Table 1. Compounds 2a–i and 3a–h, at
50 mg/kg p.o. exhibited 17%, 20%, 17%, 26%, 49%, 0.0%, 0.0%, 23%,
0.0% and 9%, 12%, 2%, 15%, 25%, 10% 34% and 17% activity, respec-
tively whereas ibuprofen exhibited 39% anti-inflammatory activity
at 50 mg/kg p.o. Analgesic activity [25] evaluation was carried out
using acetic acid writhing assay and results are summarized in
Table 1. Compounds 2a–d, f, g, i and 3a, b, d, f at 50 mg/kg p.o.
exhibited 12%, 25% 12%, 18%, 50%, 50% 40% and 8%, 8%, 10% 0.0%
analgesic activity, respectively, whereas ibuprofen exhibited 50%
analgesic activity at 50 mg/kg p.o. A look at the Table 1 indicates
that compounds 2e and 3g exhibited good anti-inflammatory
whereas compounds 2f and g exhibited good analgesic activity.
4. Experimental
4.1. General
Melting points (mp) were determined on a JSGW apparatus and
are uncorrected. Domestic microwave oven model M 197 DL
(SAMSUNG) was used for microwave irradiation. IR spectra were
recorded using a Perkin Elmer 1600 FT spectrometer 1H NMR
spectra were recorded on a Bruker WH-500 and 300 spectrometer
at a ca 5–15% (w/v) solution in DMSO-d6 (TMS as internal standard)
FAB-MS was recorded on JEOL SX-120 (FAB) spectrometer. GC–MS
was recorded on Perkin Elmer Clarus 500 mass spectrometer.
Elemental analysis was carried out on a Vario EL III elementor. Thin
layer chromatography (TLC) was performed on silica gel G for TLC
(Merck) and spots were visualized by iodine vapour or by irradia-
tion with ultraviolet light (254 nm). Column chromatography was
performed by using Qualigen’s silica gel for column chromatog-
raphy (60–120 mesh).
2.2.1. Structure–activity relationship
Aryl group substituted at position
3 of compound 2 is
substituted at its ortho or para position. Anti-inflammatory activity
is increased when aryl group is substituted at its ortho position by
–NO2 group (2e), whereas substitution by –Me group (2g) at ortho
position or no substitution on phenyl ring (2f) is favorable for
analgesic activity. In case of compound 3 substitution by –NO2
group at para position of phenyl ring (3g) is beneficial for anti-
inflammatory activity. Lipophilicity (C log P) values for the
compounds 2a–i and 3a–h were estimated by using ChemDraw
Ultra and were found to be 6.228, 5.748, 7.022, 6.052, 6.052, 6.309,
6.808, 6.228, 7.483 and 4.098, 3.618, 4.892, 3.841, 3.922, 4.75, 3.78,
3.78, respectively. From lipophilicity point of view compounds 2e
and f have lipophilicity values 6.052 and 6.309 but they show 49%
and 0.0% anti-inflammatory activity. Similarly compounds 3g and h
have lipophilicity values 3.78 and 3.78 but they show 34% and 17%
anti-inflammatory activity. Compounds 2c and g have lipophilicity
values 7.022 and 6.808 but they show analgesic activity 12% and
50%, respectively. From the above discussion it can be concluded
that molecules which meet lipophilicity, stereochemical and elec-
tronic requirements of the target in a better way exhibited good
anti-inflammatory and analgesic activities.
4.2. General procedure for the synthesis of amidine
derivatives (2a–i)
4.2.1. N-(3-(4-Methoxyphenyl)-4-phenylthiazol-2(3H)-
ylidene)picolinamidine (2a)
3-(4-Methoxyphenyl)-4-phenyl thiazol-2(3H)-imine 0.282 g
(1 mmol) was taken in 15 ml methanol and to it was added 0.104 g
(1 mmol) 2-cyanopyridine. Reaction contents were heated under
reflux for 8 h. Solvent was removed under reduced pressure and the
residue left behind was scratched with diethyl ether, solid sepa-
rated out was filtered and air dried to give crude product, which
was purified by crystallization from methanol to give pure product
2a. Yield: 0.352 g (91%); mp: 210 ꢁC; IR (KBr) nmax: 3239 (NH), 1632
(>C]N–), 1543 and 1513 (Ar) cmꢀ1. 1H NMR (500 MHz, DMSO-d6)
d
: 3.77 (s, 3H, OCH3), 6.97–6.99 (d, J ¼ 9.5 Hz, 3H, Ar), 7.22–7.23 (t,
4H, Ar), 7.27–7.29 (t, 3H, Ar), 7.40–7.43 (m, 1H, Py), 7.73–7.74 (d,
J ¼ 7.5 Hz 1H, Py), 7.82–7.85 (m, 1H, Py), 8.64–8.65 (d, J ¼ 4 Hz, 1H,
Py),10.11 (s,1H, NH, exch) FAB-MS m/z 387 (MHþ,100%). Anal. Calcd
for C22H18N4OS C, 68.39; H, 4.68; N,14.50; S, 8.29. Found C, 68.51; H,
4.34; N, 14,15; S, 8.31.
