Molecules 2014, 19(4), 5163-5190; doi:10.3390/molecules19045163

Article
Antioxidant and Antitumor Activities of New Synthesized Aromatic C-Nucleoside Derivatives
Mohamed M. El Sadek 1,*, Nagwa S. Abd El-Dayem 1, Seham Y. Hassan 1, Mohamed A. Mostafa 1 and Galila A. Yacout 2
1
Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21231, Egypt; E-Mails: nagwa_abdeldayem@yahoo.com (N.S.A.E.-D.); sehamyassen@yahoo.com (S.Y.H.); dr_abdel_zaher@hotmail.com (M.A.M.)
2
Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21231, Egypt; E-Mail: galila_69@yahoo.com
*
Author to whom correspondence should be addressed; E-Mail: mohamed.elsadik@alexu.edu.eg; Tel.: +20-01-006-544-617; Fax: +20-3-593-2488.
Received: 6 March 2014; in revised form: 9 April 2014 / Accepted: 14 April 2014 /
Published: 22 April 2014

Abstract

: The carbohydrazide 1 was used as the precursor for the synthesis of a number of new aromatic C-nucleosides containing 1,3,4-oxadiazole 7, [1,3,4]oxadiazolo[2,3-a]isoindole 10b and pyrazole units 18. On the other hand, the thiosemicarbazone 20 was used as the key intermediate for synthesis of 1,3,4-oxadiazole and 1,2,4-triazole-3-thione derivatives 21 and 23. The antioxidant activities of the prepared compounds were evaluated. The carbohydrazide 1 in particular was found to have potent antioxidant and antitumor activity.
Keywords:
oxoindoline; isopropylidene; pyrrole; indole; isoindole; oxadiazole; pyrazole; antioxidant

1. Introduction

A number of nucleoside analogues have been found to show a broad spectrum of biological effects such as antifungal [1,2], antibacterial [1,2,3], antitumor [3,4,5], antiviral [3,4,6,7,8,9,10,11,12,13,14] anti-inflammatory [15] and analgesic [15] activities. Moreover, 2'-deoxy-2'-fluoro-2'-C-methyl nucleoside analogues have showed promising activity against HCV replication [16]. In addition, nucleoside derivatives display inhibition of glucose-6-phosphatase and showed antihyperglycemic effects [17], as well as inhibition of SAH hydrolase [18]. C-Nucleosides are a subtype of these compounds that are of great interest owing to their potential biological activity together with their higher stabilities than that of the corresponding N-nucleosides. In light of these interesting biological activities and continuation of our research work to explore potent bioactive nitrogen containing molecules [1,2], some aromatic C-nucleoside derivatives were prepared and characterized by analytical and spectral methods.

2. Results and Discussion

2.1. Chemistry

Condensation of the carbohydrazide derivative 1B [19] with carbonyl compounds 2ae, afforded the corresponding carbohydrazone derivatives 3ae in 88%–100% yields. Their structures were confirmed by IR, 1H-NMR, two dimentional 1H-NMR (COSY), 13C-NMR and mass spectral data. The 1H-NMR spectrum (DMSO-d6) of compound 3c, for example, showed five singlets around δ 11.94, 11.14, 8.13, 6.83 and 6.74, supporting the presence of NH(1), NH(2) (D2O exchangeable), azomethine (CH=N), CH(pyrrole) and CH(furan) protons, respectively. Signals of the sugar protons of these derivatives 3ae were assigned from the 2D 1H-NMR spectrum of compound 3c, and the characteristic chemical shifts as compared with those reported for carbohydrazones [1], whereby, four doublets appearing at δ 5.14, 4.75, 4.60, 4.46 ppm were assigned to 1'-OH, H-1', 2'-OH and 3'-OH, respectively, and a triplet at δ (4.35) ppm for 4'-OH. Two multiplets at δ 3.56–3.50 and 3.42–3.40 ppm were assigned for H-2' overlapped with H-3' and H-4'a, and the other multiplet for H-4'b. A broad singlet at δ 2.47 ppm corresponded to the acetyl protons (COCH3), followed by two singlets at δ 2.43 and 2.28 ppm due to methyl protons at the position-2 of the furan ring and CH3(pyrrole), respectively (see Experimental Section and Scheme 1).

Periodate oxidation of 3e afforded the corresponding 5-formyl derivative 4, whose infrared spectrum showed the aldehyde carbonyl functional group at γ 1,689 cm−1. In addition the 1H-NMR spectrum (DMSO-d6) of this product, showed a high field singlet at δ 9.60 ppm for the aldehyde proton (CHO). The mass spectrum showed the molecular ion peak at m/z 297 (M+, 22.54%).

Acetylation of compounds 3b and 3e, afforded the corresponding acetyl derivatives 5 and 6, in 95% and 100% yield, respectively, as indicated by their spectral data. Oxidative cycization [1,2,20] of the carbohydrazone 5, gave the 1,3,4-oxadiazole derivative 7 which lacked the carbonyl and NH bands in its infrared spectrum. The mass spectrum gave the parent ion peak at m/z 559 (M+, 18.83%). (see Experimental Section and Scheme 2).

On the other hand, boiling of the tetrayltetraacetate 7 with hydrazine hydrate resulted in the corresponding tetrahydroxybutyl derivative 8 in 97% yield. Its IR spectrum showed the hydroxyl groups (OH) at γ 3387–3200 cm−1, while the corresponding 1H-NMR spectrum revealed the four hydroxyl protons at δ 5.23–4.37 ppm, and the mass spectrum showed the molecular ion peak in agreement with expected molecular weight of compound 8. Moreover, dehydrative cyclization of the tetraol derivative 8 with aqueous acetic acid (10%) afforded the aromatic C-nucleoside 9 in 63% yield, as detected from its spectral data. Its 1H-NMR spectrum (DMSO-d6) showed only two D2O-exchangeable hydroxyl protons for 2'-OH and 3'-OH, as two doublets at δ 5.16 and 5.03 ppm, respectively. The mass spectrum showed the expected molecular ion peak in agreement with its structure.

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Scheme 1. Synthesis of carbohydrazones 3ae and 4.

