Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives and their biological evaluation as analgesic, antipyretic and anti-inflammatory agents

Abstract

Pyrimidine derivative 3 was afforded through the reaction of compound (1) with 5-ureidohydantion (2). Product 3 underwent a cyclization to produce fused pyrimidine derivative 7, although the latter product 7 was synthesized through one step via the reaction of compound (1) with 5-ureidohydantion (2) using another catalyst. Compound 3 was oriented to react with cyclic ketones 8a,b in the presence of elemental sulfur, salicylaldehyde (10), aryldiazonium chlorides 12a,b and ω-bromo-4-methoxy- acetophenone (14), which afforded, fused thiophene derivatives 9a,b, coumarin derivative 11, arylhdrazono derivatives 13a,b and 4-methoxyphenyl butenyl derivative 15, respectively. The latter product 15 was reacted with either potassium cyanide (16a) or potassium thiocyanide (16b) to form cyano and thiocyano derivatives 17a,b, respectively. Compound 17a underwent further cyclization to afford pyridopyrimidine derivative 19. Compound 15 was reacted with either hydrazine (20a) or phenylhydrazine (20b) to produce hydrazo derivatives 21a,b and these products were cyclize to produce pyrrole derivatives 23a,b. Finally, 5-ureidohydantion (2) was reacted with compounds 24a,b,c to afford pyrimidine derivatives 25a,b,c. The structures of the synthesized compounds were confirmed using IR, 1H NMR, 13C NMR and mass spectrometry techniques. Compounds 11 and 19 have promising as analgesic and antipyretic activities.

Full text

Braz. J. Pharm. Sci. 2018;54(4):e00153 Page 1 / 13
Brazilian Journal of
Pharmaceutical Sciences
http://dx.doi.org/10.1590/s2175-97902018000400153
Article
*Correspondence: K. A. El-Sharkawy. Department of Pharmaceutical Che-
mistry, College of Pharmacy, Jazan University. P.O. Box 114, Jazan 45142,
Saudi Arabia. Phone: 00201010698361, 0966559686517 / Fax: 00238371543.
E-mail: karamsyn@yahoo.com
Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine
and pyrrole derivatives and their biological evaluation as analgesic,
antipyretic and anti-inflammatory agents
Karam Ahmed El-Sharkawy,1,2* Mohammed Mofreh AlBratty,1 Hassan Ahmad Alhazmi1
1Department of Pharmaceutical Chemistry, College of pharmacy, Jazan University, Jazan 45142, Saudi Arabia, 2Department of
Chemistry, Faculty of Biotechnology, October University for Modern Sciences and Arts(MSA), Egypt
Pyrimidine derivative 3 was aorded through the reaction of compound (1) with 5-ureidohydantion (2).
Product 3 underwent a cyclization to produce fused pyrimidine derivative 7, although the latter product
7 was synthesized through one step via the reaction of compound (1) with 5-ureidohydantion (2) using
another catalyst. Compound 3 was oriented to react with cyclic ketones 8a,b in the presence of elemental
sulfur, salicylaldehyde (10), aryldiazonium chlorides 12a,b and ω-bromo-4-methoxy- acetophenone
(14), which aorded, fused thiophene derivatives 9a,b, coumarin derivative 11, arylhdrazono derivatives
13a,b and 4-methoxyphenyl butenyl derivative 15, respectively. The latter product 15 was reacted with
either potassium cyanide (16a) or potassium thiocyanide (16b) to form cyano and thiocyano derivatives
17a,b, respectively. Compound 17a underwent further cyclization to aord pyridopyrimidine derivative
19. Compound 15 was reacted with either hydrazine (20a) or phenylhydrazine (20b) to produce hydrazo
derivatives 21a,b and these products were cyclize to produce pyrrole derivatives 23a,b. Finally,
5-ureidohydantion (2) was reacted with compounds 24a,b,c to aord pyrimidine derivatives 25a,b,c.
The structures of the synthesized compounds were conrmed using IR, 1H NMR, 13C NMR and mass
spectrometry techniques. Compounds 11 and 19 have promising as analgesic and antipyretic activities.
Keywords: Pyrimidine derivative. Thiophene. Coumarin. Pyridine. Pyrrole. Analgesic. Antipyretic and
anti-inammatory agents.
INTRODUCTION
A series of studies was introduced to discover
that hydantoin derivatives, important heterocyclic
compounds, act as antioxidant agents (Gus’kov et al.,
2004). Moreover, Imidazolidine-2,4 dione derivatives are
specic biologically active compounds and act as anti-
proliferative agents (Reddy et al., 2010), hypoglycemic,
aldose reductase inhibitor agents (Iqbal et al., 2015) and
Bcl-2 inhibitors (Wang et al., 2015).
Pyridopyrimidine derivatives have a wide variety of
biological properties, including antileishmanial (Agarwal
et al., 2005) and antitubercular activities (Horvati et al.,
2015; Rajesh et al., 2011). Additionally fused thiophene
derivatives have antitumor activity (Dallemagne et al.,
2003) and pyrimidine derivatives containing the coumarin
moiety have analgesic and anti-pyretic eects (Keri et
al., 2010). Hydrazono derivatives have shown anticancer
activity (Sztanke, Rzymowska, Sztanke, 2013) and pyrrole
derivatives have antibacterial activity (Padmavathi et al.,
2011). In this article we aimed to improve and discover
the analgesic, antipyretic and anti-inammatory activities
of synthesized compounds.
MATERIAL AND METHODS
General procedures
The melting points of the synthesized compounds
were determined in open capillaries and are uncorrected.
Elemental analyses were performed on a Yanaco CHNS
Corder elemental analyzer (Japan). IR spectra were
measured using KBr discs on a Pye Unicam SP-1000
spectrophotometer. 1H NMR and 13C NMR spectra were
measured on a Varian EM 390-200 MHz instrument

