A series of 4-methyl-5-(3-phenylacryloyl)thiazoles based on chalcones were designed, synthesized and evaluated for their influenza neuraminidase (NA) inhibitory activity in vitro. A preliminary structure–activity relationship (SAR) analysis showed that thiazoles bearing amide had greater potency. It also showed that mono-hydroxyl group at 4-position on phenyl ring was more effective than other electron-releasing groups or electron-withdraw groups. Compounds A2 and A26 were more potent against NA with IC50 values of 8.2±0.5 μg/mL and 6.2±1.4 μg/mL, respectively. Molecular docking study demonstrated that thiazoles skeleton was benefit for the NA inhibitory activity.
Research Article
Design, synthesis and Neuraminidase inhibitory activity of 4-methyl-5-(3-phenylacryloyl) thiazoles
https://doi.org/10.21203/rs.3.rs-2369060/v1
This work is licensed under a CC BY 4.0 License
Journal Publication
published 23 Mar, 2023
You are reading this latest preprint version
4-Methyl-5-(3-phenylacryloyl)thiazoles
Neuraminidase (NA) inhibitory activity
Molecular docking
Flu, caused by influenza viruses, is one of “Ten threats to global health in 2019”. According to report, influenza results in 290 000 to 650 000 deaths every year (WHO 2019). Influenza viruses are negative-strand RNA viruses belonging to Orthomyxoviridae family. On the basis of antigenic differences among nucleoproteins and matrix proteins, influenza can be divided in to three types — A, B and C [1]. Influenza A was found to be more prevalent [2]. And it can be subdivided in the line with the characterizations of haemagglutinin (HA) and neuraminidase (NA), which play important roles in influenza virus propagation [3].
Neuraminidase (NA), which promotes the release of newly formed virions from host cell, has been regarded as the primary therapeutic target against influenza since resistance was found in ion channel blockers [4]. NA inhibitors such as zanamivir and oseltamivir, are well tolerant and effective against most influenza viruses. However, highly oseltamivir-resistant strains carrying the H274Y(H1N1) or R292K(H5N1) mutation have emerged [5, 6], besides, it was reported that H7N9 was resistant to zanamivir [7]. Therefore, it becomes urgent to develop new kinds of NA inhibitors.
Chalcones have been demonstrated that they had broad biological activities like anti-cancer [8], antibacterial [9], anti-tuberculosis [10] etc. Chalcones extracted from natural products have been proved to have anti-influenza activity [11, 12, 13]. Compound 1 abstracted from Cleistocalyx operculatus exhibited potent anti-influenza activity with IC50 values of 2.56 µg/mL [14] The polyphenol 2, isolated from Glycyrrhiza uralensis— a traditional medicinal herb, showed NA inhibitory capacity with IC50 of 2.30 µg/mL [15]. Recently, the synthetic chalcones have been reported to study the structure-activity relationship (SAR) against influenza viruses [16, 17, 18]. Compound 3 showed good inhibitory activity against influenza viruses, which are substituted at 4- position. It also revealed that the α,β-unsaturated carbonyl group was important to devote the NA inhibitory activity. Thiazoles have been stated with diverse activities including NA inhibition [19, 20, 21, 22]. Nitazoxanide, with broad-spectrum antiparasitic, had been proved to inhibit H1N1 influenza virus with EC50 value of 3.25 µM [23]. Compounds with thiazoles were also reported to inhibit B influenza virus (Compound 4 [22]). In our previous work, series of thiazoles were synthesized as NA inhibitor and displayed good inhibition [24, 25]. Herein, to further study and optimize, the α,β-unsaturated carbonyl group were kept; comparing to the reported compounds, phenyl at 3-position of α,β-unsaturated carbonyl is also important to anti-influenza activity, so that phenyl was kept as well. Thiazoles were introduced aiming to improve the activity against influenza viruses.(Fig. 1). 29 compounds were synthesized, and biological activity against influenza A (H1N1) was tested in vitro.
Chemistry
The total synthesis of designed compounds was shown in Scheme 1. With pentane-2,4-dione as the starting material, 3-bromopentane-2,4-dione (Int 1) was obtained through bromination with NBS. Int 2 was generated from intermediate 1 via cyclization with Thiourea or methanethioamide. Condensation of Int 2 and p-hydroxybenzaldehyde provided A1. Acylation of Int 2 in the presence of corresponding acid and CDI in DMF for 8 h, then, reacting with commercial aromatic aldehydes, A2 ~ A26 were given by Aldol condensation in the presence of HCl(g) at room temperature. Compound B was synthesized in the same method described before with 1-(3-aminophenyl)ethan-1-one as starting material.
In vitro H1N1 viral neuraminidase inhibitory activities
All compounds were evaluated for their H1N1 viral neuraminidase by using MUNANA [2'-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acid] assay. For comparison, the reported compound 3 was also tested for the NA inhibition. The results were shown in Table 2.