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Scheme 1. Synthesis of carbohydrazones 3ae and 4.
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Scheme 2. Synthesis of aromatic C-nucleosides 59.

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Scheme 2. Synthesis of aromatic C-nucleosides 59.
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Condensative cyclization of carbohydrazone 3a with acetic anhydride in the presence of anhydrous sodium acetate gave a cyclized product that according to physical and chemical studies, could not be reconciled with the structure of 10a, that but rather was compatible with that of [1,3,4]oxadiazolo-[2,3-a]isoindole 10b. The infrared spectrum of this compound showed the disappearance of the carboxylic acid hydroxyl group, sugar hydroxyl groups, and CONH absorption bands. It showed instead an acetoxyl (OAc) group at γ 1,744 cm−1 and carbonyl groups at γ 1,725 and 1,712 cm−1. Its 1H-NMR spectrum (CDCl3) showed the disappearance of signals corresponding to the sugar protons at the δ 3.00–5.00 ppm region, and only displayed the aromatic protons as a doublet at δ 7.84 (J = 7.65 Hz) for Ar-H(a), a triplet at δ 7.65 (J = 7.65 Hz) for Ar-H(b), a triplet at δ 7.56 (J = 7.65 Hz) for Ar-H(c), and a doublet at δ 7.53 (J = 7.65 Hz) for Ar-H(d), followed by a singlet attributed to CH(furan) at δ 7.00 ppm. Three singlet signals that appeared in the upper field region at δ 2.56, 2.27 and 2.14 ppm were attributed to the CH3(furan), COCH3 and O-acetyl protons, respectively. It is noteworthy that the integration of the OAc protons (δ 2.14 ppm), indicated only one O-acetyl group, in accord with structure 10b. Moreover, the proposed mechanism for formation of 10b may proceed as illustrated in Scheme 3 and Scheme 4.

In addition, condensation of anhydro derivative 11 [2] with p-nitrobenzaldehyde, indoline-2,3-dione (isatin) and d-galactose in acidic medium afforded the corresponding aromatic C-nucleosides 1214, respectively. Compounds 12 and 13 were also obtained by acid-catalyzed dehydrative cyclization of 3b and 3e, respectively. Their structures were deduced from the respective spectral data. The signals of the sugar protons of anhydro structures 12 and 13 were assigned from the characteristic chemical shifts as compared with those reported for diol derivatives [2]. Although the coupling constant value (J1',2' = 6.85 Hz) of 12 cannot define the anomeric configuration [21], however, it could be β- in accordance with the configuration its precursor [2]. On the other hand, the anomeric configuration of 13 can be ascertained from the large observed coupling constant value (J1',2' = 9.00 Hz) which indicates a trans arrangement of the base moiety and the 2'-hydroxyl group, i.e., β-d-configuration.

Furthermore, acetylation of 12 and 13, afforded the acetylated structures 15 and 16, in 79% and 67% yields, respectively. The infrared spectra showed OAc absorption bands at γ 1,753, 1,745 cm−1, respectively. The 1H-NMR spectra (CDCl3) of these products revealed two singlet signals at δ 2.00–2.11 ppm attributed to two O-acetyl groups. Their mass spectra showed the expected molecular ion peaks in agreement with their proposed structures.

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Scheme 3. Synthesis of [1,3,4]oxadiazolo[2,3-a]-isoindole 10b.

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Scheme 3. Synthesis of [1,3,4]oxadiazolo[2,3-a]-isoindole 10b.
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Scheme 4. Proposed mechanism for formation of [1,3,4]oxadiazolo[2,3-a]isoindole 10b.

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Scheme 4. Proposed mechanism for formation of [1,3,4]oxadiazolo[2,3-a]isoindole 10b.
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The isopropylidene derivative 17 has been prepared from 13 in yield 88%. Its anomeric configuration was confirmed from the zero coupling constant value (J1',2' = 0.00 Hz), as a β-d-configuration [2,21,22]. The mass spectrum showed the expected molecular ion peak in agreement with its structure (Scheme 5).

The pyrazole derivative 18 was obtained in 100% yield from the reaction of carbohydrazide 1 with pentane-2,4-dione as previously reported on other systems [23]. The infrared spectrum showed the disappearance of absorption bands corresponding to NH and NH2. Its 1H-NMR spectrum (DMSO-d6), revealed three singlets at δ 6.18, 2.48 and 2.16 ppm for CH(pyrazole), CH3(pyrazole-a) and CH3(pyrazole-b) protons, respectively. The molecular ion peak recorded in the mass spectrum was in accordance with its molecular weight. Furthermore, the O-acetyl derivative 19 was prepared, in which the signals of the sugar protons of this product were assigned from its 2D 1H-NMR spectrum (Scheme 6).

Moreover, condensation of 1 with phenyl isothiocyanate gave the corresponding thiosemicarbazide derivative 20 [24]. Intramolecular cyclization of this thiosemicarbazide using an improved procedure involving treatment with potassium iodide and iodine in the presence of sodium hydroxide [25] resulted in 1,3,4-oxadiazole product 21 [24] in 95% yield. The tetra-O-acetyl derivative 22 was obtained in 85% yield, the signals of the sugar protons of this product were assigned from its 2D 1H-NMR spectrum, the mass spectrum showed the molecular ion peak at m/z 529 (M+, 19.12%), and 13C-NMR (CDCl3) spectrum confirmed the structure (Scheme 7).

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Scheme 5. Synthesis of aromatic C-nucleosides 1217.

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Scheme 5. Synthesis of aromatic C-nucleosides 1217.
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Scheme 6. Synthesis of pyrazole derivatives 18 and 19.

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Scheme 6. Synthesis of pyrazole derivatives 18 and 19.
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Scheme 7. Synthesis of 1,3,4-oxadiazoles 21 and 22.