K. A. El-Sharkawy, M. M. AlBratty, H. A. Alhazmi
Braz. J. Pharm. Sci. 2018;54(4):e00153
Page 2 / 13
with CD3SOCD3 as the solvent using TMS as an internal
standard material, the chemical shifts were expressed as δ
ppm. Mass spectra were recorded on Kratos (75 eV) MS
equipment (Germany).
General procedures for the synthesis of compound:
3-(4,6-diamino-1-(2,5-dioxoimidazolidin-4-yl)-2-oxo-1,2-
dihydropyrimidin-5-yl)-3-iminopropanenitrile (3)
β-amino-α,γ-dicyanocrotononitrile (1) (3.96 g,
0.03 mol) was added to a 5-ureidohydantoin solution
(2) (4.743 g, 0.03 mol) in 100 mL of ethanol containing
dimethylformamide (5mL) and triethylamine (1.0 mL) as
a catalyst. The reaction mixture was heated under reux
for 6 h, cooled and poured onto ice containing a few drops
of HCl. Then, the formed solid product was ltered out.
Compound 3: Faint yellow crystals from ethanol,
yield 54%, 4.701 g, m.p. 168-170 ºC. IR (KBr): υ/cm-1 =
3438-3355 (2NH2, 3NH), 2883 (CH2), 2765 (CH), 2223
(CN), 1673, 1668, 1661 (3CO), 1648 (C=C). 1H NMR
(DMSO-d6) δ = 3.05-3.13 (s, 2H, CH2), 4.87, 5.12 (2s, 4H,
D2O-exchangeable, 2NH2), 5.74 (s, 1H, imidazolidindione
ring), 8.35, 9.22, 9.79 (3s, 3H, D2O-exchangeable, 3NH).
13C NMR: δ = 40.9 (CH2), 62.1 (CH), 106.4 (C=NH),
116.9 (CN), 120.1, 148.6, 152.7 (pyrimidine C), 164.4,
168.3, 171.7 (3C=O). MS (relative intensity) m/z: 290
(M+, 32.2%). Calcd for C10H10N8O3 (290.24): C, 41.38;
H, 3.47; N, 38.61%. Found: C, 41.65; H, 3.24; N, 38.90%.
General procedure for the synthesis of compound:
5-(4,5,7-triamino-2-oxopyrido-[2,3-d]pyrimidin-3(2H)-yl)
imidazolidine-2,4-dione (7)
Method (A): A solution of compound 3 (0.58 g,
0.002 mol) in ethanol (50 mL) containing a catalytic
amount of piperidine (0.5 mL) was heated under reux
for 5 h, poured onto an ice/water mixture containing a few
drops of hydrochloric acid. The formed solid product was
collected by ltration.
Method (B): β-Amino-α, γ-dicyanocrotononitrile (1)
(0.396 g, 0.003 mol) was added to a solution of compound
2 (0.474 g, 0.003 mol) in sodium ethoxide (0.003 mol)
[prepared by dissolving sodium metal (0.069 g, 0.003
mol) in absolute ethanol (50 mL)]. The reaction mixture
was heated under reux for 6 h and then evaporated under
vacuum. The product was triturated with ethanol and the
formed solid product was collected by ltration.
Compound 7: Brown crystals from ethanol, yield
66%, 0.575 g, m.p. 115-117 ºC. IR (KBr): υ/cm-1 =
3488-3327 (3NH2, 2NH), 2783 (CH), 1695, 1684, 1662
(3CO), 1651 (C=N). 1H NMR (DMSO-d6) δ = 4.78,
4.93, 5.27 (3s, 6H, D2O-exchangeable, 3NH2), 5.67 (s,
1H, imidazolidindione ring), 6.87 (s, 1H, pyridine ring),
8.73, 9.95 (2s, 2H, D2O-exchangeable, 2NH). 13C NMR:
δ = 55.7 (CH), 124.3, 133.4, 138.5, 144.7, 150.3, 152.4
(pyridine C, pyrimidine C), 166.1, 169.7, 173.2 (3C=O).
Calcd for C10H10N8O3 (290.24): C, 41.38; H, 3.47; N,
38.61%. Found: C, 41.11; H, 3.73; N, 38.99%.
General procedure for the synthesis of compounds:
5-(4,6-diamino-5-((2-amino-5,6-dihydro-4H-
cyclopenta[b]thiophen-3-yl)(imino)methyl)-2-oxo-
pyrimidin-1(2H)-yl) imidazolidine-2,4-dione (9a) and
5-(4,6-diamino-5-((2-amino-4,5,6,7-tetrahydrobenzo
[b]thiophen-3-yl(imino) methyl)-2-oxopyrimidin-1(2H)
yl) imidazolidine-2,4-dione (9b)
To a solution of compound 3 (0.58 g, 0.002 mol) in
ethanol (50 mL) containing trimethylamine (0.5 mL), either
cyclopentanone (8a) (0.168 g, 0.002 mol) or cyclohexanone
(8b) (0.196 g, 0.002 mol) together with elemental sulfur
(0.064 g, 0.002 mol) were added. The reaction mixture was
heated under reux for 4 h, cooled and poured onto an ice/
water mixture containing a few drops of HCl. The formed
precipitate was collected by ltration.
Compound 9a: Brown crystals from 1,4-dioxane,
yield 63%, 0.489 g, m.p. 202-204 ºC. IR (KBr): υ/cm-1 =
3458-3336 (3NH2, 3NH), 2880 (CH2), 2796 (CH), 1683,
1674, 1663 (3CO), 1653 (C=N), 1646 (C=C), 684 (C-S).
1H NMR (DMSO-d6) δ = 2.07-2.18 (m, 6H, 3CH2), 4.54,
4.65, 5.81 (3s, 6H, D2O-exchangeable, 3NH2), 5.98 (s, 1H,
imidazolidindione ring), 8.52, 8.77, 9.12 (3s, 3H, D2O-
exchangeable, 3NH). 13C NMR: δ = 22.4, 27.3, 29.9 (3
CH2), 51.3 (CH), 93.8 (C=NH), 126.2, 131.5, 136.3, 140.5,
142.7, 149.1, 151.6 (thiophene C, pyrimidine C), 165.4,
168.8, 172.1 (3C=O). Calcd for C15H16N8O3S (388.40): C,
46.38; H, 4.15; N, 28.85; S, 8.26%. Found: C, 46.17; H,
3.89; N, 28.66; S, 8.01%.
Compound 9b: Brown crystals from 1,4-dioxane,
yield 58%, 0.477 g, m.p. 212-214 ºC. IR (KBr): υ/cm-1 =
3460-3349 (3NH2, 3NH), 2882 (CH2), 2768 (CH), 1677,
1671, 1664 (3CO), 1655 (C=N), 1649 (C=C), 676 (C-S).
1H NMR (DMSO-d6) δ = 2.18-2.39 (m, 8H, 4CH2), 4.48,
4.69, 5.45 (3s, 6H, D2O-exchangeable, 3NH2), 5.86 (s, 1H,
imidazolidindione ring), 8.61, 8.86, 9.08 (3s, 3H, D2O-
exchangeable, 3NH). 13C NMR: δ = 22.8, 25.4, 27.3, 29.6
(4 CH2), 54.7 (CH), 97.1 (C=NH), 128.1, 134.7, 138.6,
141.5, 146.6, 150.8, 153.3 (thiophene C, pyrimidine
C), 162.2, 166.7, 170.6 (3C=O). Calcd for C16H18N8O3S
(402.43): C, 47.75; H, 4.51; N, 27.84; S, 7.97%. Found:
C, 47.56; H, 4.78; N, 28.09; S, 7.68%.

