Synthesis and antiinflammatory activity of novel 2,5-disubstituted thiophene derivatives

Article abstract of DOI:10.3906/kim-1001-473

New series of 2,5-disubstituted thiophenes were synthesized. Thiosemicarbazones 1a-b were reacted with various reagents, such as diethyl-2-bromomalonate, ethyl-2-chloroacetoacetate, thioglycolic acid, 4-substituted phenacyl bromides, and acetic anhydride,

Full text of DOI:10.3906/kim-1001-473

Turk J Chem
35 (2011) , 131 – 143.
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ꢀ TUBITAK
doi:10.3906/kim-1001-473
Synthesis and antiinflammatory activity of novel
2,5-disubstituted thiophene derivatives
Sahar Mohamed Ibrahim BADR
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Mansoura University,
Mansoura 35516, EGYPT
e-mail: saharmbadr@yahoo.com
Received 18.01.2010
New series of 2,5-disubstituted thiophenes were synthesized. Thiosemicarbazones 1a-b were reacted
with various reagents, such as diethyl-2-bromomalonate, ethyl-2-chloroacetoacetate, thioglycolic acid, 4-
substituted phenacyl bromides, and acetic anhydride, to afford heterocyclic substituted thiophene deriva-
tives 2a-b, 3a-b, 4a-b, 5a-b, 6a-b, and 7a-b, respectively. Moreover, cyclization of the key intermediate
1b with chloroacetic acid yielded thiazolidine 9, which on reaction with appropriate aromatic aldehydes af-
forded the corresponding arylidene derivatives 10a-f. Finally, reaction of N\ -arylidene cyanoacetohydrazide
11 with sulfur and phenylisothiocyanate yielded thiazoline derivative 12, which on treatment with triethy-
lorthoformate and acetic anhydride afforded thiazolo[4,5-d]pyrimidinone derivative 13. Some of the newly
synthesized compounds showed promising antiinflammatory activity.
Key Words: Thiophenes, thiazoles, thiadiazoles, synthesis, antiinflammatory
Introduction
It has been reported in the literature that heterocyclic compounds such as thiophenes exhibited potent an-
tiinflammatory activity.1−6 Likewise, thiazole, 1,3,4-thiadiazole, and their derivatives were found to possess
antiinflammatory activity.7−14 In addition, hydrazone moiety also exhibited antiinflammatory activity.15,16
Encouraged by the above observations, it was planned to synthesize new substituted thiophenes incorporating
an extra heterocyclic ring, thiazole 2a-b, 3a-b, 4a-b, 5a-b, 6a-b, 9, 10a-f, 12, and 13, and thiadiazole 7a-b,
as promising nonsteroidal antiinflammatory compounds.
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Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
Experimental
Unless otherwise noted, all materials were obtained from commercial suppliers (Aldrich and Merck) and used
without further purification. Melting points were determined on a Fisher-Johns melting point apparatus and
are uncorrected. Elemental analytical data (in accordance with the calculated values) were calculated at the
microanalytical unit of Cairo University and were within 0.4% of theoretical values. The IR spectra were
recorded on a Mattson 5000 FT-IR spectrometer using a KBr disk at Mansoura University. The 1 H-NMR and
13 C-NMR spectra were recorded on an FT-NMR JNM-LA spectrometer (300 MHZ) in CDCl3 or DMSO-d6 as
solvent, using TMS as an internal standard. Chemical shifts are expressed as ppm δ units. All reactions were
followed by TLC on silica gel-protected aluminum sheets (type 60 F254 , Merck).
Synthesis of 2-(thiosemicarbazidomethyl)-5-nitrothiophene 1a. To a solution of 5-nitro-2-
thiophene carboxaldehyde (1.57g, 0.01 mol) in absolute ethanol (60 mL) was added an equimolar amount
of thiosemicarbazide (0.91 g, 0.01 mol). The reaction mixture was heated under reflux for 2 h and then cooled
to room temperature. The solid product was collected by filtration, washed with ethanol, dried, and recrystal-
lized from ethanol to give a yellow compound in 92% yield, mp 253-255 ◦ C (Lit.17 mp 255-258 ◦ C); IR (KBr,
υ, cm−1): 3380, 3280, 3140 (NH), 1620 (C=N); 1 H-NMR (DMSO-d6): δ 7.46 (d, J = 4.4 Hz, 1H, thiophene),
7.82 (d, J = 4.4 Hz, 1H, thiophene), 8.25 (s, 1H, CH=N), 9.91 (brs, 2H, NH2 , D2 O-exchangeable), 10.30 (brs,
1H, NH, D2 O-exchangeable).
Synthesis of 2-[(4-phenylthiosemicarbazido)methyl]-5-nitrothiophene 1b. In Scheme 1: as
reported procedure.18 In Scheme 2: to a solution of 5-nitrothiophene-2-carbaldehydehydrazone19 8 (1.71
g, 0.01 mol) in diethylene oxide (15 mL), phenylisothiocyanate (1.3 mL, 0.01 mol) was added. The reaction
mixture was heated under reflux for 1 h. The solvent was evaporated under reduced pressure, then the residue
was triturated with cold ethanol, filtered, dried, and recrystallized from ethanol to give a yellow compound, yield
90%, mp 210-211 ◦ C (Lit.18 mp 209-210 ˚C); IR (KBr, υ, cm−1): 3390, 3350 (NH), 1625 (C=N); 1 H-NMR
(DMSO-d6): δ 7.04 (t, J = 8.8 Hz, 1H, ar-H), 7.21 (t, J = 8.8 Hz, 2H, ar-H), 7.41 (d, J = 8.8 Hz, 2H, ar-H),
7.53 (d, J = 4.8 Hz, 1H, thiophene), 7.90 (d, J = 4.8 Hz, 1H, thiophene), 8.35 (s, 1H, CH=N), 10.42 (brs, 1H
NH, D2 O-exchangeable), 10.90 (brs, 1H, NH, D2 O-exchangeable).
General method for the synthesis of compounds 2a-b. A mixture of 2-(thiosemicarbazidomethyl)-
5-nitrothiophene 1a or 2-[(4-phenylthiosemicarbazido)methyl]-5-nitrothiophene 1b (0.005 mol), diethyl-2-bro-
momalonate (0.85 mL, 0.005 mol), and anhydrous sodium acetate (1.64 g, 0.02 mol) in absolute ethanol (80 mL)
was refluxed for 6-8 h with continuous stirring. The solvent evaporated under reduced pressure, and then the
obtained solid was triturated with cold water and cold diethylether, dried, and recrystallized from appropriate
solvent.
