Abstract
New hybrid compounds containing flavanone and pyrazoline motifs were synthesized by microwave irradiation and conventional heating methods using one-pot synthetic strategy. The products were evaluated for their antimicrobial activity.
Introduction
Pyrazole, is a structural component of several natural products and drugs [1], [2], [3]. Pyrazole derivatives are known to possess antimicrobial [4], antiviral [3], antitumor [5], [6], antihypertensive [7], antidepressant [8], insecticidal [9], antifungal [10], 5α-reductase-inhibitory [11], antiproliferative [12], antiparasitic [13], herbicidal [14], anti-inflammatory [15], [16], antiprotozoal [17], analgesic [16] and androgen receptor modulatory [18] activities. The pyrazole ring is present as the core moiety in a variety of leading drugs including lonazolac [19] and rimonabant [20] (Figure 1). Thiophene derivatives have been known for their therapeutic applications. For example, tienilic acid is a loop diuretic drug [21] (Figure 1). Flavanoids occur naturally as plant pigments in many fruits, vegetables and beverages such as tea, red wine, coffee, and beer [22]. Natural and synthetic flavanones have attracted considerable attention because of their broad spectrum of biological activities [23] including antioxidant, antifungal, antibacterial, antiinflammatory, antiasthmatic, antihypertensive, antiviral, estrogenic and diuretic activities [24], [25], [26], [27], [28], [29]. Flavanoids such as eriodictyol and pinocembrin are associated with reducing risk of certain chronic diseases [30] (Figure 1). Natural flavanones (chromen-4-ones) isolated from flowers of chromolaena odorata such as 4′-hydroxy-5,6,7-trimethoxyflavanone are reported to have antimycobacterial activity [31] (Figure 1). It has been observed that when one bioactive system is coupled with another bioactive pharmacophore, enhanced biological activity is often produced. Present work is an attempt to incorporate two biodynamic moieties in a molecule in order to study their combined effects on antimicrobial activity.
Selected biologically active pyrazole, thiophene and chromen-4-one derivatives.
Flavanones are generally synthesized by cyclization of 2′-hydroxychalcones in acetic acid, ethanol, or other suitable solvent in the presence of an acid catalyst such as sulfuric acid [32], polyphosphoric acid [33] or a base catalyst such as pyridine [34], DBU [35], TEA [36] or a neutral reagent such as DMF-DMA [37], under conventional heating or microwave irradiation. In recent years, microwaves have been extensively applied to different chemical reactions as a useful non-conventional energy source [38], [39], [40].
Here we describe a one-pot synthesis of flavanone derivatives avoiding isolation of intermediate products. The biological importance of pyrazole, thiophene and chromen-4-one derivatives prompted us to synthesize some new substituted 2-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-ones 3a–h from substitued 2-hydroxyacetophenones 1a–h and 1-phenyl-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (2) using microwave irradiation in one step. All synthesized compounds were tested for their in vitro antimicrobial activity.
Results and discussion
Chemistry
The traditional method for the synthesis of flavanones consists of an intramolecular conjugate addition of 2-hydroxychalcones to cyclic carbonyl systems [41]. In this work, 2-hydroxyacetophenone (1a) was allowed to react with 1-phenyl-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (2a) in ethanol in the presence of NaOH as base and the expected corresponding 2′-hydroxychalcone was isolated (not shown). But by maintaining the pH at 10.0, the isomeric cyclic product 2-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-one (3a, flavanone) was obtained (Scheme 1). This pH value is optimal for the synthesis of 3a. The optimized solvent for the conventional synthesis or microwave-assisted synthesis of 3a is ethanol. The structure of 3a is fully consistent with analysis of its IR, 1H NMR, 13C NMR and mass spectra and agrees well with the literature data of similar compounds [42].
In a similar manner, the reaction of compound 2 with substituted 2-hydroxyacetophenones 1b–h gave the corresponding flavanones 3b–h. The synthesis was carried out both under conventional heating and under MW irradiation. The use of MW irradiation results in a much higher reaction yield along with a significant decrease of the reaction time in comparison with conventional heating. As a general rule, the conventional synthesis of 3a–h in 50–58% yields requires heating for 6–8 h. By contrast, the microwave-assisted synthesis of 3a–h is accomplished in 80–87% yields after 12–15 min.