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Scheme 7. Synthesis of 1,3,4-oxadiazoles 21 and 22.
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Alternatively, heating the thiosemicarbazide 20 with aqueous sodium hydroxide (10%) [25] gave a product 23, whose infrared spectrum showed a C=N absorption at γ 1,624 cm−1 with the disappearance of the CONH absorption. Moreover, acetylation of 23, gave 5-(5-(1',2',3',4'-tetraacetoxybutyl)-2-methylfuran-3-yl)-4-phenyl-2-N-acetyl-1,2,4-triazole-3(4H)-thione (24) in 97% yield. The 1H-NMR spectrum (CDCl3) revealed the disappearance of the NH proton and showed a singlet due to N-acetyl protons at δ 2.77 ppm, followed by three singlets at δ 2.01, 1.99, and 1.97 ppm for four O-acetyl groups. The mass spectrum showed a molecular ion peak in accordance with its molecular formula (Scheme 8).

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Scheme 8. Synthesis of 4-phenyl-2H-1,2,4-triazole-3(4H)-thiones 2326.

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Scheme 8. Synthesis of 4-phenyl-2H-1,2,4-triazole-3(4H)-thiones 2326.
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Dehydration of 23, afforded 2',3'-diol 25 in yield of 80% (Scheme 8). The anomeric configuration of 25 can be confirmed as β-d-configuration (J1',2' = 9.00 Hz). The mass spectrum showed the expected molecular ion peak at m/z 359 (M+, 20.21%). The characteristic alcohol M-H2O peak appeared at m/z 341 (20.21), while the M-SH peak was seen at m/z 326 (20.21). The loss of a furanose moiety (C4H8O3) from the molecular ion appeared at m/z 255 (20.91). Furthermore, periodate oxidation of 23, afforded the corresponding 2-carbaldehyde derivative 26.

2.2. Bioactivity Screening of New Synthesized Aromatic C-Nucleosides

2.2.1. Antioxdant Activity Screening (Using the DPPH Assay)

The diphenylpicrylhydrazyl (DPPH) assay method is based on the reduction of the free radical DPPH with an odd electron which gives a maximum absorption at 517 nm. When antioxidants react with DPPH, giving DPPD-H the absorbance decreases due to decolorization with respect to the number of electrons captured. EC50 values for each examined compound as well as standard preparations were calculated according to the method Shahwar et al. [26]. A lower EC50 value is associated with a higher radical scavenging activity. As shown in Table 1 and Table 2 and Figure 1, Figure 2, Figure 3, Figure 4, Figure 5 and Figure 6 the DPPH radical scavenging activities of the prepared compounds 1, 3ce, 46, 13, and 1626 in terms of EC50 values were the highest in the case of compounds 20, 3c, 3d, 1 and 22 (0.380, 0.418, 0.448, 0.590 and 0.590 mg, respectively) compared to the EC50 of vitamin E used as standard (0.705). Meanwhile nearly the same activities were revealed in case of compounds 23 and 26 (0.720 and 0.725 mg), respectively. In addition, moderate activities were shown for compounds 3e, 4, 17 and 25 (0.800, 0.800, 0.825 and 0.815 mg), respectively. Lower activities were observed in case of compounds 5, 6, 13, 16, 18, 19, 21 and 24 with EC50 values equal to 0.960, ˃ 1.000, 0.900, 0.980, ˃ 1.000, 0.930, ˃ 1.000, ˃ 1.000 mg, respectively, compared to the standard, see Table 2.

Table Table 1. Absorbance and free radical scavenging activities of tested compounds.

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Table 1. Absorbance and free radical scavenging activities of tested compounds.
Conc.(mg/ mL)Compound 1Compound 3cCompound 3dCompound 3e
Absorbance% ScavengingAbsorbance% ScavengingAbsorbance% ScavengingAbsorbance% Scavenging
0.1500.0000.000.0000.000.0000.000.0000.00
0.3000.36942.610.42047.580.33747.580.42034.68
0.4500.33048.670.39950.690.31750.690.39939.50
0.6000.31251.470.38055.980.28355.980.38042.61
0.7500.29753.810.36957.540.27357.540.36947.58
0.9000.27357.540.33059.400.26159.400.33052.56
1.0000.23263.910.29760.030.25760.030.29757.54
Conc. (mg/ mL)Compound 4Compound 5Compound 6Compound 13
Absorbance% ScavengingAbsorbance% ScavengingAbsorbance% ScavengingAbsorbance% Scavenging
0.1500.0000.000.0000.000.0000.000.0000.00
0.3000.42034.680.45129.860.51120.520.45129.86
0.4500.38939.500.41136.080.49323.320.42034.68
0.6000.36942.610.38939.500.46927.060.38939.50
0.7500.33747.580.36044.010.44031.570.35245.25
0.9000.30552.560.33747.580.40337.320.33747.58
1.0000.27357.540.31750.690.37641.520.29753.81
Conc. (mg/ mL)Compound 16Compound 17Compound 18Compound 19
Absorbance% ScavengingAbsorbance% ScavengingAbsorbance% Scavenging% ScavengingAbsorbance
0.1500.0000.000.0000.000.0000.000.0000.00
0.3000.44031.570.43332.650.45129.860.46927.06
0.4500.41335.760.39139.190.44031.570.42034.68
0.6000.38739.810.37042.450.43332.650.39139.19
0.7500.36942.610.33048.670.42034.680.36942.61
0.9000.34146.960.31750.690.40337.320.33747.58
1.0000.31251.470.30352.870.37042.450.31251.47
Conc. (mg/ mL)Vitamin ECompound 20Compound 21Compound 22
Absorbance% ScavengingAbsorbance% ScavengingAbsorbance% Scavenging% ScavengingAbsorbance
0.1500.75621.250.0000.000.0000.000.0000.00
0.3000.71225.830.33547.900.54016.010.39139.19
0.4500.68428.750.30552.560.51120.520.33747.58
0.6000.61535.930.28555.670.48324.880.29753.81
0.7500.42056.250.27657.070.45030.010.28355.98
0.9000.20278.950.25260.800.42034.680.27357.54
1.0000.03796.140.24062.670.39139.190.25760.03
Conc. (mg/ mL)Compound 23Compound 24Compound 25Compound 26
absorbance% scavengingabsorbance% scavengingabsorbance% scavengingabsorbance% scavenging
0.1500.0000.000.0000.000.0000.000.0000.00
0.3000.46327.990.51120.520.37841.210.36942.61
0.4500.38739.810.46727.370.34646.180.34146.96
0.6000.32249.920.43831.880.34047.120.32649.30
0.7500.31051.780.41834.990.32549.450.31451.16
0.9000.30253.030.37641.520.31650.850.30552.56
1.0000.29254.580.35644.630.30652.410.29953.49
Table Table 2. EC50 values of the prepared compounds 1, 3c3e, 46, 13, 1626.