2-[(5-Ethoxycarbonyl-4-oxo-thiazolidin-2-ylidene)hydrazonomethyl]-5-nitrothiophene 2a.
Crystallized from ethanol/water, red compound, yield 82%, mp 200-202 ◦ C; IR (KBr, υ, cm−1): 3125 (NH),
1740 (COOET), 1710 (C=O), 1640, 1600 (C=N); 1 H-NMR (DMSO-d6): δ 1.05 (t, J = 7 Hz, 3H, CH3), 4.21
(q, J = 7 Hz, 2H, CH2), 4.91 (s, 1H, CH-thiazolidine), 7.42 (d, J = 4.8 Hz, 1H, thiophene), 7.85 (d, J =
4.8 Hz, 1H, thiophene), 8.31 (s, 1H, CH=N), 10.41 (brs, 1H, NH, D2 O-exchangeable);13 C-NMR (DMSO-d6):
δ 14.4 (CH3), 57.0 (CH2), 68.3 (CH-thiazolidine), 128.7, 128.9, 150.7, & 152.7 (C-thiophene), 146.3 (CH=N),
160.0 (C=N), 162.7 (C=O), 165.6 (C=O ring); Anal. Calcd. (%) for: C11 H10 N4 O5 S2 : C, 38.59, H, 2.94, N,
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Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
16.36, Found; C, 38.37, H, 3.15, N, 16.48.
2-[(5-Ethoxycarbonyl-4-oxo-3-phenylthiazolidin-2-ylidene)hydrazonomethyl]-5-nitrothiop-
hene 2b. Crystallized from chloroform/pet.ether, orange compound, yield 68%, mp 183-185 ◦ C; IR (KBr, υ,
cm−1): 1740 (COOET), 1710 (C=O), 1640, 1605 (C=N); 1 H-NMR (CDCl3): δ 1.14 (t, J = 7 Hz, 3H, CH3),
4.32 (q, J = 7 Hz, 2H, CH2), 4.89 (s, 1H, CH-thiazolidine), 7.06 (t, J = 8.5 Hz, 1H, ar-H), 7.28 (t, J = 8.5
Hz, 2H, ar-H), 7.41 (d, J = 8.5 Hz, 2H, ar-H), 7.50 (d, J = 4.4 Hz, 1H, thiophene), 7.91 (d, J = 4.4 Hz, 1H,
thiophene), 8.34 (s, 1H, CH=N); Anal. Calcd. (%) for: C17 H14 N4 O5 S2 : C, 48.79, H, 3.37, N, 13.39, Found;
C, 48.52, H, 3.21, N, 13.51.
General method for the synthesis of compounds 3a-b. To a mixture of 2-(thiosemicarbazidomethyl)-
5-nitrothiophene 1a or 2-[(4-phenylthiosemicarbazido)methyl]-5-nitrothiophene 1b (0.001 mol), ethyl-2-chloroa-
cetoacetate (0.21 mL, 0.0015 mol), and anhydrous sodium acetate (0.246 g, 0.003 mol) in absolute ethanol (30
mL), glacial acetic acid (0.5 mL) was added as a catalyst. The reaction mixture was heated under reflux for
22-24 h with continuous stirring, partially concentrated under reduced pressure, and then allowed to attain room
temperature; crushed ice water was poured on it. The precipitated solid was collected by filtration, washed
thoroughly with water, dried, and recrystallized from ethanol/water.
2-[(5-Ethoxycarbonyl-4-methyl-3H-thiazol-2-yl-ylidene)hydrazonomethyl]-5-nitrothiophene
3a. Red compound, yield 85%, mp 192-194 ◦ C; IR (KBr, υ, cm−1): 3147 (NH), 1725 (COOET), 1635, 1600
(C=N); 1 H-NMR (CDCl3): δ 1.36 (t, J = 7 Hz, 3H, CH3), 2.63 (s, 3H, CH3), 4.32 (q, J = 7 Hz, 2H, CH2),
7.49 (d, J = 4.4 Hz, 1H, thiophene), 7.89 (d, J = 4.4 Hz, 1H, thiophene), 8.43 (s, 1H, CH=N), 11.01 (brs,
1H, NH, D2 O-exchangeable); Anal. Calcd. (%) for: C12 H12 N4 O4 S2 : C, 42.34, H, 3.55, N, 16.46, Found; C,
42.23, H, 3.35, N, 16.56.
2-[(5-Ethoxycarbonyl-4-methyl-3H-3-phenylthiazol-2-yl-ylidene)hydrazonomethyl]-5-nitrot-
hiophene 3b. Red compound, yield 74%, mp 176-178 ◦ C; IR (KBr, υ, cm−1): 1725 (COOET), 1625, 1600
(C=N); 1 H-NMR (CDCl3): δ 1.38 (t, J = 7 Hz, 3H, CH3), 2.58 (s, 3H, CH3), 4.43 (q, J = 7 Hz, 2H, CH2),
7.08 (t, J = 8.5 Hz, 1H, ar-H), 7.22 (t, J = 8.5 Hz, 2H, ar-H), 7.41 (d, J = 8.5 Hz, 2H, ar-H), 7.53 (d, J =
4.4 Hz, 1H, thiophene), 7.91 (d, J = 4.4 Hz, 1H, thiophene), 8.42 (s, 1H, CH=N);13 C-NMR (CDCl3): δ 14.1
(CH3), 16.4 (CH3), 60.5 (CH2), 117.1 & 149.2 (C-thiazole), arC: [126.2 (C), 128.0 (2C), 128.5 (2C), & 130.8
(C)] , 128.7, 128.9, 153.3, & 155.1 (C-thiophene), 146.4 (CH=N), 161.4 (C=N), 163.2 (C=O); Anal. Calcd. (%)
for: C18 H16 N4 O4 S2 : C, 51.90, H, 3.87, N, 13.45, Found; C, 52.17, H, 3.73, N, 13.21.
General method for the synthesis of compounds 4a-b. A mixture of 2-(thiosemicarbazidomethyl)-
5-nitrothiophene 1a or 2-[(4-phenylthiosemicarbazido)methyl]-5-nitrothiophene 1b (0.001 mol) and thioglycolic
acid (0.1 mL, 0.0015 mol) in anhydrous benzene (100 mL) was heated under reflux with exclusion of moisture
for 10 h with continuous stirring. Benzene was partially concentrated under reduced pressure and then left to
cool. The precipitated solid was collected by filtration, dried, and recrystallized from acetone/water.