3. Conclusion
A number of amidine (2a–i) and amide (3a–h) derivatives have
been synthesized and characterized by spectroscopic means. On
anti-inflammatory and analgesic activity screening of 2a–i, 3a–h
and 2a–d, f, g, i; 3a, b, d, f, respectively, compounds 2e, 3g exhibited
good anti-inflammatory activity and compounds 2f and g exhibited
good analgesic activity.
Similarly were synthesized compounds 2b–i.
4.2.2. N-(3-(4-Acetylphenyl)-4-phenyl thiazol-2(3H)-
ylidene)picolinamidine (2b)
Solvent of crystallization: MeOH; Yield: 69%; mp: 245 ꢁC; IR
(KBr) nmax: 3236 (NH), 1679 (C]O), 1598 (>C]N–), 1571 and
1517(Ar) cmꢀ1. 1H NMR (500 MHz, DMSO-d6)
d: 2.61 (s, 3H, CH3),
Table 1
Anti-inflammatory and analgesic activity evaluation of compounds 2a–i and 3a–h
7.07 (s, 1H, >C]CH–), 7.23–7.29 (m, 5H, Ar), 7.42–7.44 (q, 1H, Ar),
7.55–7.57 (d, J ¼ 8 Hz, 2H, Ar), 7.70–7.72 (d, J ¼ 7.5 Hz, 1H, Py), 7.82–
7.85 (t, J ¼ 7.5 Hz, 1H, Py), 8.02–8.04 (d, J ¼ 8.5 Hz, 2H,
1H(Ar)þ1H(Py)), 8.65–8.66 (d, J ¼ 4.5 Hz, 1H, Py), 10.21 (s, 1H, NH,
exch). FAB-MS m/z 399 (MHþ, 15.52%), 398 (Mþ, 100%), 105
Compounds tested Anti-inflammatory activity
Analgesic activity
Dose mg/kg p.o. Activity % Dose mg/kg p.o. Activity %
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
17
20
17
26
49
0.0
0.0
23
0.0
9.0
12
2.0
15
25
10
34
17
43
39
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
–
12
25
12
18
NT
50
50
NT
40
8.0
8.0
NT
10
NT
(
, 11.4%). Anal. Calcd for C23H18N4OS C, 69.34; H, 4.52;
N, 14.07; S, 8.04. Found C, 69.58; H, 4.60, N, 14.45; S, 8.35.
4.2.3. N-(3-(4-Chlorophenyl)-4-phenyl thiazol-2(3H)-
ylidene)picolinamidine (2c)
Solvent of crystallization: MeOH; Yield: 91%; mp: 215 ꢁC; IR
(KBr) nmax: 3256 (NH), 1639 (>C]N–), 1545, 1508 (Ar) cmꢀ1 1H
.
NMR (500 MHz, DMSO-d6) d: 7.06 (s, 1H, >C]CH–), 7.22–7.24 (m,
2H, Ar), 7.30–7.32 (t, J ¼ 5 Hz, 3H, Ar), 7.43–7.45 (m, 3H, Ar), 7.52–
7.53 (d, J ¼ 5 Hz, 2H, Ar), 7.72–7.74 (d, J ¼ 10 Hz, 1H, Py), 7.86–7.89
(m,1H, Py), 8.66 (d,1H, Py),10.17 (s, 1H, NH, exch). APCI-MS m/z 393
0.0
NT
NT
–
3h
Aspirin
Ibuprofen
(MHþ þ 2, 33.33%), 391 (MHþ, 100%), 289(
, 6%),
50
50

S.M. Sondhi et al. / European Journal of Medicinal Chemistry 44 (2009) 1010–1015
1013
105 (
, 23.36%). Anal. Calcd for C22H18N4S C, 71.35; H,
287 (
, 20%), 105 (
5%). Anal.
4.86; N, 15.13; S, 8.65. Found C, 71.02, H, 4.3; N, 14.95; S, 8.25.