Table 2 In vitro NA inhibition activities of compounds A1-A29, B and C
| Comp. | R1 | R2 | Inhibition rate/% (40µg/mL) | IC50 (µg/mL) |
|---|---|---|---|---|
| A1 | 4-OH | H | 62.59 ± 2.12 | 24.3 ± 5.3 |
| A2 | 4-OH | CH3CONH | 92.32 ± 0.10 | 8.2 ± 0.5 |
| A3 | 4-OCH3 | CH3CONH | 65.60 ± 2.58 | 25.6 ± 0.9 |
| A4 | 4-N(CH3)2 | CH3CONH | 76.52 ± 1.87 | 16.5 ± 1.1 |
| A5 | 4-NO2 | CH3CONH | 61.33 ± 4.75 | 27.3 ± 3.3 |
| A6 | 4-COOCH3 | CH3CONH | 51.00 ± 7.99 | 42.2 ± 16.1 |
| A7 | 3-OH | CH3CONH | 33.37 | naa |
| A8 | 3,4-(OH)2 | CH3CONH | 82.80 ± 1.85 | 12.9 ± 1.7 |
| A9 | 4-OH-3-OCH3 | CH3CONH | 70.16 ± 3.25 | 23.0 ± 1.1 |
| A10 | 3-OH-4-OCH3 | CH3CONH | 76.63 ± 2.91 | 20.1 ± 1.4 |
| A11 | 4-OH-3,5-(OCH3)2 | CH3CONH | 84.14 ± 1.79 | 14.6 ± 1.4 |
| A12 | 4-OH | NHCHO | 92.78 ± 0.25 | 14.0 ± 1.1 |
| A13 | 4-OH | CH3CH2CONH | 89.52 ± 3.42 | 8.7 ± 0.7 |
| A14 | 4-OH | CH3(CH2)2CONH | 91.06 ± 1.22 | 16.4 ± 0.3 |
| A15 | 4-OH | Cl (CH2)2CONH | 74.12 ± 4.16 | 20.7 ± 1.7 |
| A16 | 4-OH | 2-C4H3OCONH | 91.83 ± 1.41 | 11.9 ± 1.7 |
| A17 | 4-OH | 3-C5H4NCONH | 83.59 ± 0.8 | 12.4 ± 0.4 |
| A18 | 4-OH | C6H5CONH | 82.72 ± 0.85 | 16.3 ± 0.2 |
| A19 | 4-OH | 4-OHC6H4CONH | 82.92 ± 2.11 | 12.6 ± 0.4 |
| A20 | 4-OH | 4-OCH3C6H4CONH | 87.73 ± 0.31 | 15.3 ± 0.5 |
| A21 | 4-OH | 4-FC6H4CONH | 85.88 ± 2.09 | 10.0 ± 0.2 |
| A22 | 4-OH | 4-CNC6H4CONH | 86.75 ± 0.76 | 9.7 ± 1.1 |
| A23 | 4-OH | 4-CF3C6H4CO | 85.33 ± 0.23 | 12.9 ± 0.7 |
| A24 | 4-OH | 4-NO2C6H4CONH | 88.12 ± 1.36 | 8.9 ± 1.0 |
| A25 | 4-OH | 3-NO2C6H4CONH | 78.54 ± 2.12 | 16.7 ± 1.5 |
| A26 | 4-OH | 3-CH3-4-NO2C6H3CONH | 94.39 ± 1.15 | 6.2 ± 1.4 |
| A27 | 4-OH | NH | 79.25 ± 2.82 | 14.0 ± 1.1 |
| A28 | 4-NH2 | CH3CONH | 64.57 ± 1.66 | 24.3 ± 1.1 |
| A29 | 4-COOH | CH3CONH | 45.74 | na |
| B | - | - | 72.53 ± 1.60 | 19.1 ± 1.4 |
| Cb | - | 0.39 | ||
| Cc | - | - | 11.89% | na |
a less than 50% at 40 µg/mL
b IC50 in literature (Kinger M et al. 2012)
c activity in this test experiment
As shown in Table 2, most of compounds displayed good inhibition rate which are more than 50% at 40 µg/mL, except A7 and A29 with inhibition lower than 50%. Unfortunately, compound 3 showed no NA inhibitory activity in our repeated test although it is active according to literature. Comparing compound B (19.1 ± 1.4 µg/mL) and A2(8.2 ± 0.5 µg/mL), the result revealed that replacing phenyl ring with thiazoles improved the activity.
Further biological activity was evaluated and IC50 values were calculated. When R2 was substituted by CH3CONH, A2 was more active than the rest of derivatives with IC50 values of 8.2 ± 0.5 µg/mL. Replacement of 4-OH(A2) with 3-OH(A3) led to substantially reduced activity. Relative to A2, replacing of 4-OH with electron-withdrawing groups like -NO2, -COOCH3 and –COOH (A5, A6 and A29 respectively) caused a 1.5–2 fold drop in NA inhibitory activity. Electron-donating groups substituted (A3, A4, A28) at 4-position of A ring also resulted in decreased the activity. The insertion of an additional electron-releasing group at the 3 and (or) 5-position lowered the NA inhibition too. As described in Table 2, the effect on NA inhibitory activities of R1 on A ring is as follows : 4-OH > 4-OH-3,5-(OCH3)2 > 3,4-(OH)2 > 4-N(CH3)2 > 3-OH-4-OCH3 > 4-OH-3-OCH3 > 4-NH2 > 4-OCH3 > 4-NO2 > 4-COOCH3 > 4-COOH > 3-OH.
When A ring was substituted by 4-OH, acylation of NH2 at 2-position of thiazoles had varying effects on NA inhibition. When R2 were alkyl groups, extending the carbon chain resulted in slightly reduced on the activity relative to the activity of A2. But the chloropropionylation homologue A15 (20.7 ± 1.7 µg/mL) was less active than its propionylation counterpart A14 (16.4 ± 0.3 µg/mL) against NA. when R2 were aryl groups, the introduction of furanyl, to furnish A16(11.9 ± 1.7 µg/mL), is more potent than A17(12.4 ± 0.4 µg/mL) and A18(16.3 ± 0.2 µg/mL). Substituents on benzene ring of thiazole system had different influences on activities. The introduction of groups at 4-position had slightly effect, however, 3-NO2 substituted on phenyl ring (A25, 16.7 ± 1.5 µg/mL) led to substantial loss in activity relative to A24 (8.9 ± 1.0 µg/mL) with 4-NO2 substituent. Comparison with A24, adding an extra methyl at 3-position to yield A26 (6.2 ± 1.4 µg/mL) resulted in 1.4-flod increased NA inhibitory activity. These results demonstrated that the introduction of aromatic rings like furan or pyridine can improve the NA inhibitory activity.
Docking Study
Molecular docking simulation using LeDock (http://www.lephar.com/) was performed on compound A26 to investigate the binding mode in the active site of NA (PDB code: 3B7E), the docking result was shown in Fig. 2. The binding energy was − 7.01 kcal/mol. As depicted in Fig. 2, there were seven hydrogen bonds between A26 and amino acid residues of NA. 4-NO2 of benzene ring formed a hydrogen bond with Arg 371, which was one of the reasons that 4-NO2 is a key group to enhance the activity of A24 compared to A18. In addition, The carbonyl oxygen on the amide bond forms three hydrogen bonds with Asn-347, Arg-371 and Arg-292, which proved that A2 is more potent than A1 and A27. The interaction of N on the thiazole ring with Asn-347, explained, to some extent, the subtle advantages of the difference between the thiazole ring and the benzene ring. The hydrogen bond of oxygen on the propylene ketone carbonyl with Ser-246 further indicated that the propylene ketone structure is an important active fragment. 4-OH on the phenyl ring forms a hydrogen bond with Glu-277, which made 4-OH the most preferred substituent on the phenyl ring. Besides, there are some other interactions, like cation-π interaction between Arg-371 and nitrobenzene. In general, The MD simulation results demonstrated the importance of the 4-OH on A ring and the 4-NO2 on benzene ring of B ring for the interactions of the ligands with the NA site. Furthermore, the results confirmed that the modification of chalcones in our study is a kind of success.