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives
Braz. J. Pharm. Sci. 2018;54(4):e00153 Page 3 / 13
General procedure for the synthesis of compound:-
5-(4,6-diamino-5-(imino(2-oxo-2H-chromen-3-yl)
methyl)-2-oxopyrimidin-1(2H)-yl)imidazolidine-2,4-dione
(11)
Salicylaldehyde (10) (0.244 g, 0.002 mol) was
added to a solution of compound 3 (0.58 g, 0.002 mol) in
1,4-dioxane (50 mL) containing piperidine (0.5 mL). The
reaction mixture was heated under reux for 5 h and then
evaporated under vacuum. The solid product was triturated
with ethanol and the formed solid product was collected
by ltration.
Compound 11: Yellowish brown crystals from
1,4-dioxane, yield 70%, 0.553 g, m.p. 185-187 ºC.
IR (KBr): υ/cm-1 = 3443-3311 (2NH2, 3NH), 3052
(CH-aromatic.), 2762 (CH), 1835, 1681, 1666, 1660
(4C=O), 1652 (C=N), 1112 (CO), 1649 (C=C). 1H NMR
(DMSO-d6) δ = 4.76, 5.25 (2s, 4H, D2O-exchangeable,
2NH2), 5.53 (s, 1H, imidazolidindione ring), 6.73 (s, 1H,
coumarin H-4), 7.51- 7.66 (m, 4H, C6H4), 8.88, 9.28, 9.55
(3s, 3H, D2O-exchangeable, 3NH). 13C NMR: δ = 59.5
(CH), 95.3 (C=NH), 125.5, 131.9, 136.8, 140.7, 144.5,
147.2, 149.1, 151.3, 153.5 (pyrimidine C, coumarin C),
161.5, 165.8, 170.3, 181.5 (4C=O). Calcd for C17H13N7O5
(395.33): C, 51.65; H, 3.31; N, 24.80%. Found: C, 51.93;
H, 3.59; N, 24.55%.
General procedure for the synthesis of compounds:-
2-(4,6-diamino-1-(2,5-dioxo- imidazolidin-4-yl)-2-
oxo1,2-dihydropyrimidin-5-yl)-2-imino-N’-phenyl-
acetohydrazonoyl cyanide (13a) and N’-(4-chlorophenyl)-
2-(4,6-diamino-1-(2,5-dioxo- imidazolidin-4-yl-2-oxo-
1,2-dihydropyrimidin-5-yl)-2-iminoaceto-hydrazonoyl
cyanide (13b)
To a cold solution (0-5 °C) of pyrimidine derivative 3
(0.58 g, 0.002 mol) in ethanol (50 mL) containing sodium
acetate (0.164 g, 0.002 mol) either benzenediazonium
chloride (12a) or 4-chlorobenzenediazonium chloride
(12b) (0.002 mol) [prepared by adding an aqueous sodium
nitrite solution (0.138 g, 0.002 mol) to a cold solution
of either aniline or 4-chloroaniline (0.002 mol) in the
appropriate amount of glacial acetic acid at (0-5 °C) with
continuous stirring] was added with continuous stirring.
The reaction mixture was stirred at room temperature for
an additional 4 h and the solid product was collected by
ltration.
Compound 13a: Pale brown crystals from ethanol,
yield 67%, 0.528 g, m.p. 137- 139 ºC. IR (KBr):
υ/cm-1 = 3476-3354 (2NH2, 4NH), 3053 (CH aromatic),
2761 (CH), 2223 (CN), 1678, 1667, 1663 (3CO), 1657
(C=N), 1646 (C=C). 1H NMR (DMSO-d6) δ = 4.54,
5.17 (2s, 4H, D2O-exchangeable, 2NH2), 5.61 (s, 1H,
imidazolidindione ring), 7.31- 7.62 (m, 5H, C6H5), 8.76,
9.13, 9.38, 9.59 (4s, 4H, D2O-exchangeable, 4NH).
13C NMR: δ = 67.3 (CH), 92.4, 109.2 (2C=N), 120.4
(CN), 123.3, 125.9, 127.9, 130.4, 132.8, 134.6, 138.4,
142.5 (pyrimidine C, C6H5), 163.9, 166.8, 169.3 (3C=O).
MS (relative intensity) m/z: 394 (M+, 17.9%). Calcd for
C16H14N10O3 (394.35): C, 48.73; H, 3.58; N, 35.52%.
Found: C, 48.48; H, 3.29; N, 35.80%.
Compound 13b: Dark brown crystals from ethanol,
yield 61%, 0.523 g, m.p. 193-195 ºC. IR (KBr): υ/cm-1
= 3451-3290 (2NH2, 4NH), 3050 (CH aromatic), 2770
(CH), 2224 (CN), 1673, 1663, 1659 (3CO), 1652 (C=N),
1647 (C=C). 1H NMR (DMSO-d6) δ = 4.63, 5.08 (2s, 4H,
D2O-exchangeable, 2NH2), 5.89 (s, 1H, imidazolidindione
ring), 7.44- 7.58 (d.d, 4H, C6H4), 8.58, 9.24, 9.55, 9.67 (4s,
4H, D2O-exchangeable, 4NH). 13C NMR: δ = 62.5 (CH),
98.4, 106.4 (2C=N), 121.7 (CN), 122.5, 124.8, 125.8, 128.3,
131.6, 135.3, 137.7, 141.5 (pyrimidine C, C6H5), 162.8,
165.7, 168.8 (3C=O). MS (relative intensity) m/z: 428
(M+, 23.4%). Calcd for C16H13ClN10O3 (428.79): C, 44.82;
H, 3.06; N, 32.67%. Found: C, 44.56; H, 3.33; N, 32.40%.
General procedure for synthesis of compound: 4-bromo-
2-((4,6-diamino-1-(2,5-dioxo- imidazolidin-4-yl)-2-oxo-
1,2-dihydropyrimidin-5-yl) (imino) methyl)-3-(4-methoxy-
phenyl) but-2-enenitrile (15)
ω-Bromo-4-methoxyacetophenone (14) (0.524 g,
0.002 mol) was added to a solution of compound 3 (0.58 g,
0.002 mol) in 1,4-dioxane (40 mL). The reaction mixture
was stirred at room temperature for 2 h and then poured
on to a beaker containing ice/water mixture. The formed
solid product was collected by ltration.
Compound 15: Brown crystals from ethanol, yield
72%, 0.712 g, m.p. 121-123 ºC. IR (KBr): υ/cm-1 = 3422-
3286 (2NH2, 3NH), 3055 (CH aromatic), 2986 (CH3),
2867 (CH2), 2766 (CH), 2225 (CN), 1680, 1669, 1662
(3CO), 1658 (C=N), 1648 (C=C). 1H NMR (DMSO-d6) δ
= 3.32 (s, 3H, OCH3), 3.77 (s, 2H, CH2), 4.81, 5.29 (2s, 4H,
D2O-exchangeable, 2NH2), 5.55 (s, 1H, imidazolidindione
ring), 7.48-7.71 (d.d, 4H, C6H4), 8.66, 9.22, 9.45 (3s, 3H,
D2O-exchangeable, 3NH). 13C NMR: δ = 41,2 (CH3),
49.5 (CH2), 65.3 (CH), 81.3, 88.6 (C=C), 103.7 (C=N),
118.3 (CN), 124.6, 126.7, 129.3, 131.5, 133.9, 135.4,
137.8 (pyrimidine C, C6H4), 160.7, 165.7, 169.8 (3C=O).
MS (relative intensity) m/z: 500 (M+, 13.8%), 502 (M+,
13.4%), Calcd for C19H17BrN8O4 (501.29): C, 45.52; H,
3.42; N, 22.35%. Found: C, 45.81; H, 3.19; N, 22.63%.