Antimicrobial activity
All compounds were screened for their antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli using ampicillin as the standard drug for comparison. The activity was determined using cup plate agar diffusion method by measuring the zone of inhibition in mm. The compounds were screened at the concentration of 50 μg mL−1 in DMSO. The results are shown in Table 1. These results are also presented graphically in Figure 2. It can be seen that compounds 3e, 3g and 3h show good antibacterial activity against the tested organisms. It can also be concluded that the activity does not depend much on the electronic nature of the compounds.
Antibacterial activity of compounds 3a–h.
| Compound | Zone of inhibition (mm) | |||
|---|---|---|---|---|
| Gram-positive bacteria | Gram-negative bacteria | |||
| Staphylococcus aureus | Bacillus subtilis | Pseudomonas aeruginosa | Escherichia coli | |
| 3a | 25 | 08 | 09 | 20 |
| 3b | 28 | 11 | 13 | 26 |
| 3c | 25 | 08 | 06 | 24 |
| 3d | 20 | 05 | 04 | 10 |
| 3e | 30 | 10 | 10 | 28 |
| 3f | 07 | 02 | 02 | 08 |
| 3g | 29 | 10 | 07 | 29 |
| 3h | 32 | 15 | 11 | 33 |
| Ampicillin | 30 | 12 | 10 | 30 |
Antibacterial activity of compounds 3a–h.
All compounds were also screened for their antifungal activity against Aspergillus niger, Penicillium italicum and Fusarium oxysporum using griseofulvin as the standard drug for comparison. The activity was determined using the methodology and conditions mentioned above. As can be seen from Table 2 and Figure 3, compounds 3a, 3g and 3h show good antifungal activity against the tested organisms. The unsubstituted compound 3a shows the highest activity against the fungi. The highly electron-rich flavanones 3g and 3h show activity that is comparable to that of the less electron rich compound 3a. Among the halogen derivates, the bromo substituted compound 3c shows significantly higher activity than chloro- and fluoro-substituted compounds 3b and 3c.
Antifungal activity of Compounds 3a–h.
| Compound | Zone of inhibition (mm) | ||
|---|---|---|---|
| Aspergillus nigerzeae | Penicillium italicum | Fusarium oxysporum | |
| 3a | 14 | 20 | 30 |
| 3b | 04 | 07 | 12 |
| 3c | 06 | 10 | 10 |
| 3d | 09 | 16 | 20 |
| 3e | 10 | 16 | 20 |
| 3f | 09 | 21 | 23 |
| 3g | 13 | 21 | 24 |
| 3h | 12 | 21 | 25 |
| Grieseofulvin | 12 | 20 | 25 |
Antifungal activity of compounds 3a–h.
Conclusions
New 2-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-one derivatives 3a–h have been synthesized by conventional and microwave-assisted methods. Compounds 3a, 3e, 3g and 3h show antimicrobial activity against selected microorganisms. They can be considered as lead compounds for further development of antimicrobial agents.
Experimental
IR spectra were recorded in KBr pellets on a Shimadzu FTIR 8400S spectrophotometer. 1H and 13C NMR spectra were recorded on a Bruker Avance II 400 spectrometer (400 and 100 MHz, respectively) in CDCl3 using TMS as internal standard. Mass spectra were recorded on a SHIMADZU LCMS 2020 mass spectrometer. The elemental analysis determinations were carried out on a Vario-11 CHN analyzer. Melting points were determined in open glass capillaries on a Stuart SMP30 apparatus and are uncorrected. Purity of the compounds was checked by TLC on silica gel 60 F254 (Merck). All microwave irradiation experiments were performed in a multiSYNTH series microwave system (Milestone). All solvents and chemicals were obtained commercially and used without further purification. Compound 2 was synthesized as previously reported [43].