2-(4-Oxo-3-thioureido-thiazolidin-2-yl)-5-nitrothiophene 4a. Yellow compound, yield 68%, mp
266-268 ◦ C; IR (KBr, υ, cm−1): 3300, 3150, 320 (NH), 1700 (CO), 1200 (CS); 1 H-NMR (DMSO-d6): δ 3.37
(s, 2H, CH2 -thiazolidine), 7.16 (s, 1H, CH-thiazolidine), 7.56 (d, J = 4.8 Hz, 1H, thiophene), 7.92 (d, J = 4.8
Hz, 1H, thiophene), 8.42 (brs, 2H, NH2 , D2 O-exchangeable), 10.67 (brs, 1H, NH, D2 O-exchangeable); Anal.
Calcd. (%) for: C8 H8 N4 O3 S3 : C, 31.56, H, 2.64, N, 18.40, Found; C, 31.72, H, 2.91, N, 18.53.
2-(4-Oxo-3-phenylthioureido-thiazolidin-2-yl)-5-nitrothiophene 4b. Yellow compound, yield
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Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
64%, mp 225-227 ◦ C; IR (KBr, υ, cm−1): 3300, 3150 (NH), 1700 (CO), 1200 (CS); 1 H-NMR (CDCl3):
δ 3.35 (s, 2H, CH2 thiazolidine), 7.03 (t, J = 8 Hz, 1H, ar-H), 7.16 (s, 1H, CH-thiazolidine), 7.29 (t, J = 8
Hz, 2H, ar-H), 7.40 (d, J = 8 Hz, 2H, ar-H), 7.57 (d, J = 4.6 Hz, 1H, thiophene), 7.97 (d, J = 4.6 Hz, 1H,
thiophene), 9.67 (brs, 1H, NH, D2 O- exchangeable), 10.96 (brs, 1H, NH, D2 O-exchangeable); Anal. Calcd.
(%) for: C14 H12 N4 O3 S3 : C, 44.19, H, 3.18, N, 14.72, Found; C, 44.26, H, 2.98, N, 14.91.
General method for the synthesis of compounds 5a-b and 6a-b. To the intermediate; 2-
(thiosemicarbazidomethyl)-5-nitrothiophene 1a or 2-[(4-phenylthio-semicarbazido)methyl]-5-nitrothiophene 1b
(0.005 mol) in absolute ethanol (100 mL) were added equimolar amounts of the appropriate phenacyl bromides
(0.005 mol) and anhydrous sodium acetate (1.6 g, 0.02 mol). The reaction mixture was heated under reflux
for 4-6 h with continuous stirring, then partially concentrated under reduced pressure and left to cool. The
reaction mixture was poured onto crushed ice with stirring. The separated product was collected by filtration,
washed thoroughly with water, dried, and recrystallized from ethanol/water.
2-{[4-(4-Bromophenyl)-3H-thiazol-2-yl-ylidene]hydrazonomethyl}-5-nitrothiophene 5a. Red
compound, yield 87%, mp 202-204 ◦ C; IR (KBr, υ, cm−1): 3130 (NH), 1625, 1595 (C=N); 1 H-NMR (DMSO-
d6): δ 7.36 (d, J = 8 Hz, 2H, ar-H), 7.49 (d, J = 4.2 Hz, 1H, thiophene), 7.61 (s, 1H, thiazole), 7.74 (d,
J = 8 Hz, 2H, ar-H), 7.93 (d, J = 4.2 Hz, 1H, thiophene), 8.42 (s, 1H, CH=N), 10.68 (brs, 1H, NH, D2 O-
exchangeable);13 C-NMR (DMSO-d6): δ 108.2 & 150.0 (C-thiazole), arC: [124.4 (C), 128.3 (2C), 130.3 (2C),
133.5 (C)], 128.8, 129.0, 154.8, & 155.6 (C-thiophene), 147.0 (CH=N), 162.3 (C=N); Anal. Calcd. (%) for:
C14 H9 BrN4 O2 S2 : C, 41.08, H, 2.21, N, 13.69, Found; C, 41.23, H, 2.41, N, 13.57.
2-{[4-(4-Bromophenyl)-3H-3-phenylthiazol-2-yl-ylidene]hydrazonomethyl}-5-nitrothiophe-
ne 5b. Orange compound, yield 76%, mp 170-172 ◦ C; IR (KBr, υ, cm−1): 1625, 1600 (C=N); 1 H-NMR
(CDCl3): δ 7.04 (t, J = 8.5 Hz, 1H, ar-H), 7.24 (t, J = 8.5 Hz, 2H, ar-H), 7.38 (d, J = 8 Hz, 2H, ar-H), 7.47
(d, J = 8.5 Hz, 2H, ar-H), 7.58 (d, J = 4.2 Hz, 1H, thiophene), 7.70 (s, 1H, thiazole), 7.81 (d, J = 8 Hz, 2H,
ar-H), 7.94 (d, J = 4.2 Hz, 1H, thiophene), 8.46 (s, 1H, CH=N); Anal. Calcd. (%) for: C20 H13 BrN4 O2 S2 :
C, 49.48, H, 2.69, N, 11.54, Found; C, 49.67, H, 2.81, N, 11.44.
2-{[4-(4-Methoxyphenyl)-3H-thiazol-2-yl-ylidene]hydrazonomethyl}-5-nitrothiophene 6a.
Brown compound, yield 82%, mp 223-225 ◦ C; IR (KBr, υ, cm−1): 3280 (NH), 1640, 1600 (C=N); 1 H-NMR
(CDCl3): δ 3.86 (s, 3H, OCH3), 7.18 (d, J = 7.5 Hz, 2H, ar-H), 7.52 (d, J = 4 Hz, 1H, thiophene), 7.63 (d, J
= 7.5 Hz, 2H, ar-H), 7.74 (s, 1H, thiazole), 7.96 (d, J = 4 Hz, 1H, thiophene), 8.32 (s, 1H, CH=N), 10.82 (brs,
1H, NH, D2 O-exchangeable); Anal. Calcd. (%) for: C15 H12 N4 O3 S2 : C, 49.98, H, 3.35, N, 15.54, Found; C,
50.25, H, 3.47, N, 15.71.