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Table 2. EC50 values of the prepared compounds 1, 3c3e, 46, 13, 1626.
Cpd no.EC50 (mg)Cpd no.EC50 (mg)
Vitamin E0.705170.825
1 [1]0.59018˃1.000
3c0.418190.930
3d0.448200.380
3e0.80021˃1.000
40.800220.590
50.960230.720
6˃1.00024˃1.000
130.900250.815
160.980260.725
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Figure 1. Free radical scavenging activity of vitamin E.

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Figure 1. Free radical scavenging activity of vitamin E.
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Figure 2. Free radical scavenging activity of compounds 1, 3ce.

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Figure 2. Free radical scavenging activity of compounds 1, 3ce.
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Figure 3. Free radical scavenging activity of compounds 46, 13.

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Figure 3. Free radical scavenging activity of compounds 46, 13.
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Figure 4. Free radical scavenging activity of compounds 1619.

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Figure 4. Free radical scavenging activity of compounds 1619.
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Figure 5. Free radical scavenging activity of compounds 2022.

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Figure 5. Free radical scavenging activity of compounds 2022.
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Figure 6. Free radical scavenging activity of compounds 2326.

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Figure 6. Free radical scavenging activity of compounds 2326.
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The obtained data revealed a potential antioxidant activity of all examined compounds but with different EC50 values compared to the standard, especially compound 20 which has a distinct thiourea group. In addition, compounds 3c and 3d revealed higher antioxidant activities as compared to the standard due to the acidic protons in the pyrrole and indole, respectively, that can be easily oxidized.

2.2.2. Anticancer Activity Screening (Cytotoxicity Against Three Cancer Cell Lines)

Different concentrations (50–1.56 µg/mL) of the examined compound 1 were used to screen their cytotoxicity against Human Breast Adrenocarcinoma Cells (MCF-7), Human Colon Carcinoma Cells (HCT) and Human Hepatocellular Liver Carcinoma Cells (HepG-2). Cytotoxic effects of these compounds on the cell viability of the cancer cell lines were observed, as shown in Table 3 and Table 4 and Figure 7, Figure 8 and Figure 9. The obtained data revealed that the carbohydrazide 1 has excellent cell growth inhibitory effects on HepG-2, HCT and MCF-7 with IC50s equal to 10.200, 8.400 and 11.700 µg, respectively compared to the IC50 of the doxorubicin (1.200, 0.469) and vinblastine (6.100) standards used, see Table 5.

Table Table 3. Effect of standard compounds on cell viability using cytotoxic assay.

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Table 3. Effect of standard compounds on cell viability using cytotoxic assay.
Conc. (μg/mL)Doxorubicin for HCTDoxorubicin for HepG-2Vinblastine for MCF-7
Viability %Viability %Viability %
50.0006.8210.957.82
25.0008.8914.2915.18
12.50014.8316.9029.6
6.25016.1621.0348.75
3.12522.2830.3260.35
1.56034.6448.2576.24
0.78045.7857.44….
0.39051.08….….
0.000100.00100.00100.00
Table Table 4. Effect of different concentrations of compound 1 on cell viability using cytotoxic assay.

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Table 4. Effect of different concentrations of compound 1 on cell viability using cytotoxic assay.
Conc. (μg/mL)Viability % for HCTViability % for HepG-2Viability % for MCF-7
50.00010.6811.5614.68
25.00019.0926.3430.49
12.50027.2539.1847.84
6.25061.8768.4764.98
3.12583.0889.0579.82
1.56094.6293.7890.18
0.000100.00100.00100.00
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Figure 7. Viability activity against HepG-2 of compound 1.

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Figure 7. Viability activity against HepG-2 of compound 1.
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Figure 8. Viability activity against HCT-116 of compound 1.

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Figure 8. Viability activity against HCT-116 of compound 1.
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Figure 9. Viability activity against MCF-7 of compound 1.

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Figure 9. Viability activity against MCF-7 of compound 1.
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Table Table 5. IC50 of compound 1 on cell viability using cytotoxic assay compared to standards.

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Table 5. IC50 of compound 1 on cell viability using cytotoxic assay compared to standards.
StandardIC50 (μg/mL)
HCTHepG-2MCF-7
0.4691.206.10
Cpd. 18.40010.2011.70

3. Experimental

3.1.General Procedures

Melting points were determined with a Melt-temperature apparatus and are uncorrected. TLC was performed on Baker-Flex silica gel 1B-F plates and the spots were detected by UV light absorption. IR spectra were recorded on a Perkin Elmer spectrometer. 1H-NMR and 13C-NMR were recorded on JEOL JNM ECA 500 MHz and 300 MHz instruments using tetramethylsilane as an internal standard. Mass spectra were recorded on a GCMS DI Analysis Shimadzu Qp-2010 Plus. Solutions were evaporated under diminished pressure unless otherwise stated. ChemDraw-Ultra-8.0 has been used in generating the names of the prepared compounds.

3.2. Chemistry

3.2.1. 5-(1',2',3',4'-Tetrahydroxybutyl)-2-methylfuran-3-carbohydrazide (1)

Mp 200–201 °C (Lit. [1], 198 °C); IR(KBr) cm−1: 3400–3137 (OH, NH), 1674 (C=O); 1H-NMR (DMSO-d6); δ: 2.46 (s, 3H, CH3(furan)), 3.34–3.40 (m, 3H, H-4'b, NH2 with H2O of DMSO), 3.44–3.58 (m, 3H, H-3', H-2', H-4'a), 4.36 (t, 1H, 4'-OH, J4',OH = 5.35 Hz, D2O-exchangeable), 4.48 (d, 1H, 3'-OH, J3',OH = 6.85 Hz, D2O-exchangeable), 4.61 (d, 1H, 2'-OH, J2',OH = 5.35 Hz, D2O-exchangeable), 4.73 (d, 1H, H-1', J1',2' = 5.35 Hz), 5.14 (d, 1H, 1'-OH, J1',OH = 6.10 Hz, D2O-exchangeable), 6.70 (s, 1H, CH(furan)), 9.79 (s, 1H, NH, D2O-exchangeable).