Calcd for C21H15N4SCl C, 64.61; H, 3.84; N, 14.36; S, 8.20. Found C,
64.73; H, 3.57; N, 14.37; S, 8.00.
4.2.8. N-(3-(2-Methoxyphenyl)-4-phenyl thiazol-2(3H)-
ylidene)picolinamidine (2h)
Solvent of crystallization: MeOH; Yield: 55%; mp: 235 ꢁC; IR
4.2.4. N-(3-(4-Nitrophenyl)-4-phenyl thiazol-2(3H)-
ylidene)picolinamidine (2d)
(KBr) nmax: 3257 (NH), 1599 (>C]N–), 1549 and 1493 (Ar) cmꢀ1. 1H
Solvent of crystallization: MeOH; Yield: 70%; mp: 215 ꢁC; IR
NMR (500 MHz, DMSO-d6)
d: 3.57 (s, 3H, OCH3), 6.96 (s, 1H,
(KBr) nmax: 3230 (NH), 1636 (>C]N–), 1595 and 1515 (Ar) cmꢀ1. 1H
>C]CH–), 7.06–7.11 (m, 2H, Ar), 7.21–7.22 (m, 2H, Ar), 7.25–7.28
(m, 3H, Ar), 7.40–7.44 (m, 3H, 2H(Ar)þ1H(Py)), 7.63–7.64 (d,
J ¼ 8 Hz, 1H, Py), 7.78–7.81 (m, 1H, Py), 8.64–8.65 (d, J ¼ 4.5 Hz, 1H,
Py), 10.08 (s, 1H, NH, exch). FAB-MS m/z 387 (MHþ, 100%). Anal.
Calcd for C22H18N4OS C, 68.39; H, 4.68; N, 14.50; S, 8.29. Found C,
68.76; H, 5.02; N, 14.55, S, 8.28.
NMR (500 MHz, DMSO-d6) d: 7.10 (s, 1H, >C]CH–), 7.24–7.25 (d,
J ¼ 5 Hz, 2H, Ar), 7.30-7.31 (d, J ¼ 4 Hz, 3H, Ar), 7.42–7.44 (t, 1H, Ar),
7.71-7.73 (d, J ¼ 9 Hz, 3H, Ar), 7.83–7.86 (t, 1H, Py), 8.30–8.32 (d,
J ¼ 8.5 Hz, 2H, Py), 8.65–8.66 (d, J ¼ 4 Hz, 1H, Py), 10.27 (s, 1H, NH,
exch). GC–MS m/z 401 (Mþ, 0.81%), 355 (Mþ-NO2, 7.59%), 267
(
,
2.19%),
221
4.2.9. N-(4-(4-Bromophenyl)-3-(naphthalen-2-yl)thiazol-2(3H)-
ylidene)picolinamidine (2i)
(
, 19.94%). Anal. Calcd for C21H15N5O2S
Solvent of crystallization: MeOH; Yield: 94%; mp: 180 ꢁC; IR
(KBr) nmax: 3439 (NH), 1630 (>C]N–), 1577 and 1550 (Ar) cmꢀ1. 1H
NMR (500 MHz, DMSO-d6) d: 7.07 (s, 1H, >C]CH–), 7.121–7.138 (d,
C, 62.84; H, 3.74; N, 17.45; S, 7.98. Found C, 62.76; H, 3.67; N, 17.67;
S, 8.03.
J ¼ 8.5 Hz, 2H, Ar), 7.29–7.31 (m, 1H, Ar), 7.35–7.37 (d, J ¼ 8.5 Hz, 2H,
Ar), 7.46–7.58 (m, 4H, Ar), 7.63–7.66 (t, J ¼ 7.5, 1H, Ar), 7.81–7.85 (m,
2H, 1H(Ar)þ1H(Py)), 7.93–7.94 (d, J ¼ 8 Hz, 1H, Py), 7.97–7.99 (d,
J ¼ 8.5 Hz, 1H, Py), 8.55–8.56 (d, J ¼ 4.5 Hz, 1H, Py), 10.12 (s, 1H, NH,
4.2.5. N-(3-(2-Nitrophenyl)-4-phenyl thiazol-2(3H)-
ylidene)picolinamidine (2e)