2-{[4-(4-Methoxyphenyl)-3H-3-phenylthiazol-2-yl-ylidene]hydrazonomethyl}-5- nitrothiop-
hene 6b. Red compound, yield 70%, mp 140-142 ◦ C; IR (KBr, υ, cm−1): 1630, 1605 (C=N); 1 H-NMR
(CDCl3): δ 3.95 (s, 3H, OCH3), 7.06 (t, J = 8 Hz, 1H, ar-H), 7.12 (d, J = 7.5 Hz, 2H, ar-H), 7.24 (t, J =
8 Hz, 2H, ar-H), 7.40 (d, J = 8 Hz, 2H, ar-H), 7.54 (d, J = 4 Hz, 1H, thiophene), 7.67 (d, J = 7.5 Hz, 2H,
ar-H), 7.78 (s, 1H, thiazole), 7.91 (d, J = 4 Hz, 1H, thiophene), 8.42 (s, 1H, CH=N);13 C-NMR (CDCl3): δ
57.6 (CH3), 107.4 & 150.0 (C-thiazole), arC: [123.6 (C), 124.8 (C), 126.3 (2C), 127.2 (2C), 129.8 (2C), 130.2
(2C), 130.8 (C), 143.5 (C)], 128.6, 128.7, 155.7, & 157.1 (C-thiophene), 147.4 (CH=N), 161.4 (C=N); Anal.
Calcd. (%) for: C21 H16 N4 O3 S2 : C, 57.78, H, 3.69, N, 12.83, Found; C, 57.94, H, 3.85, N, 12.94.
General method for the synthesis of compounds 7a-b. A solution of 2-(thiosemicarbazidomethyl)-
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Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
5-nitrothiophene 1a or 2-[(4-phenylthiosemicarbazido)methyl]-5-nitrothiophene 1b (0.001 mol) in acetic anhy-
dride (12 mL) was heated under reflux for 3-5 h with continuous stirring and then allowed to attain room
temperature. The reaction mixture was slowly added to 400 mL of ice-cooled water and then stirred at room
temperature for 1 h. The separated product was collected by filtration, washed thoroughly with water, dried,
and recrystallized from appropriate solvent.
2-(3-Acetyl-5-acetylamino-2,3-dihydro-[1,3,4]-thiadiazol-2-yl)-5-nitrothiophene 7a. Crystal-
lized from acetic acid, buff compound, yield 68%, mp >300 ◦ C; IR (KBr, υ, cm−1): 3145 (NH), 1660, 1650
(COCH3); 1 H-NMR (DMSO-d6): δ 2.03 (s, 3H, CH3), 2.06 (s, 3H, CH3), 6.53 (s, 1H, thiadiazole), 7.58 (d, J
= 4.8 Hz, 1H, thiophene), 7.90 (d, J = 4.8 Hz, 1H, thiophene), 10.71 (brs, 1H, NH, D2 O-exchangeable); Anal.
Calcd. (%) for: C10 H10 N4 O4 S2 : C, 38.20, H, 3.20, N, 17.82, Found; C, 38.42, H, 3.36, N, 17.96.
2-[3-Acetyl-5-(N -phenylacetylamino)-2,3-dihydro-[1,3,4]-thiadiazol-2-yl]-5-nitrothiophene
7b. Crystallized from chloroform/ethanol, buff compound, yield 53%, mp 230-232 ◦ C; IR (KBr, υ, cm−1):
1660, 1650 (COCH3); 1 H-NMR (CDCl3): δ 2.03 (s, 3H, CH3), 2.08 (s, 3H, CH3), 6.50 (s, 1H, thiadiazole),
7.08 (t, J = 8 Hz, 1H, ar-H), 7.26 (t, J = 8 Hz, 2H, ar-H), 7.41 (d, J = 8 Hz, 2H, ar-H), 7.52 (d, J = 4.8
Hz, 1H, thiophene), 7.89 (d, J = 4.8 Hz, 1H, thiophene); 13 C-NMR (CDCl3)δ 23.5 (CH3), 25.1 (CH3), 67.2
(CH-thiadiazole), arC: [128.1 (C), 128.3 (2C), 130.0 (2C), 138.6 (C)], 128.7, 128.9, 151.6, & 153.9 (C-thiophene),
149.2 (C=N of thiadiazole), 165.4 (C=O), 166.4 (C=O); Anal. Calcd. (%) for: C16 H14 N4 O4 S2 : C, 49.21, H,
3.61, N, 14.35, Found; C, 49.44, H, 3.34, N, 14.21.
Synthesis of 2-[(4-oxo-3-phenylthiazolidin-2-ylidene)hydrazonomethyl]-5-nitrothiophene 9.
A mixture of 2-[(4-phenylthiosemicarbazido)methyl]-5-nitrothiophene 1b (3 g, 0.01 mol), chloroacetic acid (1
g, 0.01 mol), and anhydrous sodium acetate (0.82 g, 0.01 mol) in glacial acetic acid (20 mL) was heated under
reflux for 8 h with continuous stirring. The reaction mixture was left to cool and poured into ice-cold water, and
the separated solid was filtered off, washed thoroughly with water, dried, and recrystallized from ethanol/water
to give a red compound, yield 70%, mp 168-170 ◦ C; IR (KBr, υ, cm−1): 1725 (CO), 1630, 1595 (C=N);
1 H-NMR (CDCl3): δ 4.07 (s, 2H, CH2), 7.04 (t, J = 8.8 Hz, 1H, ar-H), 7.22 (t, J = 8.8 Hz, 2H, ar-H), 7.38
(d, J = 8.8 Hz, 2H, ar-H), 7.60 (d, J = 4.4 Hz, 1H, thiophene), 7.98 (d, J = 4.4 Hz, 1H, thiophene), 8.46 (s,
1H, CH=N); Anal. Calcd. (%) for: C14 H10 N4 O3 S2 : C, 48.54, H, 2.91, N, 16.17, Found; C, 48.34, H, 2.74, N,
16.35.
General method for the synthesis of compounds 10a-f. To a solution of compound 9 (0.346 g,
0.001 mol) and anhydrous sodium acetate (0.12 g, 0.0015 mol) in glacial acetic acid (10 mL) were added the
appropriate aromatic aldehydes (0.001 mol). The mixture was heated under reflux for 6 h with continuous
stirring. The reaction mixture was left to cool and poured onto crushed ice with stirring. The separated solid
was filtered off, washed thoroughly with water, dried, and recrystallized from chloroform/pet.ether.
