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S. N. Mokale et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4424–4426
filtered, washed thoroughly with cold water and dried. All the other
The final compounds 3-(4,6-disubtituted-2-thioxo-1,2,3,4-tet-
compounds of this series were synthesized using same procedure. The
physical characteristics of the compounds (Ia–Ie) are given in Table 2.
rahydropyrimidin-5-yl) propanoic acid (IIa–IIj) have been
synthesized by the reaction of the 5-(4-subtituted phenyl)-5-oxo-
pentanoic acid (Ia–Ie) with urea and substituted aldehyde in alco-
hol in presence of potassium carbonate (Scheme 1).
Synthesis
of
3-(4,6-disubtituted-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)
propanoic acid (IIa–IIj):
A mixture of 5-(4-subtituted phenyl)-5-oxopentanoic acid (Ia–Ie) (1 0.06 mol),
thiourea (2 0.06 mol), aldehyde (3 0.06 mol) and K2CO3 (0.06 mol) in 100 ml
ethanol was refluxed in oil bath for 8–12 h. The reaction mixture was cooled
and the solid obtained was filtered. The solid was dissolved in hot water and
filtered. The filtrate was neutralized with acetic acid. The solid obtained was
filtered, dried and recrystallized from ethyl acetate. All the other compounds of
In conclusion, a new series of 3-(4,6-disubtituted-2-thioxo-
1,2,3,4-tetrahydropyrimidin-5-yl) propanoic acid derivatives has
been prepared and fully assigned by analytical and spectral data.11
The present investigation showed significant anti-inflammatory
action to all compound of the series except IIb, when compared
against vehicle treated control. The results were found to be equi-
potent with diclofenac (Table 1). The anti-inflammatory effect was
found to be most significant (p <0.05) at 1 h and gradually reduced
at subsequent hours. Overall looking at duration of action and per-
cent inhibition, the sustained and significant (p <0.05) action was
reported with IIe, IIf, IIg, IIh and IIj. Moreover, IIc and IId were also
significant (p <0.05) but had shown short duration of action.
Hence the present series could be developed as a novel class of
anti-inflammatory agents. However, further structural modifica-
tion is planned to increase the anti-inflammatory activities.
this series were synthesized using same procedure and characterized using 1
H
NMR and Mass spectrometry. The physical characteristics of the compounds
(IIa–IId) are given in Table 3.
The spectral data of each compound is given below.
3-(6-(4-Fluorophenyl)-4-(furan-2-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)
propanoic acid (IIa):
1H NMR (400 MHz, DMSO): d = 10.21 (s, 1H), 6–8.5 (m, 7H), 5.2 (s, 1H), 4.6 (s,
1H), 2.8 (d, 2H), 2.42 (d, 2H), 2.01 (br s, 1H); MS: m/z = 447 (m+1).
3-(4-(4-Hydroxy-3-methoxyphenyl)-2-thioxo-6-p-tolyl-1,2,3,4-
tetrahydropyrimidin-5yl) propanoic acid (IIb):
1H NMR (400 MHz, DMSO): d = 10.21 (s, 1H), 6.3–8.88 (m, 7H), 5.61 (s, 1H),
5.30 (s, 1H), 4.68 (s, 1H), 3.65 (s, 3H), 2.91 (s, 3H), 2.61 (d, 2H), 2.24 (d, 2H), 2.00
(br s, 1H); MS: m/z = 399 (m+1).
3-(6-(4-Chlorophenyl)-4-(furan-2-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-
yl)propanoic acid (IIc):
1H NMR (400 MHz, DMSO): d = 10.22 (s, 1H), 6.1–8.2 (m, 7H), 5.3 (s, 1H), 4.65
(s, 1H), 2.85 (d, 2H), 2.45 (d, 2H), 2.10 (br s, 1H); MS: m/z = 363 (m+1).
3-(6-(4-Chlorophenyl)-4-(2-hydroxyphenyl)-2-thioxo-1,2,3,4-
tetrahydropyrimidin-5-yl) propanoic acid (IId):
Acknowledgements
1H NMR (400 MHz, DMSO): d = 10.31 (s, 1H), 6.2–8.1 (m, 9H), 5.26 (s, 1H), 4.70
(s, 1H), 2.91 (d, 2H), 2.44 (d, 2H), 2.12 (br s, 1H); MS: m/z = 389 (m+1).
3-(2-Thioxo-6-p-tolyl-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrimidin-5-
yl) propanoic acid (IIe):
The authors thankful to the Mrs. Fatima Rafiq Zakaria Chairman
Maulana Azad Educational Trust and Dr. M.H.G. Dehghan, Princi-
pal, Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus,
Aurangabad 431 001 (M.S.), India for providing the laboratory
facility.
1H NMR (400 MHz, DMSO): d = 10.21 (s, 1H), 6.24–8.78 (m, 6H), 5.63 (s, 1H),
5.30 (s, 1H), 4.68 (s, 1H), 3.55 (s, 9H), 2.92 (s, 3H), 2.62 (d, 2H), 2.26 (d, 2H), 2.00
(br s, 1H); MS: m/z = 443 (m+1).
3-(4-(Furan-2-yl)-2-thioxo-6-p-tolyl-1,2,3,4-tetrahydropyrimidin-5-yl) propanoic
acid (IIf):
References and notes
1H NMR (400 MHz, DMSO): d = 10.21 (s, 1H), 6.2–8.35 (m, 7H), 5.31 (s, 1H),
4.62(s, 1H), 2.9 (d, 2H), 2.75 (d, 2H), 2.51 (s, 3H), 2.09 (br s, 1H); MS: m/z = 343
(m+1).