3.2.2. General Method for the Synthesis of Carbohydrazones 3ae

A mixture of 3-carbohydrazide 1 (1.923 mmoL) and carbonyl compound (1.923 mmoL) was heated under reflux in ethanol (10 mL) containing a few drops of acetic acid for 1 h. The products 3ae that separated were filtered off and dried.

2-((5-(1',2',3',4'-Tetrahydroxybutyl)-2-methylfuran-3-carboylimino)methyl)benzoic acid (3a). Obtained in 91% yield from carbohydrazide 1 (1.923 mmoL) and 2-formylbenzoic acid (1.923 mmoL); recrystallized from ethanol as white crystals; mp 209–210 °C; Rf: 0.85 (chloroform–methanol; 5:1; v/v); IR (KBr) cm−1: 3429–3305 (OH), 3187 (NH), 1703 (CO-acid), 1653 (CO-amide), 1593 (C=N); 1H-NMR (DMSO-d6); δ: 2.50 (s, 3H, CH3(furan)), 3.46–3.49 (m, 1H, H-4'b), 3.53–3.59 (m, 3H, H-3', H-2', H-4'a), 4.36 (bs, 1H, 4'-OH, D2O-exchangeable), 4.49 (bs, 1H, 3'-OH, D2O-exchangeable), 4.62 (bs, 1H, 2'-OH, D2O-exchangeable), 4.76 (s, 1H, H-1'), 5.16 (bs, 1H, 1'-OH, J1',OH = 6.00 Hz, D2O-exchangeable), 6.83 (s, 1H, CH(furan)), 7.47 (t, 1H, Ar-H(d), J = 7.65 Hz), 7.60 (t, 1H, Ar-H(c), J = 7.65 Hz), 7.85 (d, 1H, Ar-H(b), J = 7.65 Hz), 8.01 (d, 1H, Ar-H(a), J = 7.65 Hz), 9.08 (s, 1H, CH=N), 11.60 (s, 1H, NH, D2O-exchangeable), 12.58 (bs, 1H, COOH, D2O-exchangeable); MS: m/z (%), 393 (25.33, M++1), 392 (28.00, M+), 357 (25.78), 347 (23.11), 343 (40.00), 330 (32.89), 300 (40.89), 262 (46.67), 251 (52.44), 220 (36.44), 208 (37.33), 183 (46.67), 177 (25.33), 154 (32.44), 151 (32.44), 146 (38.67), 137 (32.89), 102 (33.78), 91 (38.22), 89 (100.00), 77 (43.11), 65 (38.22), 50 (28.00); Anal. Calcd for C18H20N2O8: C, 55.10; H, 5.14; N, 7.14%; found: C, 55.20; H, 5.00; N, 7.23%.

N-(4-Nitrobenzylidene)-5-(1',2',3',4'-tetrahydroxybutyl)-2-methylfuran-3-carbohydrazide (3b). Obtained in 98% yield from carbohydrazide 1 (1.923 mmoL) and p-nitrobenzaldehyde (1.923 mmoL); recrystallized from ethanol as yellow crystals. Rf: 0.38 (chloroform–methanol, 5:1, v/v); mp 163–164 °C; IR (KBr): 3447–3202 (OH, NH), 1664 (C=O), 1585 (C=N); 1H-NMR (DMSO-d6); δ: 2.51 (s, 3H, CH3(furan)), 3.38–3.42 (m, 1H, H-4'b), 3.46–3.51 (m, 1H, H-4'a ), 3.52–3.54 (m, 1H, H-3'), 3.55–3.60 (m, 1H, H-2'), 4.36 (t, 1H, 4'-OH J4',OH = 5.35 Hz, D2O exchangeable), 4.49 (d, 1H, 3'-OH, J3',OH = 6.90 Hz, D2O exchangeable), 4.61 (d, 1H, 2'-OH, J2',OH = 5.35 Hz, D2O exchangeable), 4.77 (d, 1H, H-1',J1',2' = 6.10 Hz), 5.18 (d, 1H, 1'-OH, J1',OH = 6.90 Hz, D2O exchangeable), 6.80 (s, 1H, CH(furan)), 7.92 (d, 2H, Ar-H(b), J = 7.65 Hz), 8.26 (d, 2H, Ar-H(a), J = 8.45 Hz), 8.46 (s, 1H, CH=N), 11.67 (s, 1H, NH, D2O exchangeable); MS: m/z (%), 394 (20.12, M++1), 393 (26.33, M+), 375 (16.86), 355 (28.11), 347 (24.85), 307 (28.99), 306 (25.44), 287 (25.74), 271 (16.27), 245 (15.98), 227 (23.08), 221 (28.99), 211 (47.04), 151 (100.00), 143 (20.71), 138 (21.60), 137 (26.63), 123 (52.66), 113 (24.26), 95 (42.31), 94 (42.31), 81 (26.33), 77 (24.26), 76 (19.53), 65 (22.49), 58 (23.96), 53 (37.28); Anal. Calcd for C17H19N3O8: C, 51.91; H, 4.87; N, 10.68%; found: C, 51.95; H, 4.81; N, 10.55%.

