Skip to content


Open Access

Heterocyclization of polarized system: synthesis, antioxidant and anti-inflammatory 4-(pyridin-3-yl)-6-(thiophen-2-yl) pyrimidine-2-thiol derivatives

Chemistry Central Journal201812:68

Received: 24 April 2018

Accepted: 2 June 2018

Published: 8 June 2018



Chalcones are intent in the daily diet as a favorable chemotherapeutic compound; on the other hand thiophene moiety is present in a large number of bioactive molecules having diverse biological efficiency.


Our current goal is the synthesis of (E)-1-(pyridin-3-yl)-3-(thiophen-2-yl) prop-2-en-1-one 3 thats used as a starting compound to synthesize the novel pyrimidine-2-thiol, pyrazole, pyran derivatives. Chalcones 3 was prepared by condensation of 3-acetylpyridine with thiophene 2-carboxaldehyde which reacted with thiourea to obtain pyrimidinthiol derivative 4. Compound 4 was allowed to react with hydrazine hydrate to afford 2-hydrazinylpyrimidine derivative 5. Compound 5 was used as a key intermediate for a facile synthesis of the targets 6 and 7. In contrast, pyranone 8 was obtained by transformation of compound 5. Using as a precursor for the synthesis of new pyrazolo pyrimidine derivatives 910. The major incentive behind the preparation of these compounds was the immense biological activities associated to these heterocyclic derivatives.


The newly synthesized compounds (14) showed potent anti-inflammatory activities both in vitro and in vivo. They also exhibited promising antioxidant vitalities against α, α-diphenyl-β-picrylhydrazyl scavenging activity and lipid peroxidation. In conclusion, compound 1 showed a hopefully anti-inflammatory and antioxidant activities.
Graphical Abstract image




Chalcones are distinguished by their easy synthesis from Claisen-Schmidt condensation. The chemical structure of chalcones formed of two aromatic rings joined by a thee carbon, α, β-unsaturated carbonyl system (1, 3-diphenylprop-2-en-1-one) [1, 2]. They have been authenticated with diverse biological efficiency including antibacterial [38], anti-inflammatory [912], antioxidant [1316], anti-tumor effects [1722]. Also, pyridine derivatives of different heterocyclic nucleus have shown potent pharmacological properties like cytotoxic activity [23, 24]. Recent studies have demonstrated that chalcones are target in the daily diet as a favorable chemotherapeutic compounds [25] and anti-proliferative activity [26]. On the other hand thiophene moiety is present in a large number of bioactive molecules having diverse biological activities such as anti-inflammatory [27], anticonvulsant [26], antimicrobial [27] and antitumor [28]. Moreover, thiophene moiety is a well-known isostere for benzene; for example, the replacement of benzene ring of the antidepressant drug, Viloxazine led to a prolongation of the half-life [29]. Recently we were concerned with the synthesis of polyfunctional heterocyclic compounds, where the (E)-1-(pyridin-3-yl)-3-(thiophen-2-yl) prop-2-en-1-one 3 was used as a starting compound. The remarkable biological activity of the polycyclic heterocyclic compounds encouraged us to continue our previous work on the synthesis of fused pyrimidine [3033] and their applications, by designing a polycyclic heterocyclic compounds containing five and/or six rings fused with each other to develop a superior biological activity.

Results and discussion


Aldol condensation reaction of 3-thiophenecarboxaldehyde 1 with 3-acetylpyridine 2 in ethanolic NaOH solution afforded chalcone 3. The structure of compound 3 was elucidated by its IR, 1H NMR and 13C NMR. Its IR spectrum showed a characteristic peak for a conjugated carbonyl group at 1633 cm−1, and by its 1H NMR which gave signals at δ 7.53 (d, 1H, J = 12.9 Hz, (CH=C–C=O), and 7.92 (d, 1H, J = 12.9 Hz (CH=C–C=O) and two doublet signals at δ = 7.28 and 7.94 due to thiophenyl-C 4′ H and thiophenyl-C 3′ H and another at 8.11 owing to thiophenyl-C 5′ H whereas, the 13C NMR spectrum showed a signal at (δ in ppm) 123 caused by ethylene group and 125, 126, 135, 149 and a signal due to C=O groups at 193. [3 + 3] base induced cycloaddition of chalcone 3 with thiourea gave 4-(pyridin-3-yl)-6-(thiophen-2-yl) pyrimidine-2(1H)-thione 4. IR spectra of compounds 4 showed the presence of a C=S band at 1270 cm−1 and an absorption band in the range 3433–3490 cm−1 attributed to the amine (NH). The 1H NMR spectrum of compound 4 two doublet signals at δ = 7.28 and 7.94 due to thiophenyl-C 4′ H and thiophenyl-C 3′ H and another at 8.11 as a result of thiophenyl-C 5′ H. The spectra displayed a singlet at 8.82 for NH, respectively. The hydrazinopyrimidine derivative 5 was synthesized by condensation of the thiopyrimidinone 4 with hydrazine hydrate in refluxing alcohol, the structure of compound 5 was confirmed by the IR, 1H NMR and elemental analysis, where its IR revealed the absorption bands at ν max = 3212 for the NH2 and 3184 cm−1 for the NH group, 1H NMR spectrum gave the signals at δ = 8.93–8.95 as a broad singlet for NH2, hydrazine NH, respectively (Scheme 1).
Figure 1
Scheme 1