1. Moncada, S.; Flower, R. J.; Vane, J. R. In Goodman and Gilman’s The
Pharmacological Basis of Therapeutics; Gilman, A. G., Goodman, L. S., Eds., 6th
ed.; Macmillan Publishing: New York, 1980; p 668.
[2]. Lombardino, J. G. Medicinal Chemistry of Acidic Nonsteroidal
Antiinflammatory Drugs. In Nonsteroidal Antiinflammatory Drugs;
Lombardino, J. G., Ed.; Wiley-Interscience: New York, 1985; p 255.
3. Pilotto, A.; Franceschi, M.; Leandro, G.; Dimario, F.; Valerio, G. Eur. J.
Gastroenterol. 1997, 951.
4. Pirson, Y.; Van, D. E.; Strihou, C. Am. J. Kidney Dis. 1986, 8, 337.
5. Bahekar, S. S.; Shinde, D. B. Bioorg. Med. Chem. Lett. 2004, 14, 1733.
6. Laneria, S.; Sacchia, A.; Gallitellia, M. Eur. J. Med. Chem. 1998, 33, 163.
7. Bahekar, S. S.; Shinde, D. B. Acta Pharm. 2003, 53, 223.
3-(4-(2-Hydroxyphenyl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)
propanoic acid (IIg):
1H NMR (400 MHz, DMSO): d = 10.23 (s, 1H), 6.2–8.7 (m, 9H), 5.12 (s, 1H), 4.18
(s, 1H), 2.79 (d, 2H), 2.45 (d, 2H), 2.10 (br s, 1H); MS: m/z = 355 (m+1).
3-(4-(Furan-2-yl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl) propanoic
acid (IIh):
1H NMR (400 MHz, DMSO): d = 10.25 (s, 1H), 6.22-8.27 (m, 8H), 5.18 (s, 1H),
4.20 (s, 1H), 2.81 (d, 2H), 2.50 (d, 2H), 2.14 (br s, 1H); MS: m/z = 329 (m+1).
3-(6-(4-Chlorophenyl)-4-(pyridin-2-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-
yl) propanoic acid (IIi):
1H NMR (400 MHz, DMSO): d = 10.28 (s, 1H), 6.23–8.29 (m, 8H), 5.20 (s, 1H),
4.22 (s, 1H), 2.82 (d, 2H), 2.52 (d, 2H), 2.19 (br s, 1H); MS: m/z = 374 (m+1).
3-(4-(2-Hydroxyphenyl)-6-(4-methoxyphenyl)-2-thioxo-1,2,3,4
tetrahydropyrimidin-5-yl) propanoic acid (IIj):
[8]. Ouf, N. H.; Amr, A. E. Monatsh. Chem. 2008, 139, 576.
9. Mohamed, M. S.; Awad, S. M.; Sayed, A. I. Molecules 2010, 15, 1882.
10. Winter, C. A.; Risley, E. A.; Nuss, G. W. Proc. Soc. Exp. Biol. Med. 1962, 111, 544.
11. General:
1H NMR (400 MHz, DMSO): d = 10.27 (s, 1H), 6.12–8.67 (m, 8H), 5.40 (s, 1H),
5.12 (s, 1H), 4.18 (s, 1H), 3.20 (s, 3H), 2.81 (d, 2H), 2.49 (d, 2H), 2.12 (br s, 1H);
MS: m/z = 385 (m+1).
Melting points of compounds were taken in open capillaries on Scientific
Melting point apparatus and are uncorrected. The 1H NMR spectra were
recorded using Bruker avance II 400 spectrometer with TMS as internal
standard. The mass spectra were obtained using time of Flight Mass
Spectrometer.
Anti-inflammatory activity:
All the synthesized compounds were subjected to preliminary testing for anti-
inflammatory activity using Albino rats. Albino rats of either sex (150–200 g)
were divided into different groups, containing six animals each. Animals were
fasted for 12 h before experiment. The first group was a control one and
received vehicle [Tween80 in propylene glycol (10%, v/v), 0.5 ml per rat], the
second group received diclofenac sodium 20 mg kgÀ1 body weight. All the
remaining groups received the test compounds at the same dose orally. All the
suspensions for oral dose were prepared in the vehicle mentioned above and
Synthesis of 5-(4-subtituted phenyl)-5-oxopentanoic acid (Ia–Ie):
Place substituted benzene (0.5 M) and glutaric anhydride (0.75 M) in RBF
provided with a reflux condenser and calcium chloride guard tube. Stir the
mixture and add powdered anhydrous AlCl3 (0.165 M) all at once. The reaction
starts immediately. HCl was evolved and the mixture became hot. Heat the
reaction mixture on oil bath to gentle refluxing, with continued stirring for 1 h.
Allow the reaction mixture to cool, immersed the flask in a bath of cold water
and slowly add water and conc. HCl. This leads to separation of the benzene
layer. Separate the benzene layer and keep it for overnight to form solid mass.
The crude acid was dissolved in a solution of sodium carbonate by boiling it for
10–15 min. The solution was then filtered and washed with two portions of hot
water to remove the small amount of aluminium hydroxide. Treat the hot
filtrate with decolorizing carbon, boil it for 5 min and filter. Cool the hot filtrate
to about 50 °C and cautiously acidified with concn HCl and keep it for cooling
to 0 °C in a freezing mixture of ice and salt. Thus the product obtained was
administered in
a constant volume of 0.5 ml per rat. After 1 h of the
administration of the test compound and diclofenac sodium, 0.1 ml of 1% w/
v suspension of carangeenan was injected in to the subplanatar of left paw of
control and test animals. Immediately, the paw volume was measured using
plethysmometer (initial paw volume), there after the paw volume was
measured every hour till 24 h. The difference between initial and subsequent
readings gave the edema volume for the corresponding time. Percentage
inhibition was calculated.
Mokale, Santosh N.