Solvent of crystallization: MeOH; Yield: 62%; mp: 190 ꢁC; IR
(KBr) nmax: 3252 (NH), 1611 (>C]N–), 1531 and 1506 (Ar) cmꢀ1. 1H
NMR (500 MHz, DMSO-d6) d: 7.13 (s, 1H, >C]CH–), 7.32 (s, 5H, Ar),
exch). MS m/z 486 (M þ 1, 100%), 381 (
,
7.36–7.38 (t, 1H, Ar), 7.42–7.44 (t, 1H, Ar), 7.57–7.58 (d, J ¼ 8 Hz, 1H,
Ar), 7.72–7.73 (t, 2H, 1H(Ar)þ1H(Py)), 7.83–7.84 (t, J ¼ 7.5 Hz, 1H,
Py), 8.25–8.27 (t, 1H, Py), 8.64–8.65 (d, J ¼ 4 Hz, 1H, Py), 10.22 (s, 1H,
35.77%), 380 (
, 39.28%), 105 (
,
NH, exch). GC–MS m/z 401 (Mþ, 30.95%), 134 (
,
3.57%). Anal. Calcd for C25H17N4SBr C, 61.85; H, 3.50; N, 11.54; S,
6.59. Found C, 61.55; H, 3.20; N, 11.85; S, 6.29.
51.41%), 78 ( , 100%). Anal. Calcd for C21H15N5O2S C, 62.84;
H, 3.74; N, 17.45; S, 7.98. Found C, 62.76; H, 3.67; N, 17.67; S, 8.03.
4.3. General procedure for the synthesis of amide derivatives (3a–h)
4.2.6. N-(4-(4-Ethoxyphenyl)-3-phenyl thiazol-2(3H)-
ylidene)picolinamidine (2f)
4.3.1. N-(3-(4-Methoxyphenyl)-4-phenyl thiazol-2(3H)-ylidene)-
2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide (3a)
Solvent of crystallization: MeOH; Yield: 71%; mp: 182 ꢁC; IR
(KBr) nmax: 3251 (NH), 1615 (>C]N–), 1546 and 1494 (Ar) cmꢀ1. 1H
NMR (300 MHz, DMSO-d6) d: 1.35–1.39 (t, 3H, CH3), 3.95–4.02 (q,
2H, CH2), 6.65 (s, 1H, >C]CH–), 6.71-6.74 (d, J ¼ 8.7 Hz, 2H, Ar),
7.05–7.08 (d, J ¼ 8.6 Hz, 2H, Ar) 7.28–7.35 (m, 3H, Ar), 7.38–7.42 (m,
3H, 2H(Ar)þ1H(Py)), 7.68–7.71(m, 1H, Py), 7.78–7.81 (d, J ¼ 7.6 Hz,
1H, Py). 8.60–8.61 (d, J ¼ 4.5 Hz, 1H, Py), 10.10 (s, 1H, NH, exch). GC–
MS m/z 400 (Mþ, 15.83%), 279 (Mþ-m/z 121, 8%) 178
3-(4-Methoxyphenyl)-4-phenyl-2-imino-4-thiazoline (0.282 g,
1 mmol) and orotic acid (0.156 g, 1 mmol) were taken together in
a petri dish. Both the reactants were mixed thoroughly and then
subjected to microwave irradiation for 20 min at a power level of
450 W. The reaction contents were taken in hot methanol and
filtered to remove any insoluble materials. From the filtrate so
obtained solvent was removed under reduced pressure to give the
crude product. This crude product was washed thoroughly with
ethyl acetate and the solid product left behind was purified by
crystallization from methanol to give 3a. Yield: 0.340 g (80%); mp:
225 ꢁC; IR (KBr) nmax: 3450 (NH), 1703 (>C]O), 1631 (>C]N–),
(
, 2.75%), 121 (
, 18%), 77 (C6Hþ5 ,
98%). Anal. Calcd for C23H20N4OS C, 69.00; H, 5.00; N, 14.00; S, 8.00.
Found C, 68.72; H, 4.9; N, 13.78; S, 7.7.