Synthesis of pyrimidine derivatives

Cyclocondensation of chalcone 3 and ethyl cyanoacetate in the presence of sodium ethoxide under the reflux conditions [33] gave pyranone derivative 6. Condensation with hydrazinehydrate [34, 35] in refluxing ethanol leads to ring transformation producing corresponding pyridinones 7. The structure of the target 7 was confirmed from its spectral data, where is IR spectra showed absorption bands in the region 2222 and 1688 cm−1 characteristic for C≡N and carbonyl group, respectively (Scheme 2).
Figure 2
Scheme 2

Synthesis of pyranone and pyridinones derivatives

The hydrazinopyrimidine derivative 5 was used as a precursor for the synthesis of some heterocyclic compounds. The hydrazinopyrimidine derivative 5 reacted with ethyl acetoacetate in excess manner to afford compound 8. The formation of 8 may be proceeds via the formation of pyrazolone derivative 9 followed by the attack of methylene anion of pyrazolone to ketonic function of ethyl acetoacetate followed by pyran cyclization. IR spectrum of compound 8 revealed the absorption peaks at 1715 cm−1 characteristic of C=O groups respectively, 1H NMR exhibited the two singlets at δ = 2.25 and 2.32 for 2 CH3 protons and a singlet at δ = 5.60 ppm for pyranone H. Furthermore, the pyrimidine pyrazolone compound 9 was obtained as a result of attack of hydrazinofunction of 5 to ethyl acetoacetate. The pyrazolo pyrimidine 10 was synthesized by heating an alcoholic solution of compound 5 (10.0 mmol.) with acetylacetone (10.0 mmol.) at reflux temperature for 5 h. The IR spectra of 9 and 10 showed the disappearance of the hydrazine group where the 1H NMR spectrum showed singlet pyrimidine H at δ = 8.95 ppm and two singlets for the two CH3 protons, respectively (Scheme 3).
Figure 3
Scheme 3

Synthesis of isolated and fused pyrimidine derivatives

Biological activity studies

In vitro anti-inflammatory activity

In vitro COX-1 and COX-2 inhibition

Compounds (36) were calorimetrically evaluated for their anti-inflammatory activities in vitro for COX-1 and COX-2 at 590 nm using ovine COX-1/COX-2 inhibitor screening assay kit [36]. Celecoxib was used as a standard reference drug.

In vitro 5-LOX inhibition
A bnova 5 lipoxygenase inhibitor screening assay was used [37]. Meclofenamate sodium was used as a standard reference drug. Results were expressed in Table 1 as IC 50 as means of thee determinations the selectivity index was calculated also as IC50 (COX-1)/IC50 (COX-2).
Table 1

Display the anti-inflammatory activity of the newly synthesized compounds as IC 50, µM for COX-1, COX-2 and 5-LOX


IC 50 (µM)


IC 50 (µM)



IC 50 (µM)







Meclofenamate sodium





Compound 3





Compound 4





Compound 5





Compound 6





In vivo anti- inflammatory activity

Carrageenan induced rat paw edema in rats: Fifty rats were divided into ten groups (i.e., each group, five rats). The first group (control), received carboxymethyl cellulose. The second group was given diclofenac sodium as a standard anti-inflammatory drug. Groups (3–10) were orally given the newly synthesized compounds (36) in two dosages (5 and 10 mg/kg). Results were expressed as rat paw edema percent. One hour later after administration of tested doses, carrageenan was injected sub planter in the left hind footpad of each rat as 0.05 ml of 1% solution in sterile distilled water. Plethysmometer was used to measure paw edema volume from 0 to 4 h after carrageenan injection. Paw edema volume was compared with vehicle control group and reduction percent was calculated as the following
$$\% {\text{ reduction in edema}} = \left( {1 - {\text{ Vt Vc}}} \right) \, \times \, 100$$
Where Vt and Vc are the edema volume in the group treated with drug and control, respectively [38]. Results were expressed as mean ± standard deviation (SD). Differences between means were tested for significance using a one-way analysis of variance (ANOVA) followed by Duncan’s test (Table 2).
Table 2

Inhibition percent of rat paw edema after administration of newly synthesized compounds