2-[(5-Benzylidene-4-oxo-3-phenylthiazolidin-2-ylidene)hydrazonomethyl]-5-nitrothiophene
10a. Orange compound, yield 70%, mp 180-182 ◦ C; IR (KBr, υ, cm−1): 1700 (CO), 1630, 1595 (C=N), 1561
(C=C); 1 H-NMR (CDCl3): δ 7.02 (t, J = 8.5 Hz, 1H, ar-H), 7.16 (t, J = 8 Hz, 1H, ar-H), 7.28 (t, J =
8.5 Hz, 2H, ar-H), 7.37 (t, J = 8 Hz, 2H, ar-H), 7.44 (d, J = 8.5 Hz, 2H, ar-H), 7.58 (d, J = 4.2 Hz, 1H,
thiophene), 7.69 (d, J = 8 Hz, 2H, ar-H), 7.94 (d, J = 4.2 Hz, 1H, thiophene), 8.11 (s, 1H, olefinic CH=), 8.48
(s, 1H, CH=N); 13 C-NMR (CDCl3): δ arC: [126.3 (C), 127.1 (C), 128.0 (2C), 128.2 (2C), 128.4 (2C), 129.3
(2C), 132.4 (C), 135.2 (C)], 128.7, 128.9, 154.2, & 155.3 (C-thiophene), 147.5 (CH=N), 157.0 (C=N), 158.8 &
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Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
159.3 (C=CH), 167.1 (CO); Anal. Calcd. (%) for: C21 H14 N4 O3 S2 : C, 58.05, H, 3.24, N, 12.89, Found; C,
58.24, H, 3.37, N, 12.74.
2-{[5-(3-Bromobenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]hydrazonomethyl}-5-nitr-
othiophene 10b. Brown compound, yield 65%, mp 190-192 ◦ C; IR (KBr, υ, cm−1): 1700 (CO), 1640, 1600
(C=N), 1585 (C=C); 1 H-NMR (CDCl3): δ 7.04 (t, J = 8 Hz, 1H, ar-H), 7.19 (t, J = 8 Hz, 2H, ar-H), 7.27
(t, J = 7.5 Hz, 1H, ar-H), 7.36 (d, J = 7.5 Hz, 1H, ar-H), 7.47 (d, J = 8 Hz, 2H, ar-H), 7.59 (d, J = 4.2 Hz,
1H, thiophene), 7.70 (d, J = 7.5 Hz, 1H, ar-H), 7.80 (s, 1H, ar-H), 7.93 (d, J = 4.2 Hz, 1H, thiophene), 8.14
(s, 1H, olefinic CH=), 8.46 (s, 1H, CH=N); Anal. Calcd. (%) for: C21 H13 BrN4 O3 S2 : C, 49.12, H, 2.55, N,
10.91, Found; C, 49.34, H, 2.31, N, 11.13.
2-{[5-(3-Nitrobenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]hydrazonomethyl}-5-nitrot-
hiophene 10c. Brown compound, yield 60%, mp 186-188 ◦ C; IR (KBr, υ, cm−1): 1710 (CO), 1630, 1595
(C=N), 1548 (C=C); 1 H-NMR (CDCl3): δ 7.06 (t, J = 8 Hz, 1H, ar-H), 7.15 (t, J = 8 Hz, 2H, ar-H), 7.31
(d, J = 8 Hz, 2H, ar-H), 7.46 (t, J = 7.5 Hz, 1H, ar-H), 7.59 (d, J = 4 Hz, 1H, thiophene), 7.68 (d, J = 7.5
Hz, 1H, ar-H), 7.78 (d, J = 7.5 Hz, 1H, ar-H), 7.84 (s, 1H, ar-H), 7.96 (d, J = 4 Hz, 1H, thiophene), 8.13 (s,
1H, olefinic CH=), 8.47 (s, 1H, CH=N); Anal. Calcd. (%) for: C21 H13 N5 O5 S2 : C, 52.60, H, 2.73, N, 14.60,
Found; C, 52.42, H, 2.51, N, 14.72.
2-{[5-(4Chlorobenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]hydrazonomethyl}-5-nitrot-
hiophene 10d. Orange compound, yield 68%, mp 200-202 ◦ C; IR (KBr, υ, cm−1): 1700 (CO), 1635, 1600
(C=N), 1565 (C=C); 1 H NMR (CDCl3): δ 7.03 (t, J = 8.2 Hz, 1H, ar-H), 7.18 (t, J = 8.2 Hz, 2H, ar-H), 7.29
(d, J = 7.5 Hz, 2H, ar-H), 7.40 (d, J = 8.2 Hz, 2H, ar-H), 7.53 (d, J = 4.4 Hz, 1H, thiophene), 7.70 (d, J = 7.5
Hz, 2H, ar-H), 7.91 (d, J = 4.4 Hz, 1H, thiophene), 8.04 (s, 1H, olefinic CH=), 8.44 (s, 1H, CH=N);13 C-NMR
(CDCl3): δ arC: [127.0 (C), 128.0 (C), 128.6 (2C), 129.1 (2C), 133.1 (2C), 134.4 (2C), 135.6 (C), 138.1 (C)],
128.8, 128.9, 154.2, & 155.4 (C-thiophene), 147.3 (CH=N), 157.2 (C=N), 158.1 & 159.1 (C=CH), 168.2 (CO);
Anal. Calcd. (%) for: C21 H13 ClN4 O3 S2 : C, 53.78, H, 2.79, N, 11.94, Found; C, 53.96, H, 2.63, N, 12.17.
2-{[5-(4-Flourobenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]hydrazonomethyl}-5-nit-
rothiophene 10e. Orange compound, yield 72%, mp 210-212 ◦ C; IR (KBr, υ, cm−1): 1710 (CO), 1635, 1600
(C=N), 1582 (C=C); 1 H-NMR (CDCl3)δ 7.05 (t, J = 8 Hz, 1H, ar-H), 7.18 (t, J = 8 Hz, 2H, ar-H), 7.32
(d, J = 7.5 Hz, 2H, ar-H), 7.45 (d, J = 8 Hz, 2H, ar-H), 7.60 (d, J = 4.2 Hz, 1H, thiophene), 7.72 (d, J =
7.5 Hz, 2H, ar-H), 7.89 (d, J = 4.2 Hz, 1H, thiophene), 8.00 (s, 1H, olefinic CH=), 8.38 (s, 1H, CH=N); Anal.
Calcd. (%) for: C21 H13 FN4 O3 S2 : C, 55.74, H, 2.89, N, 12.38, Found; C, 55.52, H, 2.65, N, 12.16.
2-{[5-(4-Methoxybenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]hydrazonomethyl}-5-nit-
rothiophene 10f. Orange compound, yield 78%, mp 156-158 ◦ C; IR (KBr, υ, cm−1): 1710 (CO), 1640, 1605
(C=N), 1585 (C=C); 1 H-NMR (CDCl3): δ 3.92 (s, 3H, CH3 O), 7.04 (t, J = 8.4 Hz, 1H, ar-H), 7.16 (t, J =
8.4 Hz, 2H, ar-H), 7.28 (d, J = 7.8 Hz, 2H, ar-H), 7.40 (d, J = 8.4 Hz, 2H, ar-H), 7.58 (d, J = 4.2 Hz, 1H,
thiophene), 7.73 (d, J = 7.8 Hz, 2H, ar-H), 7.90 (d, 1H, J = 4.2 Hz, thiophene), 8.12 (s, 1H, olefinic CH=),
8.40 (s, 1H, CH=N); Anal. Calcd. (%) for: C22 H16 N4 O4 S2 : C, 56.88, H, 3.47, N, 12.06, Found; C, 56.67, H,
3.35, N, 12.24.