In conclusion, a series of 4-Methyl-5-(3-phenylacryloyl) thiazoles were synthesized and tested for their NA inhibition. Compound A26 showed the most potent NA inhibitory activity with IC50 value of 6.2 ± 1.4 µg/mL. SAR analysis indicated that substituted at 4-position of A ring is essential for NA inhibition, 4-OH appeared to be the best group. The introduction of aromatic rings at 2-position of thiazole also benefits the activity. Docking study revealed that thiazole ring is better than benzene ring because of the interaction between N atom of thiazole ring and the amino acid residue Asn-347 of NA. The docking results also suggested that the amide group of thiazoles was beneficial in terms of NA inhibitory activity. Combined results from MUNANA assay and molecular docking analysis therefore indicated that compounds A2 and A26 can be used as a new template to develop new NA inhibitors.
Chemistry
Solvents and reagents were purchased from commercial vendors and were used without any further purification. 1H and 13C NMR spectra were recorded in DMSO-d6 with TMS as internal standard using VARIAN INOVA-400 at ambient temperature. Melting points were measured on an X-4 electrothermal digital melting point apparatus and uncorrected. The chemical reactions were monitored by TLC and visualized under UV light at 254 nm. Mass spectra data was obtained from an LCQ Advantage MAX spectrometer ESI-MS and an Agilent 1100 series LC-MS.
General Procedure For The Synthesis Of Int 1
A solution of pentane-2,4-dione (50 mmol) in 40 mL acetone was added NBS (50 mmol), the mixture was stirred at 0°C for 3 h. 50 mL water was poured into the solution, diluted with CH2Cl2 (3 ⋅ 90 mL), the organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford Int 1 without further purification.
General Procedure For The Synthesis Of Int 2
Thiourea (10 mmol) or methanethioamide (10 mmol), and catalytic triethylamine were dissolved in 10 mL ethanol. The obtained Int 1 was added dropwise to the solution, refluxed for 8 h, cooled to room temperature. the mixture was poured into water, diluted with EtOAc, the organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford Int 2.
General Procedure For The Synthesis Of A1
A stirred solution of compound 3 (1 mmol) and p-hydroxybenzaldehyde (1 mmol) in 6 mL ethanol was passed HCl(g) to a saturated, reacted for 6 h at ambient temperature. The formed precipitate was filtered and recrystallized from ethanol to furnish A1.
General procedure for the synthesis of A2 ~ A26 and B
N,N'-carbonyldiimidazole (CDI) (6 mmol) was added in portions to the solution of corresponding acid (6 mmol) and 10 mL DMF, stirred at room temperature for 30 min. Intermediate 2 (4 mmol) or 3-aminoacetophenone (4 mmol) was added and reacted at 85 oC for 8 h. After cooling to room temperature, the mixture was poured into 30 mL ice water, the precipitate was filtered and washed with statured NaHCO3, cooled water, recrystallized from ethyl acetate / tetrahydrofuran to furnish 4-methyl-5-acyl-2-acetamidothiazoles and 3-acetamidoacetophenone.
To a solution of 4-methyl-5-acyl-2-acetamidothiazole (1 mmol) or 3-acetamidoacetophenone (1 mmol) and the corresponding aldehyde (1 mmol) in 6 mL ethanol, dried HCl(g) was passed to a saturated, reacted at room temperature for 6 h. the formed precipitate was filtered and recrystallized from ethanol to furnish corresponding product A2 ~ A26 and B.
General Procedure For The Synthesis Of A27
HCl(g) was passed to a mixture of A2(1 mmol) and 10 mL MeOH/H2O (Vmethanol : Vwater = 1 : 1), then stirred at 50 oC for 3 h. Statured NaHCO3 was added slowly to the solution until no gas produced. The precipitate was filtered and recrystallized from methanol to afford A27.
General Procedure For The Synthesis Of A28
A5(1 mmol) and SnCl2⋅2H2O (10 mmol) were dissolved in 10 ethanol, the mixture was refluxed for 5 h. After cooling to ambient temperature, the reaction mixture was poured into water. NaOH(aq.) was added to the solution to adjust pH to 12. The formed precipitate was filtered and washed with dilute NaOH solution, brine, then recrystallized from ethanol to furnish A28.
General Procedure For The Synthesis Of A29
To a mixture of A6 and 10 mL MeOH/H2O (Vmethanol : Vwater = 1 : 1), LiOH⋅H2O(2 mmol) was added, the mixture was stirred at 65 oC for 2 h. The reaction mixture was poured into water, dilute HCl(aq.) was added to adjust pH to 2 ~ 3. he formed precipitate was filtered and washed with brine, recrystallized from ethanol to furnish A29.
Na Inhibition Assay
The in vitro NA inhibitory activity was evaluated by FL assay according to Woods et al [26], the substrate of the FL assay, MUNANA was purchased from Sigma. NA of Influenza virus A/PR/8/34 was obtained from Chinese Centers for Disease Control.