K. A. El-Sharkawy, M. M. AlBratty, H. A. Alhazmi
Braz. J. Pharm. Sci. 2018;54(4):e00153
Page 4 / 13
General procedure for the synthesis of compounds:
2-((4,6-diamino-1-(2,5-dioxo- imidazolidin-4-yl)-2-
oxo-1,2-dihydropyrimidin-5-yl) (imino) methyl)-3-
(4- methoxy-phenyl-pent-2-enedinitrile (17a) and
2-((4,6-diamino-1-(2,5-dioxo-imidazolidin-4-yl)-2-
oxo-1,2-dihydropyrimidin-5-yl)(imino)methyl)-3-(4-
methoxyphenyl)-4-thio-cyanatobut-2-enenitrile (17b)
Either potassium cyanide (16a) (0.122 g, 0.002
mol) or potassium thiocyanate (16b) (0.189 g, 0.002
mol) was added to a solution of compound 15 (1.002
g, 0.002 mol) in ethanol (50 mL) in water bath at 60
oC, with continuous stirring. The reaction mixture was
maintained in the water bath for 1 h at 60 ºC and then
poured into a beaker containing an ice/water mixture
and a few drops of HCl. The formed solid product was
collected by ltration.
Compound 17a: Dark brown crystals from ethanol,
yield 69%, 0.617 g, m.p. 157-159 ºC. IR (KBr): υ/cm-1
= 3445-3266 (2NH2, 3NH), 3051 (CH aromatic), 2978
(CH3), 2881 (CH2), 2754 (CH), 2225, 2223 (2CN), 1682,
1673, 1661 (3CO), 1657 (C=N), 1649 (C=C). 1H NMR
(DMSO-d6) δ = 3.41 (s, 3H, OCH3), 3.76 (s, 2H, CH2),
4.55, 4.87 (2s, 4H, D2O-exchangeable, 2NH2), 5.63 (s,
1H, imidazolidindione ring), 7.33-7.54 (d.d, 4H, C6H4),
8.45, 8.76, 9.33 (3s, 3H, D2O-exchangeable, 3NH). 13C
NMR: δ = 38.1 (CH3), 48.9 (CH2), 62.7 (CH), 77.7, 83.5
(C=C), 97.6 (C=N), 116.5, 119.2 (2CN), 122.8, 125.4,
128.6, 130.6, 134.4, 136.7, 138.9 (pyrimidine C, C6H4),
161.4, 164.5, 168.1 (3C=O). MS (relative intensity)
m/z: 447 (M+, 28.4%). Calcd for C20H17N9O4 (447.41):
C, 53.69; H, 3.83; N, 28.18%. Found: C, 53.96; H, 3.59;
N, 28.43%.
Compound 17b: Brown crystals from ethanol,
yield 64%, 0.613 g, m.p. 181-183 ºC. IR (KBr): υ/cm-1
= 3423-3233 (2NH2, 3NH), 3053 (CH aromatic), 2960
(CH3), 2884 (CH2), 2760 (CH), 2224, 2221 (2CN), 1680,
1672, 1662 (3CO), 1659 (C=N), 1651 (C=C). 1H NMR
(DMSO-d6) δ = 3.25 (s, 3H, OCH3), 3.44 (s, 2H, CH2),
4.51, 4.73 (2s, 4H, D2O-exchangeable, 2NH2), 5.55 (s, 1H,
imidazolidindione ring), 7.39- 7.61 (d.d, 4H, C6H4), 8.56,
8.74, 9.22 (3s, 3H, D2O-exchangeable, 3NH). 13C NMR:
δ = 41.2 (CH3), 49.7 (CH2), 63.9 (CH), 76.7, 86.8 (C=C),
97.9 (C=N), 117.2, 119.8 (2CN), 123.9, 126.7, 129.9,
132.5, 136.2, 138.9, 140.7 (pyrimidine C, C6H4), 162.2,
164.8, 167.8 (3C=O). MS (relative intensity) m/z: 479
(M+, 23.3%). Calcd for C20H17N9O4S (479.47): C, 50.10;
H, 3.57; N, 26.29; S, 6.69%. Found: C, 50.34; H, 3.28; N,
26.57; S, 6.41%.
General procedure for the synthesis of compound:
6-amino-2-(4,6-diamino-1-(2,5-dioxoimidazolidin-4-yl)-
2-oxo-1,2-dihydropyrimidin-5-yl)-4-(4-methoxyphenyl)-
nicotinonitrile (19)
The solution of compound 17a (0.447 g, 0.001 mol)
in sodium ethoxide (0.001 mol) [prepared by dissolving
sodium metal (0.023 g, 0.001 mol) in absolute ethanol (50
mL)]. The reaction was heated under reux for 4 h and then
evaporated under vacuum. The product was triturated with
ethanol and the formed product was collected by ltration.
Compound 19: Yellow crystals from ethanol, yield
57%, 0.255 g, m.p. 207-209 ºC. IR (KBr): υ/cm-1 = 3462-
3220 (3NH2, 2NH), 3054 (CH aromatic), 2985 (CH3),
2766 (CH), 2221 (CN), 1688, 1672, 1664 (3CO), 1655
(C=N), 1647 (C=C). 1H NMR (DMSO-d6) δ = 3.68 (s,
3H, OCH3), 4.38, 4.93, 5.33 (3s, 6H, D2O-exchangeable,
3NH2), 5.77 (s, 1H, imidazolidindione ring), 7.14 (s, 1H,
pyridine), 7.28-7.49 (d.d, 4H, C6H4), 8.41, 8.82 (2s, 2H,
D2O-exchangeable, 2NH). 13C NMR: δ = 40.4 (CH3),
63.3 (CH), 117.8 (CN), 120.6, 123.9, 125.2, 127.6, 131.1,
133.5, 136.2, 138.4, 140.7, 142.6, 144.5, 145.8 (Pyridine
C, pyrimidine C, C6H4), 160.8, 163.3, 166.7 (3C=O).
MS (relative intensity) m/z: 447 (M+, 30.5%). Calcd
for C20H17N9O4 (447.41): C, 53.69; H, 3.83; N, 28.18%.
Found: C, 53.44; H, 4.09; N, 28.37%.
General procedure for the synthesis of compounds:
2-((4,6-diamino -1-(2,5-dioxo- imidazolidin-4-yl)
-2-oxo -1,2-dihydropyrimidin -5-yl) (imino) methyl)
-4-hydrazinyl-3-(4-methoxyphenyl)but-2-enenitrile
(21a) and 2-((4,6-diamino-1-(2,5-dioxo –imidazol- idin-
4-yl)-2-oxo-1,2-dihydropyrimidin-5-yl) (imino) methyl)-
3-(4-methoxy -phenyl)-4-(2-phenyl- hydrazinyl)but-2-
enenitrile (21b)
Either hydrazine hydrate (20a) (0.1 g, 0.002 mol)
or phenylhydrazine (20b) (0.22 g, 0.002) was added to a
solution of compound 15 (1.002 g, 0.002 mol) in ethanol
(50 mL). The reaction mixture was heated under reux for
4 h and then poured onto an ice/water mixture containing a
few drops of hydrochloric acid. The formed solid product
was collected by ltration.
Compound 21a: Pale yellow crystals from ethanol,
yield 74%, 0.67 g, m.p. 221-223 ºC. IR (KBr): υ/cm-1
= 3389-3212 (3NH2, 4NH), 3050 (CH aromatic), 2974
(CH3), 2881 (CH2), 2760 (CH), 2227 (CN), 1683,
1667, 1660 (3CO), 1655 (C=N), 1649 (C=C). 1H NMR
(DMSO-d6) δ = 3.19 (s, 3H, OCH3), 3.28 (s, 2H, CH2),
4.58, 5.12, 5.28 (3s, 6H, D2O-exchangeable, 3NH2), 5.71
(s, 1H, imidazolidindione ring), 6.83-7.17 (d.d, 4H, C6H4),