0 h

1 h

2 h

3 h

4 h

Diclofenac sodium

0.49 ± 0.032a

30.22 ± 1.27a

33.85 ± 1.19a

36.21 ± 0.93a

41.10 ± 3.98a

Compound 3

5 mg/kg.b.wt

0.48 ± 0.027ab

21.72 ± 0.79b

22.79 ± 1.07d

24.79 ± 0.49c

28.41 ± 1.30c

Compound 3

10 mg/kg.b.wt

0.47 ± 0.04ab

31.98 ± 9.35a

29.93 ± 1.43b

34.16 ± 0.61b

41.15 ± 0.750a

Compound 4

5 mg/kg.b.wt

0.46 ± 0.03b

18.91 ± 1.19bc

20.07 ± 1.43e

21.96 ± 1.25d

27.38 ± 1.68c

Compound 4

10 mg/kg.b.wt

0.49 ± 0.01ab

21.43 ± 0.96b

26.27 ± 49e

33.13 ± 2.64b

37.15 ± 0.69b

Compound 5

5 mg/kg.b.wt

0.49 ± 0.01a

11.62 ± 1.24de

14.61 ± 1.81g

18.41 ± 1e

19.48 ± 0.89e

Compound 5

10 mg/kg.b.wt

0.48 ± 0.01ab

15.41 ± 0.83cd

18.83 ± 0.75ef

24.19 ± 1.59c

28.59 ± 2.26c

Compound 6

5 mg/kg.b.wt

0.50 ± 0.02a

9.61 ± 1.12e

12.28 ± 1.38h

17.19 ± 1.26e

18.51 ± 2.26e

Compound 6

10 mg/kg.b.wt

0.49 ± 0.01a

13.75 ± 1.15de

17.52 ± 1.13f

20.43 ± 0.65d

22.39 ± 1.16d

Values are expressed as mean ± SD

Different superscript letters are significantly different at P ≤ 0.05

Antioxidant screening

  1. a.
    DPPH free radical scavenging assay was determined (4). Results were presented in Table 3 as IC 50 (μg/ml). Ascorbic acid was used as reference standard antioxidant.
    Table 3

    Showing antioxidant activities of the newly synthesized compounds


    IC50 (μg/ml) for DPPH


    IC50 (μg/ml) for anti-lipid peroxidation

    Compound 3

    10.72 ± 0.54

    16.81 ± 2.71

    Compound 4

    12.64 ± 0.41

    22.53 ± 3.25

    Compound 5

    14.61 ± 0.72

    23.62 ± 2.31

    Compound 6

    15.26 ± 0.44

    22.67 ± 3.51

    Ascorbic acid

    13.71 ± 0.75

    25.72 ± 1.23

  2. b.

    Lipid peroxidation assay (5 and 6) was calculated as IC50 and recorded in Table 3.


The newly synthesized compounds exhibited a remarkable in vivo and in vitro anti-inflammatory activity. These results are in agreement with those obtained by other researchers [39]. They reported that some novel pyrimidine-pyridine hybrids inhibited cyclooxygenase enzyme and had a significant anti-inflammatory activity comparable to celecoxib as a standard drug. In this concern, other authors [40] reported an investigation of the efficacy of pyridine and pyrimidine analog of acetaminophen as peroxyl radical trapping antioxidants and inhibitors of enzyme catalyzed lipid peroxidation by cyclooxygenase and lipoxygenase. Compounds 3 and 4 exhibited antioxidant activity screening higher scavenging activity towards the DPPH radicals than that of ascorbic acid. Similar results were reported for new pyridine and triazolopyridine derivatives [4145].



Melting points were measured using an Electrothermal IA 9100 equipment with open capillary tube and were kept uncorrected. All experiments were done using dry solvents. TLC was performed on Merck Silica Gel 60F254 with detection by way of UV Light. The formed compound has been purified using recrystallization. The IR spectra (KBr disc) were recorded using Pye Unicam Sp-3-300 or a Shimadzu FTIR 8101 PC infrared spectrophotometer. The 1H NMR and 13C NMR spectra were measured by means of JEOL-JNM-LA 400 MHz spectrometer using DMSO-d6 as a solvent. All chemical shifts had been expressed on the δ (ppm) scale using TMS as an internal well-known reference. The coupling constant (J) values are given in Hz. Analytical information was acquired from the Microanalysis center at Cairo University, Giza, Egypt.

(E)-1-(pyridin-3-yl)-3-(thiophen-2-yl) prop-2-en-1-one (3)

To a stirred mixture of thiophene-2-carbaldehyde 1 (100 mmol) and 3-acetylpyridine 2 (100 mmol) in 200 ml ethanol at room temperature, 40% NaOH aqueous solution was added portion-wise while stirring 2 h. The pale yellow precipitate formed was filtered and washed using 4% aqueous HCl, and crystallized from ethanol to give chalcone 3 in 82% yield, mp 256–258 °C. IR (KBr) cm−1: 3336, 3255, 1678, 1645; 1H NMR (300 MHz, DMSO-d6): 6.93–6.96 (t, 1H, H5′-pyridine), 7.47–7.51 (dd, 1H, H3′-pyridine), 7.30–7.327(t, 1H, H4′-pyridine), 7.53 (d, 1H, J = 12.9 Hz, (C=O)(CH=C), 7.92 (d, 1H, J = 12.9 Hz (C=O) (C=CH), δ = 7.28(d, 1H, J = 3.6 Hz, thienyl-C 3 ′H), 7.94 (dd, 1H, thienyl-C 4 ′H), 8.11 (d, 1H, J = 5.2 Hz, thienyl-C 5 ′H).13C NMR (DMSO-d6, 150 MHz): δ = 200.18 (C1=O);153.3 (C4′-pyridine); 149.2 (C2′-pyridine); 147.4 (C3); 135.2 (C4′′); 134.9 (C6′-pyridine); 133.2 (C′′-pyridine); 132.8 (C2′′); 127.1(C2); 126.8 (C5′-pyridine);125.4 (C3′′);123.6(C1′′). Anal. Calcd for C12H9NOS (215.27): C, 66.95; H, 4.21; N, 6.51; S, 14.90; Found C, 66.89; H, 4.19; N, 6.50; S, 14.79%.