1532, 1550 (Ar) cmꢀ1. 1H NMR (500 MHz, DMSO-d6)
d: 3.57 (s, 3H,
OCH3), 5.74 (s, 1H, ]CH–), 7.02–7.03 (d, J ¼ 9 Hz, 2H, Ar), 7.13 (s, 1H,
Ar), 7.18–7.20 (d, J ¼ 7 Hz, 2H, Ar), 7.21–7.34 (m, 3H, Ar), 7.39–7.41 (d,
J ¼ 9 Hz, 2H, Ar), 9.27 (s,1H, NH, exch),10.95 (s,1H, NH, exch). GC–MS
m/z 420 (Mþ, 43.26%), 389 (Mþ OCH3, 12.47%), 343 (Mþ–ꢂC6H5;
4.2.7. N-(4-Phenyl-3-o-tolyl thiazol-2(3H)-ylidene)picolinamidine
(2g)
Solvent of crystallization: MeOH; Yield: 79%; mp: 164 ꢁC; IR
(KBr) nmax: 3253 (NH), 1633 (>C]N–), 1541 and 1494 (Ar) cmꢀ1. 1H
NMR (500 MHz, DMSO-d6) d: 2.05 (s, 3H, CH3) 7.04 (s,1H, >C]CH–),
23.46%), 134(
,9.07%), 111(
, 89.55%), 58 (
,
7.202–7.215 (d, J ¼ 6.5 Hz, 2H, Ar), 7.24–7.27 (m, 5H, Ar), 7.341–7.355
(d, J ¼ 7 Hz, 2H, Ar), 7.38–7.40 (m, 1H, Py), 7.545–7.560 (d, J ¼ 7 Hz,
1H, Py), 7.752–7.769 (m, 1H, Py), 8.627–8.635 (d, J ¼ 4 Hz, 1H, Py),
10.08 (s, 1H, NH, exch). GC–MS m/z 370 (Mþ, 5.49%), 355 (Mþ–ꢂCH3;
17.13%), 57 (
,100%). Anal. Calcd for C21H16N4O4S C, 60.00; H,
3.81; N, 13.33; S, 7.61. Found C, 59.65; H, 4.20; N, 13.15; S, 7.86.
Similarly were synthesized compounds 3b–h.
1.43%), 292
4.89%), 265 (
(
,
4.87%), 266
(
,
4.3.2. N-(3-(4-Acetylphenyl)-4-phenyl thiazol-2(3H)-ylidene)-2,6-
dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide (3b)
Solvent of crystallization: MeOH; Power level: 450 W, Irradia-
tion time: 20 min; Yield: 51%; mp: 145 ꢁC; IR (KBr) nmax: 3430 (NH),
, 4.41%), 134 (
, 21.04%),

1014
S.M. Sondhi et al. / European Journal of Medicinal Chemistry 44 (2009) 1010–1015
1686 (>C]O), 1613 (>C]N–), 1530, 1488 (Ar) cmꢀ1
.
1H NMR
(500 MHz, DMSO-d6) d: 2.577–2.598 (t, 2H, CH2), 4.16–4.19 (t, 1H,
(500 MHz, DMSO-d6) : 2.42 (s, 3H, COCH3), 5.69(s, 1H, ]CH–), 7.07
d
imidazolidin), 6.34 (s, 1H, >C]CH–), 7.10–7.12 (m, 2H, Ar), 7.17–7.19
(d, J ¼ 8.5 Hz, 2H, Ar), 7.23–7.24 (m, 3H, Ar), 7.37–7.39 (d, J ¼ 9 Hz,
2H, Ar), 7.80 (s, 1H, NH, exch), 10.59 (s, 1H, NH, exch). FAB-MS does
not give Mþ ion peak but gave 391 (MþꢀCl, 1%). Anal. Calcd for
C20H15N4O3SCl C, 56.33; H, 3.52; N, 13.14; S, 7.51. Found C, 56.02; H,
3.92; N, 13.53; S, 7.83.
(s, 1H, >C]CH–), 7.11–7.13 (m, 2H, Ar), 7.20–7.25 (m, 3H, Ar), 7.55–
7.57 (d, J ¼ 8 Hz, 2H, Ar), 7.95–7.97 (d, J ¼ 9 Hz, 2H, Ar), 9.58 (s, 1H,
NH, exch), 10.97 (s, 1H, NH, exch). GC–MS m/z 432 (Mþ, 29.96%), 139
(
, 16.4%), 119
(
, 7.82%). Anal. Calcd for
4.3.7. 2-(2,5-Dioxoimidazolidin-4-yl)-N-(3-(4-nitrophenyl)-4-
phenyl thiazol-2(3H)-ylidene)acetamide (3g)
C
22H16N4O4S C, 61.11; H, 3.70; N, 12.96; S, 7.40. Found C, 60.83; H,
3.35; N, 13.20; S, 7.24.
Solvent of crystallization: MeOH; Power level: 450 W, Irradia-
tion time: 20 min; Yield: 84%; mp: 215 ꢁC; IR (KBr) nmax: 3194 (NH),
4.3.3. N-(3-(4-Chlorophenyl)-4-phenyl thiazol-2(3H)-ylidene)-2,6-
dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide (3c)
2916 (CH2), 1765, 1712 (>C]O), 1534, 1495 (Ar) cmꢀ1 1H NMR
.