A mixture of 10 µL test compounds and 30 µL NA was added into 96 well plate, the blank, enzyme and positive control Zanamivir were also set. After 15 minutes, the reaction was initiated by the addition of 10 µL of 33 mmol/L MES buffer(pH = 6.5), 10 µL of 4 mmol/L CaCl2, 10 µL of 20 µmol/L MUNANA and 30 µL water. The mixture was incubated for 60 minutes at 37 oC. The reaction was terminated by the addition of 150 µL 1 of 14 mmol/L NaOH in 83% ethanol. 4-Methylumbelliferone, cleavage of MUNANA by NA, was quantified by fluorometric determination at excitation wavelength of 365 nm. The emission wavelength was 450 nm. The IC50 was defined as the compound concentration required to inhibit NA by 50%, The inhibition rate was calculated as follow:
$$\text{i}\text{n}\text{h}\text{i}\text{b}\text{i}\text{t}\text{i}\text{o}\text{n} \text{r}\text{a}\text{t}\text{e}\left(\text{\%}\right)= \frac{\left(enzyme value-blank\right)-\left(experimental value-blank\right)}{enzyme value-blank}100\%$$
Docking Study
The NA structure was downloaded from PDB data bank (PDB code: 3B7E, http://www.rcsb.org/). The ligand compound A26 was minimized using MM2 force filed. The pdbqt files were prepared by Ledock (http://www.lephar.com/), the parameter was set as default. The binding box was set as follow: (Xmin = -37.4, Xmax = -19.8, Ymin = 7.0, Ymax = 21.5, Zmin =12.0, Zmax = 30.2). Then result was visualized and analyzed using PyMOL.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl] thiazole(A1) Dark green solid. Yield 67.7%; m.p.215 ~ 217℃.1H NMR(400 MHz, DMSO-d6)δ: 2.74(s, 3H, CH3), 6.86(d, J = 7.8 Hz, 2H, C6H4), 7.24(d, J = 15.4 Hz, 1H, CH), 7.62 ~ 7.72(m, 3H, C6H4 + CH), 9.23(s, 1H, thiazole-H), 10.28(s, 1H, OH). 13C NMR(101 MHz, DMSO-d6) δ༚18.51, 116.43, 121.57, 125.60, 131.60, 132.13, 145.08, 156.92, 158.33, 161.02, 182.99. ESI-MS: m/z 244 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-acetylaminothiazole (A2) Yellow solid. Yield 75.2%; m.p.251 ~ 253℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.19(s, 3H, CH3CO), 2.64(s, 3H, CH3), 6.84(d, J = 8.2 Hz, 2H, C6H4), 7.19(d, J = 15.3 Hz, 1H, CH), 7.60(d, J = 15.3 Hz, 1H, CH), 7.66(d, J = 8.2 Hz, 2H, C6H4), 10.10(s, 1H, OH), 12.48(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.80, 23.08, 116.42, 121.44, 125.65, 125.74, 131.26, 143.75, 155.11, 159.69, 160.80, 169.71, 182.64. ESI-MS: m/z 301 [M-H]−.
4-methyl-5-[3-(4-methoxyphenyl) acryloyl]-2-acetylaminothiazole (A3) Yellow solid. Yield 53.1%; m.p.223 ~ 225℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.20(s, 3H, CH3CO), 2.64(s, 3H, CH3), 3.83(s, 3H, CH3O), 7.01(d, J = 7.9 Hz, 2H, C6H4), 7.25(d, J = 15.4 Hz, 1H, CH), 7.63(d, J = 15.4 Hz, 1H, CH), 7.77(d, J = 7.9 Hz, 2H, C6H4), 12.51(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.81, 23.07, 55.86, 114.94, 122.64, 125.59, 127.41, 131.06, 143.15, 155.33, 159.83, 161.84, 169.69, 182.66. ESI-MS: m/z 315 [M-H]−.
4-methyl-5-[3-(4-dimethylaminophenyl) acryloyl]-2-acetylaminothiazole (A4) Orange sloid. Yield 56.4%; m.p.204 ~ 206℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.18(s, 3H, CH3CO), 2.63(s, 3H, thiazole-CH3), 3.01(s, 6H, 2×CH3), 6.74(d, J = 8.2 Hz, 2H, C6H4), 7.11(d, J = 15.1 Hz, 1H, CH), 7.57 ~ 7.65(m, 3H, C6H4 + CH). 13C NMR(101 MHz, DMSO-d6)δ༚18.79, 23.07, 41.67, 114.92, 121.13, 121.21, 125.75, 130.94, 143.54, 150.50, 154.95, 159.61, 169.68, 182.47. ESI-MS: m/z 328 [M-H]−.
4-methyl-5-[3-(4-nitrophenyl) acryloyl]-2-acetylaminothiazole (A5) Yellow solid. Yield 71.5%; m.p.255 ~ 257℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.20(s, 3H, CH3CO), 2.65(s, 3H, CH3), 7.54(d, J = 15.5 Hz, 1H, CH), 7.70(d, J = 15.5 Hz, 1H, CH), 8.06(d, J = 7.8 Hz, 2H, C6H4), 8.24(d, J = 7.8 Hz, 2H, C6H4), 12.54(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.95, 23.06, 124.38, 125.17, 128.98, 130.15, 140.22, 141.26, 148.43, 156.74, 160.48, 169.78, 182.22. ESI-MS: m/z 330 [M-H]−.
4-methyl-5-[3-(4-methoxycarbonylphenyl) acryloyl]-2-acetylaminothiazole (A6) Yellow solid. Yield 75.9%; m.p.222 ~ 224℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.20(s, 3H, CH3CO), 2.65(s, 3H, CH3), 3.88(s, 3H, CH3O), 7.47(d, J = 15.5 Hz, 1H, CH), 7.66(d, J = 15.5 Hz, 1H, CH), 7.92(d, J = 7.8 Hz, 2H, C6H4), 7.98(d, J = 7.8 Hz, 2H, C6H4), 12.54(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.92, 23.06, 52.74, 125.22, 127.43, 129.27, 130.07, 131.19, 139.27, 141.42, 156.42, 160.30, 166.17, 169.73, 182.35. ESI-MS: m/z 343 [M-H]−.
4-methyl-5-[3-(3-hydroxyphenyl) acryloyl]-2-acetylaminothiazole (A7) Green solid. Yield 47.2%; m.p.216 ~ 218℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.11(s, 3H, CH3CO), 2.61(s, 3H, CH3), 6.86 ~ 6.89,7.17 ~ 7.31(m, 5H, C6H4 + CH), 7.51(d, J = 15.4 Hz, 1H, CH). 13C NMR(101 MHz, DMSO-d6)δ༚19.23, 24.99, 114.64, 118.11, 120.11, 123.08, 125.84, 130.49, 136.33, 141.74, 157.23, 158.37, 165.71, 173.44, 181.63. ESI-MS: m/z 301 [M-H]−.
4-methyl-5-[3-(3,4-dihydroxyphenyl) acryloyl]-2-acetylaminothiazole (A8) Yellow solid. Yield 65.1%; m.p.270 ~ 272℃. 1H NMR(400 MHz, DMSO-d6)δ: 1H NMR(400 MHz, DMSO-d6)δ༚2.19(s, 3H, CH3CO), 2.63(s, 3H, CH3), 6.83 ~ 7.21(m, 4H, C6H3 + CH), 7.51(d, J = 15.3 Hz, 1H, CH), 12.53(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.78, 23.08, 115.20, 116.43, 121.29, 122.81, 125.58, 126.21, 144.06, 146.18, 149.38, 155.10, 159.57, 169.72, 182.42. ESI-MS: m/z 317 [M-H]−.