Conventional synthesis of 3a–h
A mixture of a substituted 2-hydroxyacetophenone 1a–h (1 mmol), 1-phenyl-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (2, 247 mg, 1 mmol) in ethanol (20 mL) was made alkaline (pH 10.0) with NaOH pellets and heated under reflux for 6–8 h with progress of the reaction monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature and diluted with cold water. The resultant precipitate of 3a–h was filtered, washed with water and crystallized from methanol. Yields were in the range of 50–58%.
Microwave-assisted synthesis of 3a–h
A mixture of a substituted 2-hydroxyacetophenone 1a–h (1 mmol), 1-phenyl-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (2, 247 mg, 1 mmol) in ethanol (5 mL) was placed in a quartz tube, made alkaline (pH 10.0) with NaOH pellets and inserted into Teflon vial that was screw-capped and subjected to microwave irradiation at 180 W for 12–15 min. Workup and purification were conducted as described above. Compounds characterized below were obtained using the microwave-assisted method.
2-(1-Phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-one (3a)
Pale yellow solid; yield 80%; mp 169–171°C; IR: 1682, 1602, 1467 cm−1; 1H NMR: δ 3.11 (dd, 1H, Ha, J=3.01, J=16.18 Hz), 3.24 (dd, 1H, Hb, J=12.04, J=16.18 Hz), 5.73 (dd, 1H, Hx, J=3.01, J=12.04 Hz), 7.09 (m, 3H, Ar-H), 7.33 (m, 2H, Ar-H), 7.50 (m, 4H, Ar-H), 7.73 (d, 2H, Ar-H, J=7.78 Hz), 7.96 (d, 1H, Ar-H, J=7.52 Hz), 8.06 (s, 1H); 13C NMR: δ 42.8, 71.6, 118.2, 118.7, 119.3, 121.0, 121.9, 126.2, 126.3, 126.9, 127.0, 127.1, 127.6, 129.5, 134.4, 136.4, 139.5, 146.3, 161.0, 191.8; ESI-MS: m/z 373, [M+H]+. Anal. Calcd for C22H16N2O2S: C, 70.91; H, 4.29; N, 7.48. Found: C, 70.95; H, 4.33; N, 7.52.
6-Fluoro-2-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-one (3b)
Pale yellow solid; yield 80%; mp 184–186°C; IR: 1683, 1597, 1481 cm−1; 1H NMR: δ 3.08 (dd, 1H, Ha, J=3.01, J=16.81 Hz), 3.22 (dd, 1H, Hb, J=11.54, J=16.81 Hz), 5.72 (dd, 1H, Hx, J=3.01, J=11.54 Hz), 7.07 (m, 2H, Ar-H), 7.34 (m, 3H, Ar-H), 7.47 (m, 3H, Ar-H), 7.60 (m, 1H, Ar-H), 7.73 (d, 2H, Ar-H, J=7.78 Hz), 8.04 (s, 1H); 13C NMR: δ 42.5, 71.9, 112.0, 112.2, 118.4, 119.3, 119.9, 121.5, 123.8, 124.0, 126.2, 126.9, 127.1, 127.6, 129.5, 134.3, 139.4, 146.3, 156.3, 157.2, 158.7, 191.0; ESI-MS: m/z 390, [M+H]+. Anal. Calcd for C22H15FN2O2S: C, 67.64; H, 3.84; N, 7.14. Found: C, 67.68; H, 3.87; N, 7.18.
6-Chloro-2-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-one (3c)
Pale yellow solid; yield 82%; mp 194–196°C; IR: 1683, 1600, 1457 cm−1; 1H NMR: δ 3.11 (dd, 1H, Ha, J=3.26, J=16.81 Hz), 3.22(dd, 1H, Hb, J=11.54, J=16.81 Hz), 5.76 (dd, 1H, Hx, J=3.26, J=11.54 Hz), 7.04 (d, 1H, Ar-H, J=8.78 Hz), 7.12 (t, 1H, Ar-H, J=7.52 Hz), 7.36 (m, 2H, Ar-H), 7.47 (dd, 4H, Ar-H, J=2.25, J=8.28 Hz), 7.74 (d, 2H, Ar-H, J=8.03 Hz), 7.92(d, 1H, Ar-H, J=2.51 Hz), 8.11 (s, 1H); 13C NMR: δ 42.4, 71.9, 118.2, 119.3, 119.9, 121.8, 126.2, 126.3, 126.5, 126.9, 127.1, 127.2, 127.5, 129.54, 134.28, 136.2, 139.4, 146.3, 159.3, 190.6; ESI-MS: m/z 407, [M+H]+. Anal. Calcd for C22H15ClN2O2S: C, 64.90; H, 3.68; N, 6.84. Found: C, 64.94; H, 3.72; N, 6.88.