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives
Braz. J. Pharm. Sci. 2018;54(4):e00153 Page 5 / 13
8.43, 8.68, 8.77, 9.53 (4s, 4H, D2O-exchangeable, 4NH).
13C NMR: δ = 37.5 (CH3), 53.3 (CH2), 66.7 (CH), 79.4,
86.4 (C=C), 107.6 (C=N), 115.7 (CN), 120.5, 125.9, 128.2,
132.3, 134.7, 136.7, 138.9 (pyrimidine C, C6H4), 164.4,
166.9, 170.2 (3C=O). MS (relative intensity) m/z: 452
(M+, 27.4%). Calcd for C19H20N10O4 (452,43): C, 50.44;
H, 4.46; N, 30.96%. Found: C, 50.71; H, 4.73; N, 30.68%.
Compound 21b: Pale yellow crystals from ethanol,
yield 65%, 0.688 g, m.p. 240-242 ºC. IR (KBr): υ/
cm-1= 3368-3188 (2NH2, 5NH), 3056 (CH aromatic),
2988 (CH3), 2879 (CH2), 2758 (CH), 2225 (CN), 1688,
1666, 1661 (3CO), 1657 (C=N), 1650 (C=C). 1H NMR
(DMSO-d6) δ = 3.12 (s, 3H, OCH3), 3.22 (s, 2H, CH2),
5.17, 5.44 (2s, 4H, D2O-exchangeable, 2NH2), 5.55 (s,
1H, imidazolidindione ring), 6.91-7.12 (d.d, 4H, C6H4),
7.38-7.53 (m, 5H, C6H5), 8.22, 8.51, 8.79, 9.11, 9.58 (5s,
5H, D2O-exchangeable, 5NH). 13C NMR: δ = 39.4 (CH3),
51.7 (CH2), 69.5 (CH), 78.8, 83.2 (C=C), 110.4 (C=N),
117.6 (CN), 120.3, 122.5, 124.7, 127.1, 130.8, 132.6,
134.8, 136.5, 139.6, 141.2, 143.4, 146.4 (pyrimidine C,
C6H4, C6H5), 163.3, 165.8, 167.8 (3C=O). MS (relative
intensity) m/z: 528 (M+, 23.6%). Calcd for C25H24N10O4
(528.52): C, 56.81; H, 4.58; N, 26.50%. Found: C, 56.55;
H, 4.33; N, 26.21%.
General procedure for the synthesis of compounds:
5-(4,6-diamino-5-((1,2-diamino-4-(4-methoxyphenyl)-
1H- pyrrol- 3- yl) (imino)methyl)-2-oxopyrimidin-1(2H)-yl)
imidazolidine-2,4-dione (23a) and 5-(4,6-diamino-5-
((2-amino-4-(4-methoxyphenyl)-1-(phenylamino)-1H-
pyrrol-3-yl)(imino)methyl)-2-oxopyrimidin-1(2H)-yl)
imidazolidine-2,4-dione (23b)
The reactions began either with solutions of
compound 21a (0.452 g, 0.001 mol) or compound 21b
(0.528 g, 0.001 mol) in sodium ethoxide (0.001 mol) in
absolute ethanol (50 mL). The reaction was heated under
reflux for 3 h and then evaporated under vacuum. The
product was triturated with ethanol and the formed product
was collected by ltration.
Compound 23a: Creamy white crystals from
ethanol, yield 57%, 0.258 g, m.p. 178-180 ºC. IR (KBr):
υ/cm-1 = 3411-3264 (4NH2, 3NH), 3055 (CH aromatic),
2981 (CH3), 2768 (CH), 1689, 1668, 1663 (3CO), 1651
(C=N), 1645 (C=C). 1H NMR (DMSO-d6) δ = 3.27 (s, 3H,
OCH3), 4.38, 4.59, 4.95, 5.23 (4s, 8H, D2O-exchangeable,
4NH2), 5.63 (s, 1H, imidazolidindione ring), 6.95-7.28
(m, 4H, C6H4, 1H, pyrrole), 8.51, 8.77, 9.38 (3s, 3H, D2O-
exchangeable, 3NH). 13C NMR: δ = 39.2 (CH3), 64.4 (CH),
103.8 (C=N), 121.7, 123.6, 126.7, 128.9, 131.4, 133.6,
136.5, 138.5, 140.2, 143.4, 145.1 (pyrrole C, pyrimidine C,
C6H4), 167.1, 169.8, 173.4 (3C=O). MS (relative intensity)
m/z: 452 (M+, 21.5%). Calcd for C19H20N10O4 (452,43):
C, 50.44; H, 4.46; N, 30.96%. Found: C, 50.18; H, 4.69;
N, 30.72%.
Compound 23b: Pale yellow crystals from ethanol,
yield 55%, 0.29 g, m.p. 150-152 ºC. IR (KBr): υ/cm-1=
3386-3187 (3NH2, 4NH), 3053 (CH aromatic), 2975
(CH3), 2782 (CH), 1685, 1671, 1665 (3CO), 1656 (C=N),
1650 (C=C). 1H NMR (DMSO-d6) δ = 3.41 (s, 3H, OCH3),
4.44, 4.67, 5.21 (3s, 6H, D2O-exchangeable, 3NH2), 5.54
(s, 1H, imidazolidindione ring), 6.86-7.37 (m, 4H, C6H4,
5H, C6H5, 1H, pyrrole), 8.43, 8.68, 9.17, 9.56 (4s, 4H,
D2O-exchangeable, 4NH). 13C NMR: δ = 35.7 (CH3), 57.4
(CH), 101.4 (C=N), 120.2, 121.9, 123.3, 125.8, 127.5,
130.1, 132.7, 134.6, 136.7, 139.1, 141.5, 144.1, 146.3,
147.5 (pyrrole C, pyrimidine C, C6H4, C6H5), 163.3,
169.4, 171.8 (3C=O). MS (relative intensity) m/z: 528
(M+, 28.3%). Calcd for C25H24N10O4 (528.52): C, 56.81;
H, 4.58; N, 26.50%. Found: C, 56.55; H, 4.86; N, 26.33%.
General procedure for the synthesis of compounds:
5-(4-amino-6-imino-2-oxo-5-(1-phenylethylidene)-5,6-
dihydropyrimidin-1(2H)-yl)imidazolidine-2,4-diones
(25a), 5-(4-amino-6-imino-2-oxo-5-(2-phenylhydrazono-
5,6-dihydropyrimidin-1(2H)-yl) imidazol- idine-2,4-
dione (25b) and 5-(4-amino-5-(2-(4-chlorophenyl)
hydrazono)-6-imino-2-oxo-5,6-dihydro- pyrimidin-1(2H)-
yl)imidazolidine-2,4-dione (25c)
Either compound 24a (0.505 g, 0.003 mol), 24b
(0.614 g, 0.003 mol) or 24c (0.474 g, 0.003 mol) was added
to a solution of 5-ureidohydantion (2) (0.474 g, 0.003 mol)
in 50 mL of ethanol containing dimethylformamide
(5.0 mL) and triethylamine (1.0 mL) as a catalyst. The
reaction mixture was heated under reux for 5 h, cooled
and poured onto ice containing a few drops of HCl. The
formed solid product was ltered out.
Compound 25a: Pale brown crystals from
ethanol, yield 61%, 0.597 g, m.p. 251-253 ºC. IR (KBr):
υ/cm-1= 3407-3326 (NH2, 3NH), 3051 (CH aromatic),
2978 (CH3), 2734 (CH), 1688, 1671, 1662 (3CO), 1657
(C=N), 1647 (C=C). 1HNMR (DMSO) δ = 1.87 (s, 3H,
CH3), 4.63 (s, 2H, D2O-exchangeable, NH2), 5.65 (s, 1H,
imidazolidindione ring), 7.27-7.44 (m, 5H, C6H5), 8.22,
8.46, 9.37 (3s, 3H, D2O-exchangeable, 3NH). 13C NMR:
δ = 23.3 (CH3), 61.4 (CH), 86.4 (C=C), 118.7, 123.5,
126.7, 128.9, 130.2, 133.6, 137.4, 139.3 (pyrimidine C,
C6H5), 160.2, 162.7, 165.6 (3C=O). MS (relative intensity)
m/z: 326 (M+, 19.8%). Calcd for C15H14N6O3 (326.31): C,