4-methyl-5-[3-(4-hydroxy-3-methoxyphenyl) acryloyl]-2-acetylaminothiazole (A9) Green solid. Yield 47.2%; m.p.264 ~ 266℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.19(s, 3H, CH3CO), 2.63(s, 3H, CH3), 3.83(s, 3H, CH3O), 6.98 ~ 7.00,7.19 ~ 7.26(m, 3H, C6H3), 7.14(d, J = 15.3 Hz, 1H, CH), 7.55(d, J = 15.3 Hz, 1H, CH), 12.53(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.80, 23.08, 56.26, 112.54, 116.20, 121.85, 123.94, 125.55, 126.31, 144.19, 148.41, 150.23, 155.16, 159.68, 169.68, 182.77. ESI-MS: m/z 331 [M-H]−.
4-methyl-5-[3-(3-hydroxy-4-methoxyphenyl) acryloyl]-2-acetylaminothiazole (A10) Yellow solid. Yield 57.6%; m.p.271 ~ 273℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.19(s, 3H, CH3CO), 2.64(s, 3H, CH3), 3.83(s, 3H, CH3O), 6.98 ~ 7.00, 7.19 ~ 7.25(m, 3H, C6H3), 7.14(d, J = 15.3 Hz, 1H, CH), 7.55(d, J = 15.3 Hz, 1H, CH), 12.52(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.80, 23.08, 56.12, 112.50, 114.47, 122.38, 122.69, 125.52, 127.61, 143.61, 147.28, 150.90, 155.36, 159.72, 169.74, 182.48. ESI-MS: m/z 331 [M-H]−.
4-methyl-5-[3-(4-hydroxy-3,5-dimethoxyphenyl) acryloyl]-2-acetylaminothiazole (A11) Green solid. Yield 52.2%; m.p.264 ~ 266℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.20(s, 3H, CH3CO), 2.64(s, 3H, CH3), 3.85(s, 6H, 2×CH3O), 7.09 ~ 7.13(m, 2H, C6H2), 7.26(d, J = 15.3 Hz, 1H, CH), 7.60(d, J = 15.3 Hz, 1H, CH), 9.07(s, 1H, OH), 12.51(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.80, 23.08, 56.67, 107.27, 122.34, 125.19, 125.48, 139.26, 144.58, 148.56, 155.23, 159.70, 169.68, 182.85. ESI-MS: m/z 361 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-formylaminothiazole (A12) Yellow solid. Yield 53.2%; m.p.241 ~ 243℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.64(s, 3H, CH3), 6.84(d, J = 7.5 Hz, 2H, C6H4), 7.20(d, J = 15.3 Hz, 1H, CH), 7.61(d, J = 15.3 Hz, 1H, CH), 7.67(d, J = 7.5 Hz, 2H, C6H4), 8.60(s, 1H, CHO), 10.12(s, 1H, OH), 12.60(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.73, 116.39, 121.43, 125.81, 126.02, 131.40, 144.01, 155.15, 157.93, 160.74, 160.90, 182.64. ESI-MS: m/z 287 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-propionylaminothiazole (A13) Yellow solid. Yield 66.9%; m.p.236 ~ 238℃. 1H NMR(400 MHz, DMSO-d6)δ: 1.11(t, J = 7.3 Hz, 3H, CH3), 2.48(q, J = 7.3 Hz, 2H, CH2), 2.64(s, 3H, thiazole-CH3), 6.88(d, J = 7.7 Hz, 2H, C6H4), 7.19(d, J = 15.2 Hz, 1H, CH), 7.59(d, J = 15.6 Hz, 1H, CH), 7.65(d, J = 7.7 Hz, 2H, C6H4). 13C NMR(101 MHz, DMSO-d6)δ༚9.46, 18.82, 28.91, 121.49, 125.49, 125.69, 130.79, 131.23, 143.63, 155.20, 160.09, 160.91, 173.53, 182.60. ESI-MS: m/z 315 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-butyrylaminothiazole (A14) Yellow solid. Yield 54.5%; m.p.229 ~ 231℃. 1H NMR(400 MHz, DMSO-d6)δ: 0.91(t, J = 7.4 Hz, 3H, CH3), 1.57 ~ 1.69(m, 2H, CH2), 2.45(t, J = 7.3 Hz, 2H, CH2CO), 2.64(s, 3H, thiazole-CH3), 6.84(d, J = 8.1 Hz, 2H, C6H4), 7.19(d, J = 15.3 Hz, 1H, CH), 7.60(d, J = 15.3 Hz, 1H, CH), 7.66(d, J = 8.1 Hz, 2H, C6H4), 10.11(s, 1H, OH), 12.47(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚13.93, 18.51, 18.77, 37.31, 116.37, 121.58, 125.56, 125.86, 131.29, 143.66, 155.20, 159.65, 160.64, 172.46, 182.60. ESI-MS: m/z 329 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(3-chloropropionamido) thiazole (A15) Yellow solid. Yield 73.2%; m.p.235 ~ 237℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.63(s, 3H, CH3), 3.21(t, J = 6.4 Hz, 2H, CH2), 4.55(t, J = 6.4 Hz, 2H, CH2), 6.88(d, J = 8.3 Hz, 2H, C6H4), 7.19(d, J = 15.3 Hz, 1H, CH), 7.60(d, J = 15.3 Hz, 1H, CH), 7.68(d, J = 8.3 Hz, 2H, C6H4), 9.23(s, 1H, OH), 12.78(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚16.72, 36.57, 39.87, 116.16, 122.51, 124.14, 127.54, 130.57, 138.30, 144.27, 159.16, 164.58, 176.24, 187.65. ESI-MS: m/z 349 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(2-furanylamino) thiazole (A16) Dark grey solid. Yield 71.4%; m.p.265 ~ 267℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.68(s, 3H, CH3), 6.89(d, J = 8.0 Hz, 2H, C6H4), 7.22(d, J = 15.4 Hz, 1H, CH), 7.62(d, J = 15.4 Hz, 1H, CH), 7.67(d, J = 8.0 Hz, 2H, C6H4), 6.75 ~ 6.78, 7.73 ~ 7.75, 8.04 ~ 8.08(m, 3H, C4H3O), 9.86(s, 1H, OH). 13C NMR(101 MHz, DMSO-d6)δ༚18.58, 112.91, 116.45, 117.69, 121.45, 125.75, 126.00, 131.29, 131.59, 143.90, 145.84, 148.24, 156.80, 159.99, 160.85, 182.66. ESI-MS: m/z 349 [M-H]−. ESI-MS: m/z 353 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(3-pyridylamido) thiazole (A17) Yellow solid. Yield 55.7%; m.p.226 ~ 228℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.48(s, 3H, CH3CO), 2.60(s, 3H, CH3), 7.56 ~ 9.24(m, 4H, C5H4N). 