N-((4-Acetyl-5-methyl-1H-pyrrol-2-yl)methylene)-5-(1',2',3',4'-tetrahydroxybutyl)-2-methylfuran-3-carbohydrazide (3c). Obtained in 88% yield from carbohydrazide 1 (1.923 mmoL) and 4-acetyl-5-methyl-1H-pyrrole-2-carbaldehyde (1.923 mmoL); recrystallized from ethanol as white crystals; Rf: 0.52 (chloroform–methanol, 5:1, v/v); mp 160–161 °C; IR (KBr): 3409 (OH), 3262 (NH-pyrrole), 3222 (NH-amide), 1642 (2C=O), 1619 (C=N); 1H-NMR (DMSO-d6); δ: 2.28 (s, 3H, CH3(pyrrole)), 2.43 (s, 3H, CH3(furan)), 2.47 (bs, 3H, COCH3 with DMSO), 3.42–3.40 (m, 1H, H-4'b), 3.56–3.50 (m, 3H, H-3', H-2', H-4'a), 4.35 (t, 1H, 4'-OH, J4'-OH = 6.00 Hz, D2O-exchangeable), 4.46 (d, 1H, 3'-OH, J3',OH = 6.00 Hz, D2O-exchangeable), 4.60 (d, 1H, 2'-OH, J2',OH = 6.00 Hz, D2O-exchangeable), 4.75 (d, 1H, H-1', J1',2' = 6.00 Hz), 5.14 (d, 1H, 1'-OH, J1',OH = 6.00 Hz, D2O-exchangeable), 6.74 (s, 1H, CH(furan)), 6.83 (s, 1H, CH(pyrrole)), 8.13 (s, 1H, CH=N), 11.14 (s, 1H, NH(2), D2O exchangeable), 11.94 (s, 1H, NH(1), D2O exchangeable); 13C-NMR (DMSO-d6); δ: 13.88 (CH3-pyrrole and CH3-furan), 28.80 (COCH3), 63.84, 66.56, 71.54 and 73.25 for (C-4', C-3', C-2' and C-1'), 105.90, 115.35, 115.80, 122.17, 125.93, 139, 139.5, 155.10 and 155.89 for (pyrrole and furan carbons and CH=N), 159.86 (CO-NH), 193.86 (COCH3); MS: m/z (%), 395 (53.39, M++2), 394 (69.49, M++1), 393 (44.07, M+), 361 (57.63), 359 (71.19), 358 (55.93), 357 (59.32), 344 (62.71), 340 (55.93), 323 (64.41), 311 (60.17), 259 (59.32), 254 (57.63), 242 (79.66), 233 (53.39), 228 (72.88), 223 (66.95), 206 (55.08), 195 (71.19), 191 (64.41), 185 (60.17), 180 (64.41), 158 (59.32), 148 (66.10), 123 (66.95), 116 (64.41), 108 (55.93), 106 (68.64), 91 (100.00), 75 (55.93), 63 (60.17); Anal. Calcd for C18H23N3O7: C, 54.96; H, 5.89; N, 10.68%; found: C, 54.91; H, 5.77; N, 10.56%.

N-((4,5,6,7-Tetrahydro-6,6-dimethyl-4-oxo-1H-indol-2-yl)methylene)-5-(1',2',3',4'-tetrahydroxybutyl)-2-methylfuran-3-carbohydrazide (3d). Obtained in 90% yield from carbohydrazide 1 (1.923 mmoL) and 4,5,6,7-tetrahydro-6,6-dimethyl-4-oxo-1H-indole-2-carbaldehyde (1.923 mmoL); recrystallized from ethanol as white crystals; Rf: 0.7 (chloroform–methanol, 4:1, v/v); mp 194–195 °C; IR (KBr): 3345 (OH), 3257 (NH- indole), 3158 (NH-amide), 1656 (2C=O), 1618 (C=N); 1H-NMR (DMSO-d6); δ: 0.99 (s, 6H, 2CH3(indole)), 2.20 (s, 2H, CH2(indole)), 2.47 (s, 3H, CH3(furan) with DMSO), 2.67 (s, 2H, CH2(indole)), 3.38–3.43 (m, 1H, H-4'b), 3.49–3.56 (m, 3H, H-3', H-2', H-4'a), 4.31 (t, 1H, 4'-OH, J4',OH = 6.00 Hz, D2O-exchangeable), 4.43 (d, 1H, 3'-OH, J3',OH = 6.00 Hz, D2O-exchangeable), 4.56 (d, 1H, 2'-OH, J2',OH = 6.00 Hz, D2O-exchangeable), 4.75 (d, 1H, H-1', J1',2' = 6.00 Hz), 5.10 (d, 1H, 1'-OH, J1',OH = 9.00 Hz, D2O-exchangeable), 6.60 (s, 1H, CH(furan)), 6.74 (s, 1H, CH(indole)), 8.17 (s, 1H, CH=N), 11.15 (s, 1H, NH(2), D2O exchangeable), 11.90 (s, 1H, NH(1), D2O exchangeable); MS: m/z (%), 434 (19.10, M++1), 433 (73.03, M+), 432 (73.03), 378 (69.66), 359 (88.76), 348 (76.40), 343 (83.15), 329 (70.79), 301 (70.79), 296 (73.03), 278 (73.03), 276 (70.79), 275 (79.78), 274 (73.03), 255 (94.38), 250 (69.66), 244 (91.01), 215 (70.79), 214 (76.40), 205 (69.66), 199 (74.16), 195 (79.78), 191 (83.15), 189 (69.66), 185 (73.03), 180 (70.79), 175 (83.15), 174 (70.79), 165 (79.78), 152 (67.42), 144 (78.65), 122 (70.79), 116 (70.79), 112 (70.79), 89 (78.65), 75 (61.80), 65 (80.90), 52 (100.00); Anal. Calcd for C21H27N3O7: C, 58.19; H, 6.28; N, 9.69%; found: C, 58.14; H, 6.10; N, 9.70%.