K. A. El-Sharkawy, M. M. AlBratty, H. A. Alhazmi
Braz. J. Pharm. Sci. 2018;54(4):e00153
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55.21; H, 4.32; N, 25.75%. Found: C, 55.48; H, 4.05; N,
25.49%.
Compound 25b: Brown crystals from ethanol,
yield 53%, 0.522 g, m.p. 197-199 ºC. IR (KBr):
υ/cm-1 = 3428-3335 (NH2, 4NH), 3053 (CH aromatic), 2766
(CH), 1684, 1672, 1664 (3CO), 1656 (C=N), 1649 (C=C).
1HNMR (DMSO) δ = 4.55 (s, 2H, D2O-exchangeable, NH2),
5.43 (s, 1H, imidazolidindione ring), 7.18-7.37 (m, 5H,
C6H5), 8.33, 8.49, 8.74, 9.37 (4s, 4H, D2O-exchangeable,
4NH). 13C NMR: δ = 65.5 (CH), 120.4, 122.7, 125.9, 127.4,
130.4, 132.8, 135.8, 138.7 (pyrimidine C, C6H5), 161.7,
163.9, 165.5 (3C=O). MS (relative intensity) m/z: 328 (M+,
15.7%). Calcd for C13H12N8O3 (328.29): C, 47.56; H, 3.68;
N, 34.13%. Found: C, 47.31; H, 3.94; N, 34.37%.
Compound 25c: Brown crystals from ethanol, yield
57%, 0.62 g, m.p. 218-220 ºC. IR (KBr): υ/cm-1= 3444-
3352 (NH2, 4NH), 3057 (CH aromatic), 2761 (CH), 1682,
1670, 1663 (3CO), 1653 (C=N), 1647 (C=C). 1HNMR
(DMSO) δ = 4.72 (s, 2H, D2O-exchangeable, NH2), 5.66
(s, 1H, imidazolidindione ring), 7.39-7.54 (d.d, 4H, C6H4),
8.38, 8.62, 8.88, 9.28 (4s, 4H, D2O-exchangeable, 4NH).
13C NMR: δ = 54.8 (CH), 121.4, 123.6, 125.7, 128.5,
131.5, 133.9, 135.7, 139.5 (pyrimidine C, C6H4), 162.8,
164.7, 167.3 (3C=O). MS (relative intensity) m/z: 362
(M+, 15.7%). Calcd for C13H11ClN8O3 (362.73): C, 43.05;
H, 3.06; N, 30.89%. Found: C, 43.33; H, 3.34; N, 30.62%.
Pharmacology
Analgesic activity
Analgesic activity was introduced by the tail ick
method (Fadeyi et al., 2004; Vogel, 2002). Healthy albino
mice weighing 20.0 g to 30.0 g were divided into dierent
groups with six animals in each group. The control group
received a 0.5% w/v carboxymethylcellulose (CMC)
solution and the treated groups were given a 132 µmol/kg
orally dose of compounds 3, 7, 9a ,b, 11, 13a ,b, 15, 17a,
b, 19, 21a, b, 23a, b and 25a, b, c. The reaction times were
noted at 2 h and 4 h intervals after drug administration.
The percentage analgesic activity was calculated by the
following formula:-
Percentage analgesic activity = T2-T1/T1×100
where:- T1 is the normal reaction time; T2 is the reaction
time after treatment.
Antipyretic activity
Healthy Wistar rats were given s.c. 10mL/kg of
a 20% aqueous suspension of sterilized brewer’s yeast
powder (Fadeyi et al., 2004; Vogel, 2002) weighting
between 150 g and 200 g. Eighteen hours later, the animals
showing an increase in rectal temperature greater than 0.5
ºC were selected. The control group received a 0.5% w/v
carboxymethylcellulose solution and the treated groups
received a of 132 µmol/kg dose of compounds 3, 7, 9a,
b, 11, 13a, b, 15, 17a, b, 19, 21a, b, 23a, b and 25a, b, c.
Rectal temperatures were noted using digital thermometer
30 minute before (pretreated) and at 1 h, 2 h and 4 h after
administration of the dose.
Anti-inflammatory activity
The anti-inammatory activity was examined using
a hind paw edema method on albino rats of either six
(Fadeyi et al., 2004; Vogel, 2002). A freshly prepared of
carrageenan solution (0.1mL, 1%w/v) was injected into the
sub-plantar surface of the right hind limb of each animal.
The control group received a 0.5% w/v CMC solution and
the treated groups were orally given a 132 µmol/kg dose
of compounds 3, 7, 9a ,b, 11, 13a ,b, 15, 17a, b, 19, 21a,
b, 23a, b and 25a, b, c 30 minute before carrageenan. The
volume of each paw was measured with a plethysmometer
at 2 h and 4 h intervals after carrageenan injection. The
percentage inhibition of edema was calculated by the
following formula:
Percentage inhibition of edema: VC-VT/VC×100
where: VC is the paw volume of control animal; VT is the
paw volume of treated animals (standard /test compound).
RESULTS AND DISCUSSION
This study was a continuation of our efforts
aimed at the synthesis of new heterocyclic compounds
with significant biological potential (El-Sharkawy et
al., 2012; Mohareb, El-Sharkawy, Sherif, 2008). The
goals of this work were to study the possibility of using
compounds 2 and 3 in heterocyclic synthesis to produce
the pyridopyrimidine derivative 7; thiophene derivatives
9a,b; coumarin derivative 11; pyrimidine derivatives
13,15,17a,b,21a,b; pyridine derivative 19; pyrazole
derivatives 23a,b and iminopyrimidine derivatives
25a,b,c, as well as biologically evaluate these compounds
for analgesic, antipyretic and anti-inammatory activities.
The reaction of β-amino-α, γ-dicyanocrotono- nitrile (1)
with 5-ureidohydantion (2) using triethylamine as catalyst
produced compound 3. The latter product underwent
cyclization in the presence of piperidine. Four isomeric

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives
Braz. J. Pharm. Sci. 2018;54(4):e00153 Page 7 / 13
structures were considered, including 4,5,6 and 7. The
1HNMR spectral data showed that the final product
contained three singlets at δ = 4.78, 4.93, 5.27 ppm and
two singlets at δ = 8.73, 9.95 ppm which represented the
presence of 3NH2 and 2NH groups, respectively; thus,
the structures of compounds 4,5 and 6 were ruled out,
as those latter structures only containing 2NH2 groups.
Additionally, structure 6 contained an OH group which it
was absent in the analytical and spectral data. In contrast,
compound 7 was produced by another pathway, through
the reaction of β-amino-α, γ-dicyanocrotononitrile (1) with
5-ureidohydantion (2) in the presence of sodium ethoxide
directly. Compound 3 reacted with either cyclopentanone
(8a) or cyclohexanone (8b) in the presence of elemental
sulfur and trimethylamine afforded compounds 9a,b
respectively. The structures of compounds 9a,b were
verified by elemental analysis and spectral data. In
compound 9a, the 1HNMR spectrum indicated the
presence of a multiplet at δ = 2.07-2.18 ppm which could
be assigned to the 3CH2 groups; three singlets at δ = 4.54,
4.65, 5.81 ppm, which indicate the presence of 3NH2
groups; a singlet at δ = 5.98 ppm, which indicate the
presence of 1H of an imidazolidindione ring and three
singlets at δ = 8.52, 8.77, 9.12 ppm corresponding to
3NH groups. Coumarin derivative 11 was formed via the
reaction of compound 3 with salicylaldehyde (10) and the
structure of the compound was conrmed. The 1HNMR
spectrum indicated the presence of two singlets at δ = 4.76,
5.25 ppm, which indicate the presence of 2NH2 groups; a
singlet at δ = 5.53 ppm, which indicates the presence of an
1H of imidazolidindione ring; a singlet at δ = 6.73 ppm,
which indicate the presence of a coumarin 1H; a multiplet
at δ = 7.51-7.66 ppm corresponding to 4H of benzene
ring; and three singlets at δ = 8.88, 9.28, 9.55 ppm,
which indicate the presence of 3NH groups. Compound
3 was also reacted with aryldiazonium salts 12a,b to
aord arylhydrazono derivatives 13a,b respectively. The
elucidation of the structure for these compounds was then
FIGURE 1 - Synthesis rout for compounds 3 and 7.