6-Bromo-2-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-one (3d)
Pale yellow solid; yield 86%; mp 198–200°C; IR: 1681, 1598, 1465 cm−1; 1H NMR: δ 3.12 (dd, 1H, Ha, J=3.51, J=17.06 Hz), 3.23 (dd, 1H, Hb, J=11.29, J=17.06 Hz), 5.75 (dd, 1H, Hx, J=3.51, J=11.29 Hz), 6.98 (d, 1H, Ar-H, J=8.78 Hz), 7.12 (t, 1H, Ar-H, J=7.36 Hz), 7.36 (m, 2H, Ar-H), 7.49 (t, 3H, Ar-H, J=7.14 Hz), 7.61 (dd, 1H, Ar-H, J=2.51, J=8.78 Hz), 7.74 (d, 2H, Ar-H, J=7.52 Hz), 8.03 (s, 1H), 8.07 (d, 1H, Ar-H); 13C NMR: δ 42.4, 71.8, 114.6, 118.2, 119.3, 120.3, 122.3, 126.2, 126.3, 126.9, 127.1, 127.6, 129.5, 129.6, 134.2, 139.0, 139.4, 146.3, 159.7, 190.5; ESI-MS: m/z 451, [M+H]+. Anal. Calcd for C22H15BrN2O2S: C, 58.51; H, 3.31; N, 6.17. Found: C, 58.55; H, 3.35; N, 6.21.
6-Methyl-2-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-one (3e)
Pale yellow solid; yield 87%; mp 174–176°C; IR: 1680, 1620, 1487 cm−1; 1H NMR: δ 2.34 (s, 3H, Me-H), 3.08 (dd, 1H, Ha, J=3.26, J=16.81 Hz), 3.25 (dd, 1H, Hb, J=11.79, J=16.81 Hz), 5.69 (dd, 1H, Hx, J=3.26, J=11.79 Hz), 6.96 (d, 1H, Ar-H, J=8.53 Hz), 7.1 (t, 1H, Ar-H, J=7.25 Hz), 7.3–7.36 (m, 3H, Ar-H), 7.47 (m, 3H, Ar-H), 7.74 (t, 3H, Ar-H, J=7.78 Hz), 8.05 (s, 1H); 13C NMR: δ 20.4, 42.8, 71.6, 117.9, 118.8, 119.3, 120.7, 126.1, 126.3, 126.7, 126.9, 127.0, 127.6, 131.4, 134.4, 137.4, 139.5, 146.4, 159.0, 192.6; ESI-MS: m/z 387, [M+H]+. Anal. Calcd for C23H18N2O2S: C, 71.44; H, 4.65; N, 7.21. Found: C, 71.48; H, 4.69; N, 7.25.