5-(1',2',3',4'-Tetrahydroxybutyl)-2-methyl-N-(2-oxoindolin-3-ylidene)furan-3-carbohydrazide (3e). Obtained in 100% yield from carbohydrazide 1 (1.923 mmoL) and isatin (1.923 mmoL); recrystallized from ethanol as yellow needles; mp 206–207 °C; Rf: 0.61 (chloroform–methanol; 5:1; v/v); IR (KBr) cm−1: 3402 (OH), 3250 (2NH), 1675 (2CO), 1620 (C=N); 1H-NMR (DMSO-d6); δ: 2.55 (s, 3H, CH3(furan)), 3.39–3.42 (m, 1H, H-4'b), 3.51–56 (m, 3H, H-3', H-2', H-4'a), 4.32 (t, 1H, 4'-OH, J4',OH = 3.00 Hz, D2O-exchangeable), 4.53 (d, 1H, 3'-OH, J3',OH = 6.00 Hz, D2O-exchangeable), 4.58 (d, 1H, 2'-OH, J2',OH = 3.00 Hz, D2O-exchangeable), 4.79 (d, 1H, H-1', J1',2' = 6.00 Hz), 5.20 (d, 1H, 1'-OH, J1',OH = 6.00 Hz, D2O-exchangeable), 6.52 (s, 1H, CH(furan)), 6.93 (d, 1H, Ar-H(d), J = 9.00 Hz), 7.07 (t, 1H, Ar-H(c), J = 9.00 Hz), 7.35 (t, 1H, Ar-H(b), J = 9.00 Hz), 7.55 (d, 1H, Ar-H(a), J = 9.00 Hz), 11.25 (bs, 1H, NH(2), D2O-exchangeable), 13.40 (bs, 1H, NH(1), D2O-exchangeable); MS: m/z (%), 391 (11.64, M++2), 390 (13.87, M++1), 389 (11.13, M+), 379 (11.99), 374 (12.16), 333 (11.13), 314 (12.55), 302 (12.50), 283 (12.16), 269 (12.67), 268 (12.50), 263 (15.24), 252 (13.53), 236 (13.87), 229 (12.16), 221 (13.53), 196 (13.36), 194 (13.53), 154 (13.36), 149 (16.27), 137 (17.64), 125 (14.73), 124 (18.15), 123 (13.36), 119 (13.87), 115 (14.73), 113 (13.01), 112 (17.12), 111 (23.46), 110 (12.16), 109 (21.58), 107 (13.01), 103 (11.99), 101 (15.75), 100 (12.67), 99 (12.16), 98 (12.67), 97 (38.01), 96 (29.79), 95 (32.19), 94 (15.75), 85 (29.79), 84 (35.79), 83 (44.86), 82 (22.60), 81 (36.64), 79 (20.89), 73 (20.89), 71 (45.03), 70 (32.53), 69 (82.53), 68 (23.97), 67 (38.70), 66 (13.87), 60 (19.52), 57 (100.00), 56 (37.67), 55 (88.01), 54 (24.32); Anal. Calcd for C18H19N3O7: C, 55.53; H, 4.92; N, 10.79%; found: C, 55.42; H, 5.00; N, 10.88%.

3.2.3. 5-Formyl-2-methyl-N-(2-oxoindolin-3-ylidene)furan3-carbohydrazide (4)

A solution of compound 3e (3.856 mmol) in distilled water (20 mL) was treated dropwise with a solution of sodium metaperiodate (11.568 mmol) in distilled water (20 mL) under continuous stirring for 3 h, and the formyl derivative that separated out was filtered off, washed with water, and dried. Yield 92%; recrystallized from ethanol as yellow crystals; mp 280 °C; Rf: 0.44 (chloroform–methanol; 30:1; v/v); IR (KBr) cm−1: 3158 (2NH), 1689 (CHO), 1665 (2CO), 1623 (C=N); 1H-NMR (DMSO-d6); δ: 2.67 (s, 3H, CH3(furan)), 6.93 (d, 1H, Ar-H(d), J = 9.00 Hz), 7.07 (t, 1H, Ar-H(c), J = 9.00 Hz), 7.36 (t, 1H, Ar-H(b), J = 9.00 Hz), 7.58 (d, 1H, Ar-H(a), J = 9.00 Hz), 7.78 (bs, 1H, CH(furan)), 9.60 (s, 1H, CHO), 11.34 (bs, 1H, NH(2), D2O exchangeable), 13.48 (bs, 1H, NH(1), D2O exchangeable); MS: m/z (%), 299 (0.83, M++2), 298 (4.73, M++1), 297 (22.54, M+), 269 (7.98), 161 (6.47), 160 (56.39), 159 (11.55), 138 (9.53), 137 (100.00), 136 (6.51), 133 (5.46), 132 (34.79), 104 (19.95), 103 (7.02), 95 (27.88), 90 (5.27), 80 (25.66), 79 (5.02), 78 (6.35), 77 (26.54), 76 (12.05), 64 (26.21), 52 (17.43), 51 (28.02), 50 (13.37); Anal. Calcd for C15H11N3O4: C, 60.61; H, 3.73; N, 14.14%; found: C, 60.55; H, 3.78; N, 14.00%.

3.2.4. General Method for the Synthesis of the Acetylated Acyclic Aromatic C-Nucleosides 5 and 6

A solution of 1',2',3',4'-tetrahydroxybutyl derivatives 3b and 3e (2.544 mmoL) in dry pyridine (10 mL) was treated with acetic anhydride (10 mL), and the mixture was kept at room temperature for 5–12 h with occasional shaking. Then it was poured onto crushed ice, the acetyl derivative that separated out, was filtered off, washed with water and dried.

N-(4-Nitrobenzylidene)-5-(1',2',3',4'-tetraacetoxybutyl)-2-methylfuran-3-carbohydrazide (5). Obtained in 95% yield from compound 3b (2.544 mmoL); recrystallized from methanol as yellow crystals; Rf: 0.67 (n-hexane–ethyl acetate, 1:1, v/v); mp 158–159 °C; IR (KBr): 3286 (NH), 1741 (OAc), 1648 (CO-amide), 1580 (C=N); 1H-NMR (CDCl3); δ: 1.95, 2.03 and 2.04 (3s, 12H, 4OAc), 2.51 (s, 3H, CH3(furan)), 4.08–4.12 (dd, 1H, H-4'b, J3',4'b = 5.35 Hz, J4'b,4'a = 12.20 Hz), 4.18 (d, 1H, H-4'a, J4'b,4'a = 11.50 Hz), 5.05–5.06 (m, 1H, H-3'), 5.44 (bs, 1H, H-2'), 5.99 (d, 1H, H-1', J1',2' = 4.6 Hz), 6.98 (s, 1H, CH(furan)), 7.93 (d, 2H, Ar-H(b), J = 7.65 Hz), 8.26 (d, 2H, Ar-H(a), J = 7.65 Hz), 8.43 (s, 1H, CH=N), 11.69 (s, 1H, NH, D2O exchangeable); MS: m/z (%), 562 (10.89, M++1), 561 (15.45, M+), 546 (16.04), 520 (20.79), 515 (14.46), 489 (10.30), 439 (11.88), 417 (15.64), 397 (11.88), 385 (18.61), 345 (10.89), 324 (11.88), 273 (10.30), 265 (20.99), 252 (10.89), 227 (10.69), 180 (10.69), 109 (17.62), 108 (15.45), 94 (15.64), 81 (46.73), 80 (18.22), 72 (17.62), 69 (100.00), 66 (10.69), 65 (11.49), 57 (54.65), 55 (49.50); Anal. Calcd for C25H27N3O12: C, 53.48; H, 4.85; N, 7.48%; found: C, 53.40; H, 4.71; N, 7.50%.