4-(pyridin-3-yl)-6-(thiophen-2-yl) pyrimidine-2(1H)-thione (4)

Chalcone 3 (10 mmol) was added to sodium ethoxide solution [prepared from sodium metal (0.23 g, 10 mmol) and 50 ml of absolute ethanol] then thiourea (10 mmol) was added. The reaction mixture was refluxed for 16 h., left to cool and poured into crushed ice and neutralized with diluted hydrochloric acid, filtration, washed with ethanol and dried. Crystallization from EtOH afforded the pyrimidine derivatives 4. Yellow powder, yield 74%, mp 220–225 °C; IR (KBr): 3433 (NH), 1270 (C=S) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 6.93–6.96 (t, 1H, H5′-pyridine), 7.47–7.51 (dd, 1H, H3′-pyridine), 7.30–7.327(t, 1H, H4′-pyridine), 7.28(d, 1H, J = 3.6 Hz, thienyl-C 3 ′H), 7.94 (dd, 1H, thienyl-C 4 ′H), 8.11 (d, 1H, J = 5.2 Hz, thienyl-C 5 ′H), 8.82 (s, D2O-exchangeable, 1H, pyrimidin NH). 13CNMR (DMSO-d6, 100 MHz) δ: 110.2, 123.9, 127.1, 128.2, 130.5, 136.6, 137.2, 151.5, 152.0, 157.164.6, 180.4. Anal. Calcd for C13H9N3S2 (271.36): C, 57.54; H, 3.34; N, 15.48; S, 23.63; Found: C, 57.49; H, 3.32; N, 15.49; S, 23.59%.

1-(4-(pyridin-3-yl)-6-(thiophen-2-yl)pyrimidin-2-yl)hydrazine (5)

The reaction of thiopyrimidinone 4 (10.0 mmol) with hydrazine hydrate (10.0 mmol) catalyzed by acetic acid (5 drops) in refluxing ethanol for 6 h. Evaporation of alcohol and recrystallization with ethanol gave compound 5 as pale brown crystals mp 180–182 °C, yield 85%. IR: νmax/cm−1: 3212 (NH2), 3184 (NH). 1H NMR (DMSO-d6): δ = 6.93–6.96 (t, 1H, H5′-pyridine), 7.47–7.51 (dd, 1H, H3′-pyridine), 7.30–7.327(t, 1H, H4′-pyridine), δ = 7.28(d, 1H, J = 3.6 Hz, thienyl-C 3 ′H), 7.53 (dd, 1H, thienyl-C 4 ′H), 7.89 (d, 1H, J = 5.2 Hz, thienyl-C 5 ′H) 0.7.94 (s, 1H, pyrimidin), 8.93–8.95 (brs, 3H, D2O Exch., NH2, NH). 13C NMR (DMSO-d6, 100 MHz) δ: 98.4, 123.9, 127.1, 128.2, 130.5, 134.1, 137.2, 151.5, 152.0, 148.0, 149.1, 155.8, 157, 161.1. Anal.Calcd. For C13H11N5S (269.32): C, 57.97; H, 4.12; N, 26.00; S, 11.91; Found: C, 57.96; H, 4.09; N, 26.03%.

2-oxo-6-(pyridin-3-yl)-4-(thiophen-2-yl)-2H-pyran-3-carbonitrile (6)

To a stirred solution of chalcone 3 (10 mmol) and ethyl cyanoacetate (10 mmol) in 50 ml absolute ethanol, a sodium ethoxide solution prepared from 0.23 g sodium metal (10 mmol) and 10 ml absolute ethanol was added refluxing the reaction mixture for 8 h. The solid that formed after cooling was collected by filtration, washed with water, dried and finally crystallized from ethanol to afford compound 6 as pale yellow crystals in 72% yield, mp 210–212 °C; IR (KBr): 2222 (C≡N), 1688 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 7.32 (s, 1H, C5), 6.93–6.96 (t, 1H, H5′-pyridine), 7.47–7.51 (dd, 1H, H3′-pyridine), 7.30–7.327(t, 1H, H4′-pyridine), 7.28(d, 1H, J = 3.6 Hz, thienyl-C 3 ′H), 7.94 (dd, 1H, thienyl-C 4 ′H), 8.11 (d, 1H, J = 5.2 Hz, thienyl-C 5 ′H). 13C-NMR (DMSO-d6, 100 MHz) δ: 98.8, 113.3, 115.9, 123.8, 127.1, 128.2, 130.5, 137.7, 136.6, 149.6, 157.4, 173.4. Anal. Calcd for C15H8N2O2S (280.3): C, 64.27; H, 2.88; N, 9.99; S, 11.44; Found: C, 64.25; H, 2.84; N, 9.96; S, 11.42%.