K. A. El-Sharkawy, M. M. AlBratty, H. A. Alhazmi
Braz. J. Pharm. Sci. 2018;54(4):e00153
Page 8 / 13
confirmed. The 1HNMR spectrum for compound 13a
showed the presence of two singlets at δ = 4.54, 5.17 ppm,
which indicate the presence of 2NH2 groups; a singlet at
δ = 5.61 ppm, which indicates the presence of 1H of an
imidazolidindione ring; a multiplet at δ = 7.31-7.62 ppm
corresponding to 5H of benzene ring; and four singlets at
δ = 8.76, 9.13, 9.38, 959 ppm which indicate the presence
of 4NH groups.
The last reaction of compound 3, was performed
with ω-bromo-4-methoxyacetophenone (14), and the
4-methoxyphenylbutenyl derivative 15 was afforded.
The elucidation of this structure was based on analytical
and spectral data. Compound 15 was reacted with either
potassium cyanide (16a) or potassium thiocyanate (16b)
to form either the 4-methoxyphenylbutenyl cyanide
derivative 17a or 4-methoxyphenylbutenyl thiocyanide
derivative 17b, respectively. The structures of compounds
17a,b were verified by analytical and spectral data.
Compound 17a underwent a cyclization in presence of
sodium ethoxide to afford pyridine derivative 19 via
formation of intermediate 18. The structure of compound
19 was then confirmed. The 1HNMR spectrum of
compound 19 detected the presence of singlet at δ = 3.68
ppm, which indicates the presence of 3H of CH3 group;
three singlets at δ = 4.38, 4.93 5.33 ppm, which indicate the
presence of 3NH2 groups; a singlet at δ = 5.77 ppm, which
indicates the presence of 1H of imidazolidindione ring; a
singlet at δ = 7.14 ppm which indicates the presence of
1H of pyridine ring; a doublet of doublets at δ = 7.28-7.49
ppm corresponding to 4H of benzene ring and two singlets
at δ = 8.41, 8.82 ppm, which indicate the presence of 2NH
groups. Compound 15 was reacted with either hydrazine
hydrate (20a) or phenyl hydrazine (20b) to produce
hydrazono derivatives 21a,b, respectively. The structures
of these compounds were confirmed by analytical and
spectral data. The latter products underwent a cyclization
to form pyrrole derivatives 23a,b through the intermediate
formation of 22a,b, respectively. The structures of
compounds 23a,b were conrmed using analytical and
spectral data. The 1HNMR spectrum of compound 23a
FIGURE 2 - Synthesis rout for compounds 9a,b, 11, 13a,b and 15.

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives
Braz. J. Pharm. Sci. 2018;54(4):e00153 Page 9 / 13
FIGURE 3 - Synthesis rout for compounds 17a,b, 19 and 21a,b.
FIGURE 4 - Synthesis rout for compounds 23a,b and 25a,b,c.

K. A. El-Sharkawy, M. M. AlBratty, H. A. Alhazmi
Braz. J. Pharm. Sci. 2018;54(4):e00153
Page 10 / 13
detected the presence of a singlet at δ = 3.27 ppm, which
indicates the presence of 3H from a CH3 group; four
singlets at δ = 4.38, 4.59, 4.95, 5.23 ppm, which indicate
the presence of 4NH2 groups; a singlet at δ = 5.63 ppm,
which indicates the presence of 1H of imidazolidindione
ring; a multiplet at δ = 6.95-7.28 ppm corresponding to 4H
of benzene ring and 1H of pyrrole ring and three singlets
at δ = 8.51, 8.77, 9.38 ppm, which indicate the presence
of 3NH groups. Finally 5-ureidohydantion (2) was reacted
with compounds 24a,b,c to produce iminopyrimidine
derivatives 25a,b,c, respectively and the structure of these
compounds were confirmed by analytical and spectral
data.
All the synthesized compounds were evaluated for
their in vitro analgesic, antipyretic and anti-inammatory
activities. Acetaminophen was used as a reference
TABLE I - Analgesic activities of the synthesized compounds
Comp. No Normal reaction
time (sec)
Change in reaction time (sec) ± SEM % Analgesic activity ± SD
2 h 4 h 2 h 4 h
Control 2.80±0.15 0.20±0.014 0.25±0.018 7.09±1.45 9.05±0.87
32.20±0.09 3.21±0.15 2.25±0.08 113.1±1.57 89.76±2.23
72.35±0.08 3.24±0.10 2.35±0.07 115.4±1.38 94.53±0.44**
9a 2.60±0.07 3.20±0.08 2.33±0.06 129.1±1.65 95.24±1.53**
9b 2.57±0.07 3.17±0.09 2.36±0.05 131.3±1.58 92.56±1.38**
11 2.38±0.08 3.18±0.08 2.43±0.03 125.1±1.68 97.56±0.55***
13a 2.56±0.06 3.22±0.11 2.38±0.04 133.6±1.76 95.84±2.05**
13b 2.48±0.06 3.21±0.08 2.29±0.07 136.4±1.48 94.11±0.43**
15 2.53±0.08 3.32±0.15 2.42±0.08 140.5±1.54 84.82±1.23
17a 2.16±0.07 3.33±0.19 1.96±0.05 145.6±1.64 86.52±1.18
17b 2.36±0.12 3.48±0.12 2.21±0.03 138.8±1.98 89.33±2.66
19 2.20±0.11 3.15±0.07 2.40±0.06 119.5±1.45 96.5±0.25***
21a 2.25±0.09 3.44±0.13 2.25±0.08 147.1±1.77 90.5±1.46
21b 3.15±0.06 3.38±0.14 2.05±0.07 144.3±1.48 103.55±1.53
23a 2.60±0.12 3.47±0.18 1.98±0.07 141.1±1.88 92.4±2.36*
23b 2.50±0.12 3.31±0.13 1.96±0.06 112.3±1.93 90.9±0.95*
25a 2.75±0.09 3.34±0.16 2.15±0.08 117.3±1.73 89.5±1.65
25b 2.80±0.08 3.38±0.17 2.22±0.05 113.1±2.00 104.2±2.44
25c 2.65±0.06 3.39±0.15 2.18±0.06 108.3±1.43 88.7±2.98
Ref. Standard
(Acetaminophen)
2.50±0.10 3.10±0.05 2.5±0.03 128.6±1.75 103.6±1.58***
Note: The reaction time value is the mean ± SEM (n=6). Statistical analysis was performed with the student’s unpaired t-test
(Kulkarni, 2003). *p < 0.05, **p < 0.01 and ***p < 0.001, 132 µmol/kg dose.
standard drug. Based on the results from (Tables I
and II), it is clear that compounds 11 and 19 showed
promising actions as analgesic and antipyretic agents.
This may be due their containing a coumarin moiety and
4-methoxyphenylpyridine moiety, respectively. In contrast,
compounds 7, 9a, b, 13a, b showed moderate analgesic
and antipyretic effects. The remaining compounds 3,
15, 17a, b, 21a, b, 23a, b, 25a, b, c exhibited poor
analgesic and antipyretic eects. Compound 11 exhibited
high signicance as an anti-inammatory agent, which
may be due to the presence of the coumarin moiety.
Compounds 7, 9b, 13b, 19 were considered as moderate
anti-inammatory eects. The remaining compounds 3,
9a, 13a, 15, 17a, b, 21a, b, 23a, b, 25a, b, c exhibited
poor biological signicance as anti-inammatory agents
(Table III).