6,8-Dichloro-2-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-one (3f)
Pale yellow solid; yield 86%; mp 175–177°C; IR: 1682, 1604, 1482; 1H NMR: δ 3.15 (dd, 1H, Ha, J=3.08, J=16.84 Hz), 3.25 (dd, 1H, Hb, J=11.56, J=16.84 Hz), 5.82 (dd, 1H, Hx, J=3.08, J =11.54 Hz), 7.02 (d, 1H, Ar-H, J=8.78 Hz), 7.15 (t, 1H, Ar-H, J=7.15 Hz), 7.28–7.37 (m, 2H, Ar-H), 7.49 (dd, 3H, Ar-H, J=2.25, J=8.28 Hz), 7.69 (d, 2H, Ar-H, J=8.03 Hz), 7.94 (d, 1H, Ar-H, J=2.51 Hz), 7.98 (s, 1H); 13C NMR: δ 41.4, 71.7, 118.3, 118.9, 119.9, 121.8, 126.2, 126.3, 126.5, 126.9, 127.1, 127.0, 127.6, 131.4, 134.4, 137.4, 139.4, 146.3, 159.0, 192.7; ESI-MS: m/z 441, [M+H]+. Anal. Calcd for C22H14Cl2N2O2S: C, 16.03; H, 3.16; N, 6.31. Found: C, 59.87; H, 3.20; N, 6.35.
6-Chloro-7-methyl-2-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-one (3g)
Pale yellow solid; yield 80%; mp 161–163°C; IR: 1684, 1598, 1484 cm−1; 1H NMR: δ 2.31 (s, 3H, Me-H), 3.12 (dd, 1H, Ha, J=3.26, J=16.81 Hz), 3.29 (dd, 1H, Hb, J=11.79, J=16.81 Hz), 5.73 (dd, 1H, Hx, J=3.26, J=11.79 Hz), 7.21 (d, 1H, Ar-H, J=8.53 Hz), 7.25 (t, 1H, Ar-H, J=7.42 Hz), 7.34 (m, 3H, Ar-H), 7.47 (m, 2H, Ar-H), 7.73 (t, 3H, Ar-H, J=7.27 Hz), 8.08 (s, 1H); 13C NMR: δ 20.5, 42.8, 71.6, 117.9, 118.8, 119.3, 120.6, 126.1, 126.2, 126.7, 126.9, 127.0, 127.6, 131.4, 134.4, 137.4, 139.5, 146.4, 159.0, 192.7. ESI-MS: m/z 421, [M+H]+. Anal. Calcd for C23H17 ClN2O2S: C, 65.60; H, 4.03; N, 6.62. Found: C, 65.63; H, 4.07; N, 6.66.
6-Methoxy-2-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)chroman-4-one (3h)
Pale yellow solid; yield 85%; mp 181–183°C; IR: 1682, 1600, 1476 cm−1; 1H NMR: δ 3.02 (dd, 1H, Ha, J=17.0, J=12.7 Hz), 3.24 (dd, 1H, Hb, J=17.0, J=3.1 Hz), 3.98 (s, 3H, OCH3), 5.68 (dd, 1H, Hx, J=12.7, J=3.1 Hz), 7.10 (m, 2H, Ar-H), 7.32 (m, 1H, Ar-H), 7.49 (m, 4H, Ar-H), 7.81 (m, 3H, Ar-H), 7.98 (dd, 1H, Ar-H, J=8.2, J=1.7 Hz), 8.15 (s, 1H); 13C NMR: δ 43.5, 55.2, 72.0, 118.2, 119.2, 119.4, 121.2, 121.7, 126.7, 127.0, 128.2, 128.3, 128.5, 128.6, 129.4, 132.9, 140.0, 151.9, 160.3, 161.3, 191.4; ESI-MS: m/z 403, [M+H]+. Anal. Calcd for C23H18N2O3S: C, 68.64; H, 4.51; N, 6.96. Found: C, 68.60; H, 4.49; N, 6.94.
Biological activities
Compounds were screened for their antimicrobial activity against two strains of Gram-positive bacteria (S.aureus and Bacillus subtilis), two strains of Gram-negative bacteria (E. coli and P. aeruginosa) and three strains of fungi (Aspergillus niger, P. italicum and F.oxysporum). Standard antibiotic drugs amoxicillin for bacteria and mycostatin for fungi were used at a concentration of 50 μg/mL for comparison. The biological activities of these compounds were evaluated by the filter paper disc method [44] for 50 μg/mL solutions in DMF. The inhibition zones of microbial growth surrounding the filter paper disc (5 mm) were measured in millimeters at the end of an incubation period of 3 days at 37°C for E. coli and at 28°C for other bacteria and fungi; DMF alone showed no inhibition zone.
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