1-amino-6-oxo-4-(thiophen-2-yl)-1,6-dihydro-[2,3′-bipyridine]-5-cabonitrile (7)

To a solution of the pyranone 6 (2 mmol) in 30 ml of ethanol, hydrazine hydrate (2 mmol) was added. The mixture was refluxed for 6 h. Left to cool, the formed solid product was filtered off, dried, and then crystallized from ethanol to give compounds 7. Yellow powder, yield 70%, mp 250–252 °C; IR (KBr): 3320, 3190 (NH2, NH), 2219 (C≡N), 1670 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.51(s, D2O-exchangeable, 2H, NH2), 6.93–6.96 (t, 1H, H5′-pyridine), 7.47–7.51 (dd, 1H, H3′-pyridine), 7.30–7.327(t, 1H, H4′-pyridine), 7.28(d, 1H, J = 3.6 Hz, thienyl-C 3 ′H), 7.94 (dd, 1H, thienyl-C 4 ′H), 8.11 (d, 1H, J = 5.2 Hz, thienyl-C 5 ′H). 13C-NMR (DMSO-d6, 100 MHz) δ: 110.8, 115.9, 121.3, 123.8, 127.1, 128.2, 130.5, 131.6, 136.8, 149.6, 150.0, 160.5, 169.4. Anal. Calcd for C15H10N4OS (294.33): C, 61.21; H, 3.42; N, 19.04; S, 10.89; Found: C, 61.20; H, 3.40; N, 19.09; S, 10.90%.

3,4-dimethyl-1-(4-(pyridin-3-yl)-6-(thiophen-2-yl)pyrimidin-2-yl)pyrano[2,3-c]pyrazol-6(1H)-one (8)

Compound 5 (10 mmol) and ethyl acetoacetate in excess (30 ml) was heated at reflux temperature for 6 h. The mixture was poured into ice cold water and the obtained product washed with water, dried and recrystallized from ethanol to give pale brown crystals of the pyrazolone compound 8 mp 190–192 °C, yield 80% IR: νmax/cm−1 3367 (NH), 1715 (C=O). 1H NMR (DMSO-d6): δ 2.25 (s, 3H, CH3), 2.32 (s, 3H, CH3), 5.60 (s, 1H, pyranone), 6.93–6.96 (t, 1H, H5′-pyridine), 7.47–7.51 (dd, 1H, H3′-pyridine), 7.30–7.327(t, 1H, H4′-pyridine), 7.28(d, 1H, J = 3.6 Hz, thienyl-C 3 ′H), 7.94 (dd, 1H, thienyl-C 4 ′H), 8.11 (d, 1H, J = 5.2 Hz, thienyl-C 5 ′H). 13C-NMR (DMSO-d6, 100 MHz) δ: 11.9, 21.2, 101.5, 105, 118.5, 124.0, 125.5, 127.9, 33.1, 134.1, 141.7, 148.0, 149.1, 152.8, 155.6, 159.0, 160.9, 161.0. Anal. Calcd. For C21H15N5O2S (401.44): C, 62.83; H, 3.77; N, 17.45; S, 7.99; Found: C, 62.79; H, 3.79; N, 17.47; S, 7.95%.

3-methyl-1-(4-(pyridin-3-yl)-6-(thiophen-2-yl) pyrimidin-2-yl)-1H-pyrazol-5(4H)-one (9)

Compound 5 (10 mmol) and ethyl acetoacetate (10 mmol) in acetic acid (30 ml) was heated at reflux temperature for 6 h. The mixture was poured into ice cold water and the obtained product washed with ice cold water, dried and recrystallized from ethanol to afford pale brown crystals of 9 mp 225–227 °C, yield 76% IR: νmax/cm−1: 3216 (NH), 1718 (C=O). 1H NMR (DMSO-d6): δ 1.20 (s, 3H, CH3), 2.25 (s, 2H, CH2, pyrazol), 6.93–6.96 (t, 1H, H5′-pyridine), 7.47–7.51 (dd, 1H, H3′-pyridine), 7.30–7.327(t, 1H, H4′-pyridine), 7.28(d, 1H, J = 3.6 Hz, thienyl-C 3 ′H), 7.94 (dd, 1H, thienyl-C 4 ′H), 8.11 (d, 1H, J = 5.2 Hz, thienyl-C 5 ′H), 8.90 (s, 1H, pyrimidin).13C-NMR (DMSO-d6, 100 MHz) δ: 24.6, 42.4, 99.9, 124.0, 125.5, 127.6, 133.1, 134.1, 140, 148.0, 149.1, 156.1, 160.2, 163.1, 159.5, 172.8. Anal. Calcd. For C17H13N5OS (335.38): C, 60.88; H, 3.91; N, 20.88; S, 9.56; Found: C, 60.90; H, 3.90; N, 20.86; S, 9.55%.