(500 MHz, DMSO-d6)
d
: 2.60–2.61 (d, J ¼ 5 Hz, 2H, CH2), 4.18–4.20
Solvent of crystallization: MeOH; Power level: 450 W, Irradia-
tion time: 20 min; Yield: 84%; mp: 155 ꢁC; IR (KBr) nmax: 3447 (NH),
(t, J ¼ 5; 10.5 Hz, 1H, imidazolidin), 6.42 (s, 1H, >C]CH–), 7.11–7.13
(m, 2H, Ar), 7.24–7.25 (m, 3H, Ar), 7.41–7.43 (d, J ¼ 9 Hz, 2H, Ar),
7.85 (s.1H, NH, exch), 8.14–8.16 (d, J ¼ 9 Hz, 2H, Ar), 10.59 (s, 1H, NH,
1733 (>C]O), 1618(>C]N–), 1533 and 1486 (Ar) cmꢀ1 1H NMR
.
(500 MHz, DMSO-d6) d: 5.73 (s, 1H, ]CH–), 7.11 (s, 1H, >C]CH–),
exch), GC–MS m/z 437 (M,þ 1.32%), 296 (
,
7.18–7.20 (d, J ¼ 7 Hz, 2H, Ar), 7.29–7.35 (m, 3H, Ar), 7.52–7.54 (d,
J ¼ 8.5 Hz, 2H, Ar), 7.57–7.59 (d, J ¼ 8.5 Hz, 2H, Ar), 9.52 (s,1H, NH,
exch),10.93 (s.1H, NH, exch). FAB-MS does not give Mþ ion peak but
31.34%), 99 (
, 2.87%), 77 (C6Hþ5 , 21.07%), 76 (
, 100%).
Anal. Calcd for C20H15N5O5S C, 54.91; H, 3.43; N, 16.01; S, 7.32.
Found C, 55.23; H, 3.02; N, 15.85; S, 7.73.
gave m/z 313 (Mþ-m/z 111, 2.77%), 290 (
25%), 289 (m/z 290 H, 90%), 288 (m/z 289 H, 20%), 287 (m/z 288 H,
100%), 134 ( , 4.14%), 111 ( , 2.77%). Anal. Calcd for
,
˙
˙
4.3.8. 2-(2,5-Dioxoimidazolidin-4-yl)-N-(3-(2-nitrophenyl)-4-
phenylthiazol-2(3H)-ylidene)acetamide (3h)
Solvent of crystallization: MeOH; Power level: 450 W, Irradia-
tion time: 20 min; Yield: 74%; mp: 175 ꢁC; IR (KBr) nmax: 3320 (NH),
1700 (>C]O), 1581, 1531 (Ar) cm.ꢀ1 1H NMR (500 MHz, DMSO-d6)
C20H13N4O3SCl C, 56.60; H, 3.06; N, 13.20; S, 7.54. Found C, 57.03; H,
3.47; N, 13.65; S, 7.23.
d
: 2.60–2.61 (d, J ¼ 5.5 Hz, 2H, CH2), 4.18–4.20 (t, J ¼ 5; 10 Hz, 1H,
imidazolidin), 6.37 (s, 1H, >C]CH–), 7.14–7.22 (m, 3H, Ar), 7.23–
7.25 (m, 3H, Ar), 7.50–7.53 (m, 1H, Ar), 7.57–7.61 (m, 1H, Ar), 7.82 (s,
1H, NH, exch), 8.01–8.03 (dd, J1 ¼8 Hz, J2 ¼ 1 Hz, 1H, Ar), 10.59 (s,
1H, NH, exch). FAB-MS does not give Mþ ion peak but gave 391
(MþꢀNO2, 2.77%). Anal. Calcd for C20H15N5O5S C, 54.91; H, 3.43; N,
16.01; S, 7.32. Found C, 54.59; H, 3.72; N, 16.43; S, 7.02.
4.3.4. N-(4-(4-Methoxyphenyl)-3-(4-nitrophenyl)thiazol-2(3H)-
ylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-
carboxamide (3d)
Solvent of crystallization: MeOH; Power level: 300 W, Irradia-
tion time: 25 min; Yield: 60%; mp: 215 ꢁC; IR (KBr) nmax: 3400 (NH),
1683 (>C]O), 1606(>C]N–), 1528, 1493 (Ar) cmꢀ1 1H NMR
.