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives
Braz. J. Pharm. Sci. 2018;54(4):e00153 Page 11 / 13
TABLE II - Antipyretic activities of the synthesized compounds
Comp. No Before drug (ºC) After drug (oC)
-18 h 0.0 h 1 h 2 h 4 h
Control 37.47±5.68 38.22±0.05 38.08±0.08 38.04±0.05 37.83±0.5
337.35±0.05 38.17±0.75 37.88±0.07 37.58±0.08 37.33±0.05
737.41±0.05 38.38±0.05 38.12±0.05 37.55±0.06 37.28±0.05**
9a 37.36±0.04 38.33±0.06 37.95±0.08 37.65±0.07 37.32±0.05**
9b 37.32±0.05 38.35±0.06 38.14±0.07 37.54±0.08 37.26±0.05**
11 37.23±0.09 38.40±0.08 37.93±0.06 37.63±0.05 37.44±0.06***
13a 37.40±0.05 38.37±0.05 38.25±0.08 37.55±0.06 37.31±0.05**
13b 37.44±0.06 38.39±0.05 37.98±0.06 37.38±0.08 37.27±0.05**
15 37.36±0.06 38.34±0.05 38.08±0.07 37.88±0.06 37.45±0.05
17a 37.34±0.06 38.37±0.08 38.05±0.08 37.68±0.07 37.39±0.03
17b 37.44±0.05 38.39±0.08 38.18±0.06 37.91±0.05 37.58±0.07
19 37.28±0.04 38.31±0.07 38.05±0.07 37.60±0.05 37.37±0.04***
21a 37.30±0.06 38.27±0.35 37.95±0.08 37.58±0.07 37.31±0.05
21b 37.43±0.08 38.41±0.45 38.12±0.07 37.74±0.08 37.47±0.02
23a 37.39±0.08 38.44±0.53 38.19±0.08 37.87±0.05 37.55±0.04*
23b 37.31±0.07 38.39±0.06 38.10±0.07 37.64±0.05 37.42±0.07*
25a 37.29±0.06 38.32±0.07 38.04±0.07 37.34±0.09 37.18±0.09
25b 37.35±0.05 38.38±0.07 37.85±0.08 37.85±0.06 37.46±0.09
25c 37.44±0.08 38.44±0.35 37.92±0.07 37.92±0.05 37.42±0.08
Ref. Standard
(Acetaminophen)
37.18±0.07 37.88±0.05 37.72±0.04 37.41±0.04 37.20±0.05***
Note: The reaction time value is the mean ± SEM (n=6). Statistical analysis was performed with student’s unpaired t-test (Kulkarni,
2003). *p < 0.05, **p < 0.01 and *** p < 0.001, 132 µmol/kg dose.
CONCLUSIONS
In this article, the synthesized pyrimidines
3, 7, 13a,b, 15, 17a,b, 21a,b, 25a, b, c; thiophenes
9a, b; coumarin 11 , pyridine 19 and pyrroles 23a,
b were evaluated as analgesic, antipyretic and anti-
inammatory agents compared to the reference standard
drug acetaminophen. Among the newly synthesized
compounds, compounds 11 and 19 showed promising
signicant analgesic and antipyretic activities compared
to the other compounds. Additionally compounds 7,
9a,b and 13a,b had moderately signicant analgesic and
antipyretic activities. Moreover, compound 11 had clear
anti-inammatory properties compared to the remaining
compounds.
ACKNOWLEDGEMENTS
The authors would like to thank the research group
working in the Pharamacology Depatment, Faculty of
Pharmacy, October University for Modern Sciences and
Arts. We would also like to thank the Poison Control and
Medical Forensic Chemistry Center team from Jazan
Health, Jazan City, Kingdom of Saudi Arabia for recording
the analytical and spectral data for the newly synthesized
compounds.

K. A. El-Sharkawy, M. M. AlBratty, H. A. Alhazmi
Braz. J. Pharm. Sci. 2018;54(4):e00153
Page 12 / 13
TABLE III - Anti-inammatory activities of the synthesized compounds
Comp. No Change in reaction time (sec)±SEM % Anti-inammatory activity±SD
2 h 4 h 2 h 4 h
Control 1.29±0.01 1.32±0.007
30.83±0.01 0.80±0.01 34.56±3.38 35.78±3.52
70.82±0.02 0.83±0.01 31.34±2.87 33.59±2.26**
9a 0.82±0.01 0.85±0.01 32.44±2.55 34.23±2.68
9b 0.81±0.03 0.82±0.01 31.12±3.51 34.19±3.07**
11 0.82±0.02 0.84±0.01 29.34±2.97 32.08±2.05***
13a 0.81±0.01 0.85±0.01 32.56±3.08 33.38±3.17
13b 0.83±0.03 0.84±0.01 32.34±2.26 35.27±2.02**
15 0.84±0.02 0.81±0.01 27.88±2.66 32.17±1.87
17a 0.83±0.02 0.86±0.01 34.23±3.44 37.18±3.25
17b 0.86±0.01 0.87±0.01 35.56±3.14 36.34±1.48
19 0.81±0.01 0.83±0.01 30.34±3.24 34.03±2.53**
21a 0.83±0.03 0.85±0.01 26.23±2.57 29.28±1.38
21b 0.85±0.01 0.81±0.01 35.39±3.28 37.31±1.93
23a 0.84±0.02 0.88±0.01 34.18±2.73 35.98±3.02
23b 0.78±0.02 0.82±0.01 33.85±3.27 35.58±2.17
25a 0.83±0.02 0.80±0.01 33.37±3.26 36.18±1.59
25b 0.79±0.01 0.83±0.01 32.94±2.62 35.42±3.46
25c 0.83±0.03 0.87±0.01 34.23±3.17 36.14±1.83
Ref. Standard
(Acetaminophen)
0.83±0.01 0.84±0.01 28.83±3.05 32.82±1.33***
Note: The reaction time value is the mean ± SEM (n=6). Statistical analysis was performed with student’s unpaired t-test (Kulkarni,
2003). *p < 0.05, **p < 0.01 and *** p < 0.001, 132 µmol/kg dose.
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Received for publication on 16th October 2016
Accepted for publication on 09th January 2018
This is an open-access article distributed under the terms of the Creative Commons Attribution License.