2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-(pyridin-3-yl)-6-(thiophen-2-yl)pyrimidine (10)

A solution of compound 5 (10 mmol) in absolute ethanol and acetylacetone (10 mmol) was heated at reflux temperature for 5 h. the obtained product was recrystallized from ethanol to afford pale brown crystals of pyrazolo pyrimidine derivative 10. mp 190–188 °C, yield 70% IR: νmax/cm−1 3170 (NH), 1600 (C=N), 1574 (C=N). 1H NMR (DMSO-d6): δ 2.3 (s, 3H, CH3), 2.58 (s, 3H, CH3), 6.99 (s, 1H, pyrazole), 6.93–6.96 (t, 1H, H5′-pyridine), 7.47–7.51 (dd, 1H, H3′-pyridine), 7.30–7.327(t, 1H, H4′-pyridine), 7.28(d, 1H, J = 3.6 Hz, thienyl-C 3 ′H), 7.94 (dd, 1H, thienyl-C 4 ′H), 8.11 (d, 1H, J = 5.2 Hz, thienyl-C 5 ′H), 8.94 (s, 1H, pyrimidine).13C-NMR (DMSO-d6, 100 MHz) δ: 11.1, 18, 105, 125.5, 127.6, 133.1, 140, 144.3, 148.0, 149.1, 155.6, 159.0, 161.0. Anal. Calcd. For C18H15N5S (333.41): C, 64.84; H, 4.53; N, 21.01; S, 9.62; Found: C, 64.80; H, 4.52; N, 21.02, S, 9.60%.


We have reported the synthesis of (E)-1-(pyridin-3-yl)-3-(thiophen-2-yl) prop-2-en-1-one 3 and using to designing a polycyclic heterocyclic compounds containing five and/or six rings fused. Moreover, we concluded that compounds 3 and 4 showed a significant antioxidant activity regarding cyclooxygenase inhibitory activity, compound 3 presented the highest inhibitory activity in comparison to the standard reference drug [IC50 as 3.7 and 0.39 µM for COX-1 and COX-2, respectively compared to 5.47 and 0.86 for the standard celecoxib]. Compound 4 also showed a potent inhibitory activity for COX-2 with IC50 0.44. Compounds 5 and 6 showed inhibitory activity against COX-1 and COX-2 nearly like that of the standard drug. Compound 3 showed the highest inhibitory potential for 5-lipoxygenase with IC50 (4.71 µM) compared to (6.15 µM) of the standard anti-inflammatory drug meclofenamate sodium.





nuclear magnetic resonance


infrared radiation


dimethyl sulfoxide








2, 2-diphenyl-1-picrylhydrazil


Authors’ contributions

WSS carried the literature and designed synthetic schemes (synthesis and purification). SMM contributed to study of anti-inflammatory activities both in vitro and in vivo and Antioxidant vitalities against α, α-diphenyl-β-picrylhydrazyl (DPPH) scavenging activity and lipid peroxidation. MHA records the 13CNMR of all compounds. All authors read and approved the final manuscript.


The authors are very thankful to all the associated personnel in any reference that contributed in/for the purpose of this research.

Competing interests

The authors declare that they have no competing interests

Consent for publication

All authors consent to publication.


This research is not funded though any source.

Ethics approval and consent to participate

Not applicable.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
Department of Pharmaceutical Chemistry, Deanship of Scientific Research, Taif University, Taif, Kingdom of Saudi Arabia
Departments of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt


  1. Firoozpour L, Edraki N, Nakhjiri M, Emami S, Safavi M, Ardestani SK, Khoshneviszadeh M, Shfiee A, Foroumadi A (2012) Cytotoxic activity evaluation and QSAR study of chromene—based chalcone. Arch Pharm Res 35:2117–2125View ArticleGoogle Scholar
  2. Baviskar BA, Baviskar B, Shiradkar MR, Deokate UA, Khadabadi SS (2009) Synthesis and antimicrobial activity of some novel. Benzimidazolyl chalcones. Eur J Chem 6:196–200Google Scholar
  3. Munawar MA, Azad M, Siddiqui HL (2008) Synthesis and antimicrobial studies of some quinolinylpyrimidine derivatives. J Chin Soc 55:394–400View ArticleGoogle Scholar
  4. Azad M, Munawar MA, Siddiqui HL (2007) Antimicrobial activity and synthesis of quinoline-base chalcones. J Appl Sci 7:2485–2489View ArticleGoogle Scholar
  5. Kalirajan R, Sivakumar SU, Jubie S, Gowramma B, Suresh B (2009) Synthesis and biological evaluation of some heterocyclic derivatives of chalcones. Int J ChemTech Res 1:27–34Google Scholar
  6. Talia JM, Debattista NB, Pappano NB (2011) New antimicrobial combinations: substituted chalcones-oxacillin against methicillin resistant Staphylococcus aureus. Braz J Microbiol 42:470–475View ArticleGoogle Scholar
  7. Eumkeb G, Siriwong S, Phitaktim S, Rojtinnakorn N, Sakdarat S (2012) Synergistic activity and mode of action of flavonoids isolated from smaller galangal and amoxicillin combinations against amoxicillin-resistant Escherichia coli. J Appl Microbiol 112:55–64View ArticleGoogle Scholar
  8. Do TH, Nguyen DM, Truong VD, Do THT, Le MT, Pham TQ, Thai KM, Tran TD (2016) Synthesis and selective cytotoxic activities on rhabdomyosarcoma and noncancerous cells of some heterocyclic chalcones. Molecules 21(3):329. View ArticleGoogle Scholar
  9. Sato Y, Shibata H, Arakaki N, Higuti T (2004) 6,7-dihydroxyflavone dramatically intensifies the susceptibility of methicillin-resistant or -sensitive Staphylococcus aureus to beta-lactams. Antimicrob Agents Chemother 48:1357–1360View ArticleGoogle Scholar
  10. Babasaheb PB, Sachin AP, Rajesh NG (2010) Synthesis and biological evaluation of nitrogencontaining chalcones as possible anti-inflammatory and antioxidant agents. Bioorg Med Chem Lett 20:730–733View ArticleGoogle Scholar
  11. Vogel S, Barbic M, Jürgenliemk G, Heilmann J (2010) Synthesis, cytotoxicity, anti-oxidative and anti-inflammatory activity of chalcones and influence of A-ring modifications on the pharmacological effect. Eur J Med Chem 45:2206–2213View ArticleGoogle Scholar
  12. Tran T-D, Park H, Kim HP, Ecker GF, Thai K-M (2009) Inhibitory activity of prostaglandin E2 production by the synthetic 21-hydroxychalcone analogues: synthesis and SAR study. Bioorg Med Chem Lett 19:1650–1653View ArticleGoogle Scholar
  13. Kim BT, Kwang-Joong O, Chun JC, Hwang KJ (2008) Synthesis of dihydroxylated chalcone derivatives with diverse substitution patterns and their radical scavenging ability toward DPPH free radicals. Bull Korean Chem Soc 29:1125–1130View ArticleGoogle Scholar
  14. Doan TN, Tran T-D (2011) Synthesis, antioxidant and antimicrobial activities of a novel series of chalcones, pyrazolic chalcones, and allylic chalcones. Pharmacol Pharm 2:282–288View ArticleGoogle Scholar
  15. Sivakumar PM, Prabhakar PK, Doble M (2011) Synthesis, antioxidant evaluation, and quantitative structure–activity relationship studies of chalcones. Med Chem Res 20:482–492View ArticleGoogle Scholar
  16. Vogel S, Ohmayer S, Brunner G, Heilmann J (2008) Natural and non-natural prenylated chalcones: synthesis, cytotoxicity and anti-oxidative activity. Bioorg Med Chem 16:4286–4293View ArticleGoogle Scholar
  17. Echeverria C, Santibañez JF, Donoso-Tauda O, Escobar CA, Ramirez-Tagle R (2009) Structural antitumoral activity relationships of synthetic chalcones. Int J Mol Sci 10:221–231View ArticleGoogle Scholar
  18. Modzelewska A, Pettit C, Achanta G, Davidson NE, Huang P, Khan SR (2006) Anticancer activities of novel chalcone and bis-chalcone derivatives. Bioorg Med Chem 14:3491–3495View ArticleGoogle Scholar
  19. Vogel S, Heilmann J (2008) Synthesis, cytotoxicity, and antioxidative activity of minor prenylated chalcones from Humulus lupulus. J Nat Prod 71:1237–1241View ArticleGoogle Scholar
  20. Kamal A, Kashi Reddy M, Viswanath A (2013) The design and development of imidazothiazole-chalcone derivatives as potential anticancer drugs. Expert Opin Drug Discov 8:289–304View ArticleGoogle Scholar
  21. Do TH, Nguyen DM, Truong VD, Do THT, Le MT, Pham TQ, Thai KM, Tran TD (2016) Synthesis and selective cytotoxic activities on rhabdomyosarcoma and noncancerous cells of some heterocyclic chalcones. Molecule 21:329. View ArticleGoogle Scholar
  22. Neves MP, Lima RT, Choosang K, Pakkong P, de São José Nascimento M, Vasconcelos MH, Pinto M, Silva AM, Cidade H (2012) Synthesis of a natural chalcone and its prenyl analogs—evaluation of tumor cell growth-inhibitory activities, and effects on cell cycle and apoptosis. Chem Biodivers 9:1133–1143View ArticleGoogle Scholar