Synthesis of N\ -[(5-nitrothiophen-2-yl)methylene]-2-cyanoacetohydrazide 11. A mixture of
5-nitro-2-thiophenecarboxaldehyde (3.14 g, 0.02 mol) and cyanoacetic acid hydrazide (1.98 g, 0.02 mol) in
136

Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
absolute ethanol (30 mL) was heated under reflux for 2 h. The precipitate formed after cooling was filtered
off, dried, and recrystallized from ethanol to give a buff compound, yield 85%, mp 235-237 ◦ C; IR (KBr, υ,
cm−1): 3200 (NH), 2226 (CN), 1695 (CO), 1600 (C=N); 1 H-NMR (DMSO-d6): δ 4.12 (s, 2H, CH2 CN), 7.61
(d, J = 4.8 Hz, 1H, thiophene), 7.93 (d, J = 4.8 Hz, 1H, thiophene), 8.43 (s, 1H, CH=N), 10.24 (brs, 1H,
NH, D2 O-exchangeable); Anal. Calcd. (%) for: C8 H6 N4 O3 S: C, 40.33, H, 2.53, N, 23.52, Found; C, 40.12,
H, 2.68, N, 23.34.
Synthesis of 4-amino-N\ -[(5-nitrothiophen-2-yl)methylene]-3-phenyl-2-thioxo-2,3-dihydrot-
hiazole-5-carbohydrazide 12. To a mixture of 11 (0.47 g, 0.002 mol), finely divided sulfur (0.065 g, 0.002
mol), and triethylamine (0.3 mL) in absolute ethanol (40 mL), phenyl isothiocyanate (0.2 mL, 0.002 mol) was
added. The reaction mixture was heated at 60 ◦ C for 4 h with continuous stirring. The reaction mixture
was cooled to room temperature, then poured into ice water containing a few drops of hydrochloric acid. The
formed solid product was collected by filtration, washed thoroughly with water, dried, and recrystallized from
ethanol/water to give a red compound, yield 65%, mp 140-142 ◦ C; IR (KBr, υ, cm−1): 3300, 3250 (NH2), 3150
(NH), 1675 (CO), 1605 (C=N), 1235 (CS); 1 H-NMR (DMSO-d6): δ 6.29 (brs, 2H, NH2 , D2 O-exchangeable),
7.11 (t, J = 8.5 Hz, 1H, ar-H), 7.27 (t, J = 8.5 Hz, 2H, ar-H), 7.43 (d, J = 8.5 Hz, 2H, ar-H), 7.63 (d,
J = 4.4 Hz, 1H, thiophene), 7.92 (d, J = 4.4 Hz, 1H, thiophene), 8.36 (s, 1H, CH=N), 8.95 (brs, 1H, NH,
D2 O-exchangeable); Anal. Calcd. (%) for: C15 H11 N5 O3 S3 : C, 44.42, H, 2.73, N, 17.27, Found; C, 44.53, H,
2.86, N, 17.02.
Synthesis of 6-{[(5-nitrothiophen-2-yl)methylene]amino}-3-phenyl-2-thioxo-2,3-dihydrot-
hiazolo-[4,5-d]-pyrimidin-7(6H)-one 13. A solution of compound 12 (0.81 g, 0.002 mol) in a mixture of
triethylorthoformate (2.5 mL) and acetic anhydride (2.5 mL) was heated under reflux for 3 h with continuous
stirring. The reaction mixture was allowed to cool to room temperature and left overnight in a refrigerator. The
crude product was collected by filtration, washed with cold diethylether, dried, and recrystallized from ethanol
to give a brown compound, yield 61%, mp 180-182 ◦ C; IR (KBr, υ, cm−1): 1680 (CO), 1640 (C=N), 1600
(C=C), 1238 (C=S); 1 H-NMR (DMSO-d6): δ 7.13 (t, J = 8 Hz, 1H, ar-H), 7.30 (t, J = 8 Hz, 2H, ar-H), 7.46
(d, J = 8 Hz, 2H, ar-H), 7.64 (d, J = 4.4 Hz, 1H, thiophene), 7.97 (d, J = 4.4 Hz, 1H, thiophene), 8.46 (s,
1H, CH=N), 9.16 (s, 1H, pyrimidine);13 C-NMR (DMSO-d6): δ 116.1, 140.4, 160.3, & 165.0 (C-pyrimidinone),
arC: [128.4 (C), 129.1 (2C), 132.4 (2C), 134.0 (C)], 128.7, 128.8, 154.6, & 156.2 (C-thiophene), 147.2 (CH=N),
176.5 (CS); Anal. Calcd. (%) for: C16 H9 N5 O3 S3 : C, 46.25, H, 2.18, N, 16.85, Found; C, 46.01, H, 2.33, N,
16.98.
Antiinflammatory activity
The newly synthesized compounds were evaluated for their in vivo antiinflammatory activity using the carragee-
nan-induced hind paw edema method.20 Adult Sprague-Dawley rats, weighing 150-200 g, were used. The
animals were allowed food and water ad libitum, except during the experiment. They were housed in a room
at 23
2
◦ C with a 12 h light/dark cycle. The animals were randomly allocated into groups of 6 animals
each at the beginning of the experiment and were fasted for 24 h before the experiment with free access to
water. All of the compounds and the reference drug were suspended in a 0.5% carboxymethyl cellulose (CMC)
solution. The standard drug Celecoxib was administered orally at a dose of 20 mg/kg. The tested compounds
137

Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
were administered orally at an equimolar oral dose relative to 20 mg/kg of Celecoxib. The control group
received a 0.5% CMC solution. Into the subplantar region of the right hind paw of each rat, 0.1 mL of 1%
carrageenan solution in saline was injected subcutaneously, 1 h after the administration of the test compounds
and standard drug. The right hind paw volume was measured after 3 h of carrageenan treatment by means of a
plethysmometer. The percent edema inhibition was calculated from the mean effect in the control and treated
animals according to the following equation:
percent edema inhibition = (vc – vt / vc)× 100,
where vt represents the mean increase in paw volume in rats treated with tested compounds and vc
represents the mean increase in paw volume in the control group of rats. The potency was calculated as regards
the percentage of the change of the standard and tested compounds, as depicted in the Table.