13C NMR(101 MHz, DMSO-d6)δ༚18.50, 30.57, 123.95, 124.84, 129.74, 136.32, 149.86, 152.96, 154.70, 163.30, 166.39, 190.83. ESI-MS: m/z 349 [M-H]−. ESI-MS: m/z 364 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-benzoylaminothiazole (A18) Yellow solid. Yield 67.7%; m.p.262 ~ 264℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.70(s, 3H, CH3), 6.89(d, J = 8.0 Hz, 2H, C6H4), 7.24(d, J = 15.3 Hz, 1H, CH), 7.53 ~ 7.72, 8.13 ~ 8.15(m, 8H, C6H4 + C6H5 + CH), 9.79(s, 1H, OH), 12.48(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.64, 116.45, 121.57, 125.86, 125.93, 128.79, 129.15, 131.30, 132.09, 133.43, 143.87, 154.81, 160.49, 160.82, 166.22, 182.75. ESI-MS: m/z 363 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(4-hydroxybenzoylamino) thiazole (A19) Yellow solid. Yield 69.1%; m.p.244 ~ 246℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.50(s, 3H, CH3), 2.61(s, 3H, CH3CO), 6.89(d, J = 8.0 Hz, 2H, C6H4), 8.02(d, J = 8.0 Hz, 2H, C6H4), 10.43(s, 1H, OH), 12.70(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.47, 30.57, 115.77, 122.41, 125.69, 131.07, 154.74, 160.97, 162.37, 165.47, 191.15. ESI-MS: m/z 379 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(4-methoxybenzoylamino) thiazole (A20) Yellow solid. Yield 61.5%; m.p.272 ~ 273℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.69(s, 3H, CH3), 3.86(s, 3H, CH3O), 6.85(d, J = 8.0 Hz, 2H, C6H4), 7.09(d, J = 8.0 Hz, 2H, C6H4CO), 7.23(d, J = 15.4 Hz, 1H, CH), 7.62(d, J = 15.4 Hz, 1H, CH), 7.67(d, J = 8.0 Hz, 2H, C6H4), 8.14(d, J = 8.0 Hz, 2H, C6H4CO), 10.14(s, 1H, OH), 12.85(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.69, 56.04, 114.48, 116.40, 121.56, 121.66, 124.06, 125.78, 125.88, 130.90, 131.32, 143.72, 155.18, 160.66, 163.47, 165.42, 182.70. ESI-MS: m/z 393 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(4-fluorobenzoylamino) thiazole (A21) Yellow solid. Yield 79.3%; m.p.＞300℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.69(s, 3H, CH3), 6.88(d, J = 7.6 Hz, 2H, C6H4), 7.23(d, J = 15.3 Hz, 1H, CH), 7.63(d, J = 15.3 Hz, 1H, CH), 7.67(d, J = 7.6 Hz, 2H, C6H4), 7.39 ~ 7.43, 8.20 ~ 8.23(m, 4H, C6H4CO), 10.61(s, 1H, OH). 13C NMR(101 MHz, DMSO-d6)δ༚18.60, 116.22(d), 116.42, 121.49, 125.77, 125.90, 128.69, 131.32, 131.66, 131.75, 143.89, 160.53, 160.80, 164.63, 166.57, 182.70. ESI-MS: m/z 381 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(4-cyanobenzoylamino) thiazole (A22) Yellow solid. Yield 64.5%; m.p.＞300℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.69(s, 3H, CH3), 6.88(d, J = 7.7 Hz, 2H, C6H4), 7.22(d, J = 15.3 Hz, 1H, CH), 7.62(d, J = 15.3 Hz, 1H, CH), 7.67(d, J = 7.7 Hz, 2H, C6H4), 8.04(d, J = 7.6 Hz, 2H, C6H4CO), 8.25(d, J = 7.6 Hz, 2H, C6H4CO), 10.27(s, 1H, OH), 13.30(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.41, 114.94, 115.38, 116.44, 116.51, 118.07, 118.62, 121.34, 125.73, 129.56, 131.34, 133.07, 144.03, 155.88, 160.87, 173.78, 182.66. ESI-MS: m/z 388 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(4-trifluoromethylbenzoylamino) thiazole (A23) Yellow solid. Yield 88.0%; m.p.＞300℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.70(s, 3H, CH3), 6.88(d, J = 7.8 Hz, 2H, C6H4), 7.23(d, J = 15.4 Hz, 1H, CH), 7.63(d, J = 15.4 Hz, 1H, CH), 7.68(d, J = 7.9 Hz, 2H, C6H4), 7.94(d, J = 7.9 Hz, 2H, C6H4CO), 8.30(d, J = 7.9 Hz, 2H, C6H4CO), 10.27(s, 1H, OH), 13.30(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.48, 116.43, 121.38, 122.89, 125.60, 125.75, 126.06, 128.31, 129.73, 131.35, 132.63, 132.95, 136.12, 144.01, 145.05, 160.86, 182.69. ESI-MS: m/z 431 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(4-nitrobenzoylamino) thiazole (A24) Yellow solid. Yield 73.3%; m.p.＞300℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.68(s, 3H, CH3), 6.85(d, J = 7.7 Hz, 2H, C6H4), 7.20(d, J = 15.2 Hz, 1H, CH), 7.61(d, J = 15.2 Hz, 1H, CH), 7.66(d, J = 7.7 Hz, 2H, C6H4), 8.31(d, J = 7.9 Hz, 2H, C6H4CO), 8.35(d, J = 7.9 Hz, 2H, C6H4CO), 10.15(s, 1H, OH), 13.36(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.39, 121.16, 121.25, 121.30, 121.36, 124.02, 124.10, 125.79, 126.04, 130.32, 131.36, 137.88, 143.98, 150.18, 160.75, 182.58. ESI-MS: m/z 408 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(3-nitrobenzoylamino) thiazole (A25) Yellow solid. Yield 56.9%; m.p.＞300℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.69(s, 3H, CH3), 6.87(d, J = 7.8 Hz, 2H, C6H4), 7.21(d, J = 15.3 Hz, 1H, CH), 7.62(d, J = 15.3 Hz, 1H, CH), 7.66(d, J = 7.8 Hz, 2H, C6H4), 7.83 ~ 8.97(m, 4H, C6H4CO). 13C NMR(101 MHz, DMSO-d6)δ༚18.22, 116.42, 121.24, 123.59, 125.68, 125.75, 125.79, 127.59, 130.87, 131.33, 134.07, 135.06, 143.99, 148.24, 153.57, 160.76, 165.10, 182.64. ESI-MS: m/z 408 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-(3-methyl-4-nitrobenzoylamino) thiazole (A26) Yellow solid. Yield 70.0%; m.p.＞300℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.56(s, 3H, CH3), 2.69(s, 3H, CH3C6H3), 6.88(d, J = 8.2 Hz, 2H, C6H4), 7.21(d, J = 15.2 Hz, 1H, CH), 7.62(d, J = 15.2 Hz, 1H, CH), 7.66(d, J = 8.2 Hz, 2H, C6H4), 8.11 ~ 8.21(m, 3H, C6H3), 10.30(s, 1H, OH), 13.20(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.39, 19.76, 116.44, 121.30, 125.04, 125.72, 127.71, 131.25, 131.33, 133.18, 133.29, 136.04, 136.12, 143.74, 144.03, 151.61, 159.67, 160.89, 182.67. ESI-MS: m/z 422 [M-H]−.