(500 MHz, DMSO-d6) d: 3.72 (s, 3H, OCH3), 5.76 (s, 1H, ]CH–),
6.86–6.87 (d, J ¼ 8 Hz, 2H, Ar), 6.99 (s, 1H, >C]CH–), 7.13–7.15 (d,
J ¼ 7.5 Hz, 2H, Ar), 7.78–7.80 (d, J ¼ 7.5 Hz, 2H, Ar), 8.36–8.38 (d,
J ¼ 8.5 Hz, 2H, Ar), 9.69 (s, 1H, NH, exch),11.00 (s, 1H, NH, exch). GC–
MS m/z 465 (Mþ, 4.25%),358 (Mþ-m/z 107, 3.06%). 326
4.4. Anti-inflammatory activity
Paw oedema inhibition test was used on albino rats of charles
Foster by adopting the method of Winter et al. [24] Groups of five
animals of both sexes (body weight 120–160 g), excluding pregnant
females, were given a dose of test compound. Thirty minutes later,
0.20 ml of 1% freshly prepared carrageenan suspension in 0.9% NaCl
solution was injected subcutaneously into the planter aponeurosis
of the hind paw and the volume was measured by a water ple-
thysmometer apparatus and then measured again 1–3 h later. The
mean increase of paw volume at each interval was compared with
that of control group (five rats treated with carrageenan but not
with test compound) at the same intervals and percent inhibition
value calculated by the formula is given below.
(
, 3.06%), 122 (
, 79.87%),
107 (
, 65.26%), Anal. Calcd for C21H15N5O6S C, 54.19;
H, 3.22; N, 15.05; S, 6.88. Found C, 54.43; H, 2.95; N, 15.45; S, 6.65.
4.3.5. N-(3-(2-Nitrophenyl)-4-phenyl thiazol-2(3H)-ylidene)-2,6-
dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide(3e)
Solvent of crystallization: MeOH; Power level: 450 W, Irradia-
tion time: 20 min; Yield: 68%; mp: 220 ꢁC; IR (KBr) nmax: 3250 (NH),
1688 (>C]O), 1533, 1486 (Ar) cmꢀ1. 1H NMR (500 MHz, DMSO-d6)
% Anti-inflammatory activity ¼ ½1 ꢀ Dt=Dcꢃ ꢄ 100
Dt and Dc are paw volumes of oedema in tested and control groups,
respectively. Compounds 2a–i and 3a–h were screened for anti-
inflammatory activity and results are summarized in Table 1.
d: 5.78 (s, 1H,
), 6.99 (s, 1H, >C]CH–), 7.12–7.13 (t, 2H,
Ar), 7.25–7.33 (m, 3H, Ar), 7.72–7.77 (m, 2H, Ar), 7.84–7.88 (m, 1H,
Ar), 8.16–8.17 (dd, 1H, Ar), 9.84 (s, 1H, NH, exch), 11.02 (s, 1H, NH,
exch). FAB-MS does not give Mþ ion peak but gave 392 (Mþ-HNCO,
2%). Anal. Calcd for C20H13N5O5S C, 55.17; H, 2.98; N, 16.09; S, 7.35.
Found C, 55.42; H; 3.02; N, 15.95; S, 7.80.
4.5. Analgesic activity
Acetic acid writhing test was performed on mice by following the
method of Davis et al. [25] groups of five mice of both sexes (body
weight 20–30 g), pregnant females excluded, were given a dose of
test compound. Thirty minutes later, the animals were injected
0.25 ml/mice of 0.5% acetic acid solution and writhes were counted
during the following 60 min. The mean number of writhes of each
4.3.6. N-(3-(4-Chlorophenyl)-4-phenylthiazol-2(3H)-ylidene)-2-
(2,5-dioxoimidazolidin-4-yl)acetamide (3f)
Solvent of crystallization: MeOH; Power level: 450 W, Irradia-
tion time: 20 min; Yield: 67%; mp: 200 ꢁC; IR (KBr) nmax: 3441 (NH),
1721 (>C]O), 1615(>C]N–), 1532 and 1487 (Ar) cmꢀ1 1H NMR
.

S.M. Sondhi et al. / European Journal of Medicinal Chemistry 44 (2009) 1010–1015
1015
[9] A. Bielawska, K. Bielawski, A. Muszynska, Il Farmaco 59 (2004) 111–117.
[10] S. Ozden, D. Atabey, S. Yildiz, H. Goker, Bioorg. Med. Chem. 13 (2005) 1587–
1597.
[11] M.J. Rudolph, C.R. Illig, N.L. Subasinghe, K.J. Wilson, J.B. Hoffman, T. Randle,
D. Green, C.T. Molloy, R.M. Soll, F. Lewandowski, M. Zhang, R. Bone,
J.C. Spurlino, I.C. Deckman, C. Manthey, C. Sharp, D. Maguire, B.L. Grasberger,
R.L. Desjarlais, Z. Zhou, Bioorg. Med. Chem. Lett. 12 (2002) 491–495.