Results and discussion
The synthetic procedures adopted to obtain the target compounds are outlined in Schemes 1, 2, and 3.
The key intermediate; 2-(thiosemicarbazidomethyl)-5-nitrothiophene 1a, was prepared previously in the litera-
ture through the reaction of 5-nitrothiophene-2-carboxaldehyde diacetate with thiosemicarbazide.17 But in the
present report, intermediate 1a was obtained in high yield by a modified procedure through the condensation
of 5-nitro-2-thiophene carboxaldehyde with thiosemicarbazide in absolute ethanol. In Scheme 1; the interme-
diate; 2-[(4-phenylthiosemicarbazido)methyl]-5-nitrothiophene 1b was prepared following a previously reported
literature procedure.18 The reaction of the key intermediates 1a-b with diethyl-2-bromomalonate in refluxing
ethanol containing a catalytic amount of anhydrous sodium acetate afforded 2-[(5-ethoxycarbonyl-2-[(4-oxo-
3-substituted thiazolidin-2-ylidene)hydrazonomethyl]-5-nitrothiophene 2a-b. Their IR spectra showed bands
due to COOEt and CO at 1740 and 1710 cm−1 , respectively. The 1 H-NMR spectra showed a signal at 4.89-
4.91 ppm attributed to CH-thiazolidine. The thiosemicarbazone derivatives 1a-b were allowed to react with
ethyl-2-chloroacetoacetate in an absolute ethanol solution that contained anhydrous sodium acetate and glacial
acetic acid to produce 2-[(5-ethoxycarbonyl-4-methyl-3H-3-substituted thiazol-2-yl-ylidene)hydrazonomethyl]-
5-nitrothiophene 3a-b in good yield. Their IR spectra showed a band at 1725 cm−1 due to COOEt. In
addition, reaction of intermediates 1a-b with thioglycolic acid in anhydrous benzene afforded the corresponding
thioureido-thiazolidinone derivatives 4a-b. Their IR spectra showed, beside the bands due to NH, a carbonyl
absorption band at 1700 cm−1 . Their 1 H-NMR spectra showed signals characteristic for NH protons and 2 new
singlets at 3.35-3.37 and 7.16 ppm attributed to the CH2 and CH of 4-oxothiazolidinyl, respectively. Further-
more, treatment of thiosemicarbazone derivatives 1a-b with 4-substituted phenacyl bromides in boiling ethanol
in the presence of anhydrous sodium acetate yielded the corresponding thiazol-2-yl-ylidene derivatives 5a-b and
6a-b. Their 1 H-NMR spectra showed a new singlet at 7.61-7.78 ppm attributed to CH thiazol-2-yl-ylidene.
Moreover, 2-[3-acetyl-5-(N -substituted acetylamino)-2,3-dihydro-[1,3,4]thiadiazol-2-yl)-5-nitrothiophene 7a-b
were prepared by refluxing the thiosemicarbazones 1a-b with acetic anhydride. Their IR spectra showed a new
band at 1650, 1660 cm−1 attributed to an acetyl group. Their 1 H-NMR spectra showed a new singlet at 6.50-
6.53 ppm attributed to the CH of 1,3,4-thiadiazoline, in addition to signals due to methyl groups (2CH3 CO)
at 2.03-2.08 ppm.
138

Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
In conclusion, the reaction time and the corresponding yields of the reaction of 1a-b with reagents diethyl-
2-bromomalonate, ethyl-2-chloroacetoacetate, and 4-substituted phenacyl bromides revealed that intermediate
1a was more reactive than intermediate 1b because the steric effect of the phenyl group on the NH reduced
the ability of compound 1b to undergo nucleophilic cyclization, and the greater electron density of the NH2 in
compound 1a than in the NH in compound 1b increased the ability of compound 1a to undergo nucleophilic
cyclization. Likewise, the reaction time and the reaction yields of thiosemicarbazones 1a-b with acetic anhydride
R
R
O
N
N
CH3
N
N
N
N
S
S
S
O2N
S
CO2C2H5
2a-b
O2N
CO2C2H5
3a-b
R: a = H
R: a = H
b
H
= C6H5
C
H
b
= C6H5
O
O
BrCH(CO2C2H5)2
CH3COONa
C2H5OH
C
l
H
C
C
H
/
C
a
O
N
C
O
H
O
C
C
H
C
H
S
N
O
NH
N
R
NH2NHCSNH2
S
N
HN
O
S
1a-b
HSCH2COOH
C6H6
S
S
O2N
C2H5OH
O2N
O2N
S
4a-b
a
R: = H
HN
C
A
H
C
b = C6H5
a
R: = H
r
R
C
O
O
b = C6H5
C
O
H
N
a
B
/
r
C
O
O
H
O
R
H
H3C
O
CH3
Ar
N
N
N
R
N
S
S
O2N
CH3
S
5a-b & 6a-b
O
N
N
5a: Ar = 4BrC6H4 ; R= H
S
5b: Ar = 4BrC6H4 ; R= C6H5
6a: Ar = 4CH3OC6H4 ; R= H
6b: Ar = 4CH3OC6H4 ; R= C6H5
O2N
H3C
7a-b
R: a = H
O
b
= C6H5
Scheme 1. Synthesis of compounds 2a-b – 7a-b.
139

Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
revealed that compound 1a was more reactive than compound 1b. The NH2 of intermediate 1a, with strong
nucleophilicity and without steric effect, may facilitate further nucleophilic substitution with acetic anhydride
to yield the desired diacetyl-substituted compound 7a (reaction time was 3 h). Meanwhile, the resonance effect
between NH and the phenyl group of intermediate 1b and the steric effect of phenyl group on the NH may
reduce nucleophilic substitution with acetic anhydride. Therefore, the initial monoacetyl-substituted product
was gradually converted to the desired diacetyl-substituted thiadiazoline 7b by further heating (reaction time
was 5 h) (Scheme 1).