4-methyl-5-[3-(4-hydroxyphenyl) acryloyl]-2-aminothiazole (A27) Yellow solid. Yield 82.6%; m.p.211 ~ 213℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.62(s, 3H, CH3), 5.28(s, 2H, NH2), 6.87(d, J = 7.9 Hz, 2H, C6H4), 7.12(d, J = 15.3 Hz, 1H, CH), 7.62(d, J = 15.3 Hz, 1H, CH), 7.66(d, J = 7.9 Hz, 2H, C6H4). 13C NMR(101 MHz, DMSO-d6)δ༚15.84, 116.45, 119.61, 121.10, 125.59, 131.57, 144.77, 161.10, 169.20, 169.24, 181.32. ESI-MS: m/z 259 [M-H]−.
4-methyl-5-[3-(4-aminophenyl) acryloyl]-2-acetylaminothiazole (A28) Red solid. Yield 89.7%; m.p.244 ~ 246℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.18(s, 3H, CH3CO), 2.62(s, 3H, CH3), 5.93(s, 2H, NH2), 6.60(d, J = 7.8 Hz, 2H, C6H4), 7.04(d, J = 15.1 Hz, 1H, CH), 7.48(d, J = 7.8 Hz, 2H, C6H4), 7.54(d, J = 15.1 Hz, 1H, CH), 12.41(s, 1H, NH). 13C NMR(101 MHz, DMSO-d6)δ༚18.71, 23.06, 114.15, 118.31, 121.95, 125.93, 131.43, 144.88, 152.56, 154.43, 159.33, 169.71, 182.52. ESI-MS: m/z 300 [M-H]−.
4-methyl-5-[3-(4-carboxyphenyl) acryloyl]-2-acetylaminothiazole (A29) Yellow solid. Yield 88.5%; m.p.267 ~ 269℃. 1H NMR(400 MHz, DMSO-d6)δ: 2.18(s, 3H, CH3CO), 2.63(s, 3H, CH3), 7.44(d, J = 15.5 Hz, 1H, CH), 7.69(d, J = 15.5 Hz, 1H, CH), 7.92(d, J = 7.8 Hz, 2H, C6H4), 7.99(d, J = 7.8 Hz, 2H, C6H4). 13C NMR(101 MHz, DMSO-d6)δ༚16.69, 23.06, 121.04, 125.94, 129.25, 130.04, 130.27, 130.39, 132.60, 138.79, 142.01, 167.29, 169.98, 181.24. ESI-MS: m/z 329 [M-H]−.
3-[3-(4-hydroxyphenyl) acryloyl] acetaminobenzene (B) Yellow solid. Yield 43.5%; m.p.229 ~ 231℃.
Acknowledgements
Authors would like to acknowledge and thank Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College for the NA inhibition assays.The authors acknowledge financial support by Changsha Natural Science Foundation (kq2202183).
Conflicts of interest
There are no conflicts to declare
- Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka YC (1992) Evolution and ecology of influenza A viruses. Microbiol Mol Biol Rev 56: 152–179. https://doi.org/10.1128/mr.56.1.152-179
- Wu Y, Wu Y, Tefsen B, Shi Y, Gao GF (2014) Bat-derived influenza-like viruses H17N10 and H18N11. Trends Microbiol 22(4), 183–191. https://doi.org/10.1016/j.tim.2014.01.010
- Matrosovich M, Klenk HD (2003) Natural and synthetic sialic acid-containing inhibitors of influenza virus receptor binding. Rev Med.Virol 13: 85–97. https://doi.org/10.1002/rmv.372
- Grienke U, Schmidtke M, von Grafenstein S, Kirchmair J, Liedl KR, Rollinger JM (2012) Influenza neuraminidase: a druggable target for natural products. Nat Prod.Rep 29: 11–36. https://doi.org/10.1039/C1NP00053E
- Hauge SH, Dudman S, Borgen K, Lackenby A, Hungnes O (2009) Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007-08. Emerging Infect 15: 155. https://doi.org/10.3201/EID1502.081031
- Chachra R, Rizzo RC (2008) Origins of resistance conferred by the R292K neuraminidase mutation via molecular dynamics and free energy calculations. J Chem Theory Comput 4: 1526–1540. https://doi.org/10.1021/ct800068v
- Hai R, Schmolke M, Leyva-Grado VH, Thangavel RR, Margine I, Jaffe E.L, Krammer F, Solorzano A, Garcia-Sastre A, Palese P, Bouvier NM (2013) Influenza A (H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility. Nat Commun 4: 2854. https://doi.org/10.1038/NCOMMS3854
- Coskun D, Erkisa M, Ulukaya E, Coskun MF, Ari F (2017) Novel 1-(7-ethoxy-1-benzofuran-2-yl) substituted chalcone derivatives: synthesis, characterization and anticancer activity. Eur J. Med Chem 136: 212–222. https://doi.org/10.1016/j.ejmech.2017.05.017
- Wang YH, Dong HH, Zhao F, Wang J, Yan F, Jiang YY, Jin YS (2016) The synthesis and synergistic antifungal effects of chalcones against drug resistant Candida albicans. Bioorganic Med Chem Lett 26: 3098–3102. https://doi.org/10.1016/j.bmcl.2016.05.013
- Gomes MN, Braga RC, Grzelak EM, Neves BJ, Muratov E, Ma R, Klein LL, Cho S, Oliveira GR, Franzblau SG, Andrade CH (2017) QSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity. Eur J Med Chem 137: 126–138. https://doi.org/10.1016/j.ejmech.2017.05.026
- Park JY, Jeong HJ, Kim YM, Park SJ, Rho MC, Park KH, Lee WS (2011) Characteristic of alkylated chalcones from Angelica keiskei on influenza virus neuraminidase inhibition. Bioorganic Med Chem Lett 21: 5602–5604. https://doi.org/10.1016/j.bmcl.2011.06.130