  23. Forejtníková H, Lunerová K, Kubínová R, Jankovská D, Marek R, Suchý V, Vondrácek J (2005) Chemoprotective and toxic potentials of synthetic and natural chalcones and dihydrochalcones in vitro. Toxicology 208:81–93View ArticleGoogle Scholar
  24. Orlikova B, Tasdemir D, Golais F, Dicato M, Diederich M (2011) Dietary chalcones with chemopreventive and chemotherapeutic potential. Genes Nutr 6:125–147View ArticleGoogle Scholar
  25. Ekhlass N, El-Badry YA, Eltoukhy AMM, Ayyad RR (2016) Synthesis and antiproliferative activity of 1-(4-(1H-Indol-3-Yl)-6-(4-Methoxyphenyl)Pyrimidin-2-yl)hydrazine and its pyrazolo pyrimidine derivatives. Medicinal chemistry. Med chem 6:4. Google Scholar
  26. Murakami N, Takase H, Saito T, Iwata K, Miura H, Naruse T (1998) Effects of a novel non-steroidal anti-inflammatordrug (M-5011) on bone metabolism in rats with collageninduced arthritis. Eur J Pharmacol 352(1):81–90View ArticleGoogle Scholar
  27. Kulandasamy R, Adhikari AV, Stables JP (2009) A new class of anticonvulsants possessing 6Hz activity: 3,4-dialkyloxy thiophene bishydrazones. Eur J Med Chem 44(11):4376–4384View ArticleGoogle Scholar
  28. Lu X, Wan B, Franzblau SG, You Q (2011) Design, synthesis and anti-tubercular evaluation of new 2-acylated and 2-alkylated amino-5-(4-(benzyloxy) phenyl)thiophene-3-carboxylic acid derivatives. Part 1. Eur J Med Chem 46(9):3551–3563View ArticleGoogle Scholar
  29. Kaushik NK, Kim HS, Chae YJ et al (2012) Synthesis and anticancer activity of di(3-thienyl)methanol and di(3-thienyl)methane. Molecules 17(10):11456–11468View ArticleGoogle Scholar
  30. Shehab WS, Saad HA, Mouneir SM (2017) Synthesis and antitumor/antiviral evaluation of 6-thienyl-5-cyano-2-thiouracil derivatives and their thiogalactosides analogs. Curr Org Synth 14:291–298View ArticleGoogle Scholar
  31. Shehab WS, Mouneir SM (2015) Design, synthesis, antimicrobial activity and anticancer screening of some new1,3-thiazolidin-4-ones derivatives. Eur J Chem 6:157View ArticleGoogle Scholar
  32. Shehab WS (2009) Synthesis of tetrahydropyrimidine derivatives and its glycosides. Curr Org Chem 13:14View ArticleGoogle Scholar
  33. Corral C, Lissavetzky J, Manzanares I et al (1999) Synthesis and preliminary pharmacological evaluation of thiophene analogues of viloxazine as potentialantidepressant drugs. Bioorg Med Chem 7(1):349–1359Google Scholar
  34. Abdel-Wahab BF, Abdel-Aziz HA, Ahmed EM (2009) Synthesis and antimicrobial evaluation of 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones and 3-(benzofuran-2-yl)-4, 5-dihydro-5-aryl-1-[4-(aryl)-1, 3-thiazol-2-yl]-1H-pyrazoles. Eur J Med Chem 44:2632–2635View ArticleGoogle Scholar
  35. Kulmacz RJ, Lands WEM (1983) Requirements for hydroperoxide by the cyclooxygenase and peroxidase activities of prostaglandin H synthase. Prostaglandins 25:531–540View ArticleGoogle Scholar
  36. Jacob J, Prakash Kumar B (2015) Dual COX/LOX inhibition: screening and evaluation of effect of medicinal plants of Kerala as Antiinflammatory agents Pharmacogn. Phytochemistry 3:62–66Google Scholar
  37. Kuroda T, Suzuki F, Tamura T, Ohmori K, Hosoe H (1992) A novel synthesis and potent antiinflammatory activity of 4-hydroxy-2(1H)-oxo-1-phenyl-1,8-naphthyridine-3-carboxamides. J Med Chem 36:1130–1136View ArticleGoogle Scholar
  38. Simone RD, Chini MG, Bruno I, Riccio R (2011) Benzimidazole-1,2,3-triazole hybrid molecules: synthesis and evaluation for antibacterial/antifungal activity. J Med Chem 54:1565–1575View ArticleGoogle Scholar
  39. Khalil NA, Ahmed EM, Mohamed KO, Nissan YM (2014) Synthesis and biological evaluation of new pyrazolone–pyridazine conjugates as anti-inflammatory and analgesic agents. Bioorg Med Chem 22:2080–2089View ArticleGoogle Scholar
  40. Lokwani D, Azad R, Sarkate A, Reddanna P, Shinde D (2015) Structure based library design (SBLD) for new 1, 4-dihydropyrimidine scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors. Bioorg Med Chem 23:4533–4543View ArticleGoogle Scholar
  41. Abdelgawad MA, Bakr RB, Azouz AA (2018) Novel pyrimidine-pyridine hybrids: synthesis, cyclooxygenase inhibition, anti-inflammatory activity and ulcerogenic liability. Bioorg Chem 77:339–348View ArticleGoogle Scholar
  42. Nam TG, Nara SJ, Zagol-Ikapitte I, Cooper T, Valgimigli L, Oates JA, Porter NA, Boutaud O, Pratt DA (2009) Pyridine and pyrimidine analogs of acetaminophen as inhibitors of lipid peroxidation and cyclooxygenase and lipoxygenase catalysis. Org Biomol Chem 7(24):5103–5112View ArticleGoogle Scholar
  43. Kotb ER, Soliman HA, Morsy EMH, Abdelwahed NAM (2017) New pyridine and triazolopyridine derivatives: synthesis, antimicrobialand antioxidant evaluation. Acta Pol Pharm 74(3):861–872Google Scholar
  44. Mojarrab M, Soltani R, Aliabadi A (2013) Pyridine based chalcones: synthesis and evaluation of antioxidant activity of 1-phenyl-3-(pyridin-2-yl)prop-2-en-1-one derivatives. Jundishapur J Nat Pharm Prod 8(3):125–130View ArticleGoogle Scholar
  45. Rani J, Saini M, Kumar S, Verma PK (2017) Design, synthesis and biological potentials of novel tetrahydroimidazo[1,2-a]pyrimidinederivatives. Chem Cent J 11:16View ArticleGoogle Scholar


© The Author(s) 2018