[12] D. Galanakis, A.P. Kourounakis, K.C. Tsiakitzis, C. Doulgkeris, E.A. Rekka,
A. Gavalas, C. Kravaritou, C. Christos, P.N. Kourounakis, Bioorg. Med. Chem.
Lett. 14 (2004) 3639–3643.
experimental group and percent decrease compared with control
group (five mice not treated with test compounds) were calculated.
Compounds 2a–d, f, g, i and 3a, b, d, f were screened for anal-
gesic activity and results are summarized in Table 1.
Acknowledgements
We are thankful to the technical staff of the Chemistry Depart-
ment, I.I.T. Roorkee, for spectroscopic studies and elemental anal-
ysis. One of the authors Mr. Jaiveer Singh (SRF-NET) is thankful to
CSIR, New Delhi, for financial assistance.
[13] P. Kumar, E.E. Knaus, Eur. J. Med. Chem. 28 (1993) 881–885.
[14] M. Ban, H. Taguchi, T. Katushima, M. Takahashi, K. Shinoda, A. Watanabe,
T. Tominaga, Bioorg. Med. Chem. 6 (1998) 1069–1076.
[15] C. Papadopoulou, A. Geronikaki, D. Hadjpaulou-Litina, Il Farmaco 60 (2005)
969–973.
[16] I.O. Zhuravel, S.M. Kovalenko, A.V. Ivachtchenko, K.V. Balakin,
V.V. Kazmirchuk, Bioorg. Med. Chem. Lett. 15 (2005) 5483–5487.
[17] I.V. Ukrainets, L.V. Sidorenko, L.A. Petrushovo, O.V. Gorokhova, Chem. Heter-
ocycl. Comput. 42 (2006) 64–69.
References
[18] S.M. Sondhi, R.N. Goyal, A.M. Lahoti, N. Singh, R. Shukla, R. Raghubir, Bioorg.
Med. Chem. 13 (2005) 3185–3195.
[1] S.M. Sondhi, N. Singhal, M. Johar, B.S.N. Reddy, J.W. Lown, Curr. Med. Chem. 9
(2002) 1045–1074.
[19] S.M. Sondhi, N. Singh, M. Johar, A. Kumar, Bioorg. Med. Chem. 13 (2005) 6158–
6166.
[20] S.M. Sondhi, N. Singh, A. Kumar, O. Lozach, L. Meijer, Bioorg. Med. Chem. 14
(2006) 3758–3765.
[21] S.M. Sondhi, S. Jain, M. Dinodia, R. Shukla, R. Raghubir, Bioorg. Med. Chem. 15
(2007) 3334–3344.
[22] S.M. Sondhi, M. Dinodia, S. Jain, A. Kumar, Eur. J. Med. Chem. (available on
line).
[23] M.P. Mahajan, S.K. Vasundeva, N.K. Ralhan, Ind. J. Chem. 10 (1972) 318–319.
[24] C.A. Winter, E.A. Risley, G.W. Nuss, Proc. Soc. Exp. Biol. Med. 111 (1962) 544–
550.
[25] J.E. Davis, D.N. Kellet, J.C. Penningtn, Arch. Int. Pharmacodyn. Ther. 221 (1976)
274–284.
[2] C.C. Chan, S. Boyce, C. Brideatt, A.W. Ford-Hutchinson, R. Gordon, D. Guay,
R.G. Hill, C.S. Li, J. Mancini, M. Penneton, J. Pharmacol. Exp. Ther. 274 (1995)
1531–1537.
[3] A. Bentolini, A. Ottani, M. Sandrini, Curr. Med. Chem. 9 (2002) 1033–1043.
[4] L.S. Simon, Arthritis Care Res. 45 (2001) 209–215.
[5] V.A. Glushkov, L.V. Anikina, Yu.B. Vikharev, E.V. Feshina, Yu.V. Shklyaev,
Pharm. Chem. J. 39 (2005) 533–536.
[6] A. Panico, P. Vinici, M. Inert, V. Cardile, B. Gentile, G. Ronsisvalle, Il Farmaco 57
(2002) 671–675.
[7] T.M. Sielecki, J. Liu, S.A. Mousa, A.L. Racanelli, E.A. Hausner, R.R. Wexler,
R.E. Olson, Bioorg. Med. Chem. Lett. 11 (2001) 2201–2204.
[8] P. Sienkiewich, K. Bielawski, A. Bielawska, J. Palka, Environ. Toxicol. Pharmacol.
20 (2005) 118–124.