- Jeong HJ, Kim YM, Kim JH, Kim JY, Park JY, Park SJ, Lee WS (2012) Homoisoflavonoids from Caesalpinia sappan displaying viral neuraminidases inhibition. Biol Pharm Bull 35: 786–790. https://doi.org/10.1248/bpb.35.786
- Yu M, Wang Y, Tian L, Wang Y, Wang X, Liang W, Fang X (2015) Safflomin A inhibits neuraminidase activity and influenza virus replication. RSC Adv 5: 94053–94066. https://doi.org/10.1039/C5RA17336A
- Dao TT, Tung BT, Nguyen PH, Thuong PT, Yoo SS, Kim EH, Kim SK, Oh WK (2010) C-methylated flavonoids from Cleistocalyx operculatus and their inhibitory effects on novel influenza A (H1N1) neuraminidase. J Nat Prod 73: 1636–1642. https://doi.org/10.1021/np1002753
- Ryu YB, Kim JH, Park SJ, Chang JS, Rho MC, Bae KH, Lee WS (2010) Inhibition of neuraminidase activity by polyphenol compounds isolated from the roots of Glycyrrhiza uralensis. Bioorganic Med Chem Lett 20: 971–974. https://doi.org/10.1016/j.bmcl.2009.12.106
- Kinger M, Park YD, Park JH, Hur MG, Jeong HJ, Park, SJ, Yang SD (2012) Design, synthesis, and anti-influenza viral activities of 1, 3-diarylprop-2-en-1-ones: a novel class of neuraminidase inhibitors. Arch Pharm Res 35: 633–638. https://doi.org/10.1007/s12272-012-0406-2
- Yaeghoobi M, Frimayanti N, Chee CF, Ikram KK, Najjar BO, Zain SM, Rahman NA (2016) QSAR, in silico docking and in vitro evaluation of chalcone derivatives as potential inhibitors for H1N1 virus neuraminidase. Med Chem Res 25: 2133–2142. https://doi.org/10.1007/s00044-016-1636-5
- Chintakrindi AS, Gohil DJ, Kothari ST, Chowdhary AS, Kanyalkar MA (2018) Design, synthesis and evaluation of chalcones as H1N1 Neuraminidase inhibitors. Med Chem Res 27: 1013–1025. https://doi.org/10.1007/s00044-017-2124-2
- Xie J, Si X, Gu S, Wang M, Shen J, Li H, Zhu J (2017) Allosteric inhibitors of SHP2 with therapeutic potential for cancer treatment. J. Med. Chem 60: 10205–10219. https://doi.org/10.1021/acs.jmedchem.7b01520
- Kang IJ, Hsu SJ, Yang HY, Yeh TK, Lee CC, Lee YC, Yueh, A (2016) A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus:(S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl) pyrrolidine-2-carboxamide. J Med Chem 60: 228–247. https://doi.org/10.1021/acs.jmedchem.6b00962
- Liu Y, Zhang L, Gong J, Fang H, Liu A, Du G, Xu W (2011) Design, synthesis, and biological activity of thiazole derivatives as novel influenza neuraminidase inhibitors. J Enzyme Inhib Med Chem 26: 506–513. https://doi.org/10.3109/14756366.2010.534732
- Hao LH, Li YP, He WY, Wang HQ, Shan GZ, Jiang JD, Li ZR (2012) Synthesis and antiviral activity of substituted bisaryl amide compounds as novel influenza virus inhibitors. Eur J Med Chem 55: 117–124. https://doi.org/10.1016/j.ejmech.2012.07.008
- Rossignol JF, La Frazia S, Chiappa L, Ciucci A, Santoro MG (2009) Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem 284: 29798–29808. https://doi.org/10.1074/jbc.M109.029470
- Wu Z, Peng J, Hu A, Ye J, Li G (2016) Design, synthesis and neuraminidase inhibitory activity of N-(5-benzyl-4-(tert-butyl) thiazol-2-yl) benzamides. Medicinal Chemistry Research 25: 356–368. https://doi.org/10.1007/s00044-015-1487-5
- Cui MY, Nie JX, Yan ZZ, Xiao MW, Lin D, Ye J, Hu AX (2019) Design, synthesis, bioactivity, and DFT calculation of 2-thiazolyl-hydrazone derivatives as influenza neuraminidase inhibitors. Med Chem Res 28: 938–947. https://doi.org/10.1007/s00044-019-02343-3
- Woods JM, Bethell RC, Coates JA, Healy N, Hiscox SA, Pearson BA, Walcott SM (1993) 4-Guanidino-2, 4-dideoxy-2, 3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro. Antimicrob Agents CH 37: 1473–1479. https://doi.org/10.1128/AAC.37.7.1473
Scheme 1 is available in Supplementary Files section.
No competing interests reported.
- supportinformation.doc
- GraphicalAbstract.png
- Scheme1.png
Scheme 1 Reagents and conditions: (a) acetone, 0 oC , 3 h; (b) 1) thiourea or methanethioamide, EtOH, r.t, 30 min; reflux, 8 h; (c) 1) acid, CDI, DMF, r.t, 30 min; 85 oC, 8 h; 2) aldehydes, HCl(g), EtOH, r.t, 6 h; (d) MeOH, HCl(g), 50 oC, 3h; (e) SnCl2, EtOH, reflux; (f) LiOH-H2O, MeOH, 65 oC, 2h.