In Scheme 2; the intermediate 2-[(4-phenylthiosemicarbazido)methyl]-5-nitrothiophene 1b was synthe-
sized by a new method in an excellent yield in 2 consequential steps by condensing 5-nitro-2-thiophene carbox-
aldehyde with hydrazine hydrate to afford 5-nitrothiophene-2-carbaldehydehydrazone19 8, which was heated
under reflux with phenyl isothiocyanate in diethylene oxide to afford the desired intermediate 1b. Refluxing of
this intermediate 1b with chloroacetic acid in the presence of anhydrous sodium acetate in glacial acetic acid
afforded 2-[(4-oxo-3-phenyl thiazolidin-2-ylidene)hydrazonomethyl]-5-nitrothiophene 9. Its IR spectra showed
the disappearance of NH bands of substituted thiosemicarbazone moiety and the presence of a new band at 1725
cm−1 attributed to a carbonyl group of thiazolidin-4-one. The 1 H-NMR spectra lacked signals characteristic
of NH protons and showed a new singlet at 4.07 ppm attributed to CH2 thiazolidinone. The condensation of
compound 9 with substituted benzaldehyde derivatives in the presence of freshly fused sodium acetate in boiling
glacial acetic acid yielded the corresponding arylidene derivatives 10a-f.
C6H5NCS
Diethylene oxide
NH2
N
1b
S
O2N
8
ClCH2CO2H
CH3COOH
CH3COONa
C6H5
N
C6H5
O
O
N
N
N
ArCHO
N
N
S
S
CH3COOH
S
S
Ar
O2N
O2N
9
CH3COONa
10a-f
a = C H ;
Ar:
b
= 3Br C6H4 ;
c = 3NO2 C6H4
f = 4CH3OC6H4
6
5
d
e
= 4Cl C6H4 ; = 4FC6H4 ;
Scheme 2. Synthesis of compounds 10a-f.
On the other hand, condensation of 5-nitro-2-thiophene carboxaldehyde with cyanoacetic acid hydrazide
afforded the desired intermediate N\ -arylidene cyanoacetic acid hydrazide 11, which on treatment with sul-
fur and phenyl isothiocyanate in the presence of triethylamine as a basic catalyst afforded 4-amino-N\-
[(5-nitrothiophen-2-yl)methylene]-3-phenyl-2-thioxo-2,3-dihydrothiazole-5-carbohydrazide 12. Its IR spectra
140

Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
showed absorption bands at 3300, 3250, and 3150 cm−1 attributed to NH, a band at 1675 cm1 due to hydrazide
C=O, and a band at 1235 cm−1 attributed to C=S. Finally, 6-{[(5-nitrothiophen-2-yl)methylene]amino}-3-
phenyl-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one 13 was prepared by heating compound 12 with
a mixture of triethylorthoformate and acetic anhydride (1:1). Its IR spectra showed a band at 1680 cm−1
attributed to the C=O of pyrimidone. The 1 H-NMR showed a new signal at 9.16 ppm attributed to thiazolopy-
rimidine C-5-H (Scheme 3). All of the newly synthesized compounds were spectroscopically characterized.
O
H2N
CN
H
N
N
H
N
O
CN
S
S
O
O2N
O2N
C2H5OH
11
S/C6H5NCS
(C2H5)3N
C6H5
C6H5
N
O
N
H2N
O
N
O
O
O
S
S
H
N
N
N
S
H3C
CH3
S
N
S
S
O2N
(C2H5O)3CH
O2N
13
12
Scheme 3. Synthesis of target compound 13.
The antiinflammatory activity of the newly synthesized compounds was evaluated by the carrageenan-
induced paw edema method.20 The standard drug Celecoxib was administered orally at a dose of 20 mg/kg.
The tested compounds were administered orally at an equimolar oral dose relative to 20 mg/kg of Celecoxib.
The synthesized compounds showed antiinflammatory activity ranging from 12.41% to 62.79% (Table), whereas
the standard drug Celecoxib showed 72.88% inhibition of edema after 3 h.
The structure of the antiinflammatory activity relationship among the synthesized compounds revealed
that the activity was dependent on the basic molecular skeleton; thiazolines and thiazolidines incorporated
to the thiophene ring through hydrazono moiety. Compounds 2a-b, 3a-b, 5a-b, 6a-b, 9, 10a-f, and 12
showed activity from moderate to good, at 49.76%, 47.30%, 53.48%, 55.06%, 62.79%, 58.13%, 53.48%, 50.37%,
48.83%, 51.16%, 51.95%, 48.04%, 56.60%, 58.93%, 52.69%, and 47.30%, respectively. Also; thiazolo[4,5-
d]pyrimidinone attached to the thiophene ring through methylene amino moiety, 13, also showed good activity,
52.69%. Meanwhile, thiazolidines and thiadiazolidines attached directly to thiophene ring 4a-b and 7a-b
showed minimum activity, at 12.41%, 14.74 %, 17.06%, and 16.27%, respectively.
141

Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
Table. The anti-inflammatory activity of the newly synthesized compounds.
Compound Edema volume S.E. % Inhibition of inflammationa Potencyb
after 3 h
after 3 h
49.76
47.30
53.48
55.06
12.41
14.74
62.79
58.13
53.48
50.37
17.06
16.27
48.83
51.16
51.95
48.04
56.60
58.93
52.69
47.30
52.69
72.88
-
2a
2b
1.080 0.030∗
1.133 0.049∗
1.000 0.025∗
0.966 0.021∗
1.883 0.074
1.833 0.060
0.800 0.036∗
0.900 0.051∗
1.000 0.025∗
1.067 0.033∗
1.783 0.054
1.800 0.036
1.100 0.057∗
1.050 0.034∗
1.033 0.042∗
1.117 0.030∗
0.933 0.061∗
0.883 0.047∗
1.017 0.074∗
1.133 0.049∗
1.017 0.074∗
0.583 0.060∗
2.150 0.056
0.68
0.64
0.73
0.75
0.17
0.20
0.86
0.79
0.73
0.69
0.23
0.22
0.67
0.70
0.71
0.65
0.77
0.80
0.72
0.64
0.72
1
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
9
10a
10b
10c
10d
10e
10f
12
13
Celecoxib
Control
-
*Significant from control, P < 0.01.
aPercent edema inhibition was calculated as regards control group.
bPotency was calculated as regards the percentage inhibition of the Celecoxib-treated group.
In conclusion, the best antiinflammatory activity was exhibited by compound 5a of chemical skeleton; 2-
{[4-(4-bromophenyl)-3H-thiazol-2-yl-ylidene]hydrazonomethyl}-5-nitrothiophene and compound 10e of chemi-
cal skeleton; 2-{[5-(4-flourobenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]hydrazonomethyl}-5-nitrothiophene,
at 62.79% and 58.93%, respectively; comparable to the other synthesized compounds with respect to the stan-
dard Celecoxib.
Acknowledgements
The author is very grateful to Dr. Manar Nader and Dr. Ahmad Ramadan, Department of Pharmacology,
Faculty of Pharmacy, Mansoura University, Egypt, for performing the antiinflammatory evaluation.
142

Synthesis and antiinflammatory activity of novel..., S. M. I. BADR
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