5-(1',2',3',4'-Tetraacetoxybutyl)-2-methyl-N-(N'-acetyl-2-oxoindolin-3-ylidene)furan-3-carbohydrazide (6). Obtained in 100% yield from compound 3e; recrystallized from ethanol as yellow needles; mp 154–155 °C; Rf: 0.54 (n-hexane–ethyl acetate; 5:1; v/v); IR (KBr) cm−1: 3283 (NH), 1748 (OAc), 1712 (2CO & NAc), 1608 (C=N); 1H-NMR (CDCl3); δ: 2.03, 2.05, 2.10 (3s, 12H, 4OAc), 2.65 (s, 3H, CH3(furan)), 2.73 (s, 3H, N-Ac), 4.10–4.16 (dd, 1H, H-4'b, J4'a,4'b = 12.00 Hz, J4'b,3' = 3.00 Hz), 4.23–4.28 (dd, 1H, H-4'a, J4'a,4'b = 12.00 Hz, J4'a,3' = 3.00 Hz), 5.16–5.21 (m, 1H, H-3'), 5.60–5.64 (dd, 1H, H-2', J1',2' = 3.00 Hz, J2',3' = 6.00 Hz), 6.08 (d, 1H, H-1', J1',2' = 3.00 Hz), 6.70 (s, 1H, CH(furan)), 7.27 (t, 1H, Ar-H(d), J = 9.00 Hz), 7.42 (t, 1H, Ar-H(c), J = 9.00 Hz), 7.82 (d, 1H, Ar-H(b), J = 9.00 Hz), 8.23 (d, 1H, Ar-H(a), J = 9.00 Hz), 13.01 (bs, 1H, NH, D2O exchangeable); MS: m/z (%), 601 (16.75, M++2), 600 (14.35, M++1), 599 (18.90, M+),567 (22.73), 562 (22.49), 556 (14.35), 540 (17.70), 525 (22.49), 518 (21.53), 513 (13.88), 511 (21.29), 490 (18.66), 469 (18.66), 454 (17.70), 452 (23.92), 439 (23.21), 403 (20.10), 397 (52.63), 381 (14.83), 353 (26.56), 340 (26.56), 335 (19.38), 302 (27.27), 272 (21.29), 234 (25.84), 202 (30.14), 193 (92.82), 175 (38.52), 166 (21.53), 151 (32.30), 137 (100.00), 124 (26.56), 115 (28.23), 110 (39.23), 95 (33.97), 77 (42.34), 55 (28.47), 53 (15.55); Anal. Calcd for C28H29N3O12: C, 56.09; H, 4.88; N, 7.01%; found: C, 56.03; H, 4.92; N, 6.89%.

1'-[(5-Methyl-4-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)furan-2-yl)]butane-1',2',3',4'-tetrayl tetraacetate (7). A solution of compound 5 (5.523 mmol) in dry ether (75 mL) was stirred with yellow mercuric oxide (4.80 g), magnesium oxide (0.48 g), and iodine (4.00 g) at room temperature for 48 h under anhydrous conditions. The reaction mixture was filtered off, and the filtrate washed with potassium iodide solution, sodium thiosulphate, and water respectively, and dried over anhydrous sodium sulphate. On evaporation of the dried filtrate, a yellow crystalline mass was obtained. An additional crop was obtained by extracting the inorganic residue with chloroform which upon concentration yielded the same product. Yield (50%); recrystallized from methanol as yellow crystals; Rf: 0.74 (n-hexane–ethyl acetate; 2:1; v/v); mp 147–148 °C; IR (KBr) cm−1: 1750 (OAc), 1635 (C=N); 1H-NMR (CDCl3); δ: 1.96, 1.97, 2.05, 2.06 (4s, 12H, 4OAc), 2.65 (s, 3H, CH3(furan)), 4.11–4.14 (dd, 1H, H-4'b, J4'a,4'b = 12.20 Hz, J4'b,3' = 5.35 Hz), 4.20–4.23 (dd, 1H, H-4'a, J4'a,4'b = 12.20 Hz, J4'a,3' = 3.05 Hz), 5.08–5.11 (m, 1H, H-3'), 5.46–5.49 (dd, 1H, H-2', J1',2' = 5.35 Hz, J2',3' = 6.90 Hz), 6.05 (d, 1H, H-1', J1',2' = 4.60 Hz), 7.03 (s, 1H, CH(furan)), 8.29 (d, 2H, Ar-H(b), J = 8.45 Hz), 8.40 (d, 2H, Ar-H(a), J = 9.15 Hz); MS: m/z (%), 561 (13.74, M++2), 560 (23.92, M++1), 559 (18.83), 549 (19.34), 528 (21.88), 471 (20.10), 462 (20.61), 457 (29.52), 378 (20.87), 368 (19.34), 301 (25.45), 289 (20.10), 270 (24.68), 250 (24.94), 209 (21.88), 185 (21.37), 183 (21.88), 138 (21.37), 119 (21.37), 82 (23.41), 75 (19.85), 64 (23.41), 63 (17.81), 60 (100.00), 55 (23.92), 57 (22.14); Anal. Calcd for C25H25N3O12: C, 53.67; H, 4.50; N, 7.51%; found: C, 53.71; H, 4.44; N, 7.44%.

1'-[(5-Methyl-4-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)furan-2-yl)]butane-1',2',3',4'-tetraol (8). A solution of compound 7 (0.894 mmoL) was heated with hydrazine hydrate (10 mL) in methanol (10 mL) under reflux for 1 h. The 1',2',3',4'-tetraol 8 that separated out was filtered off, washed with methanol and dried. Yield 97%; recrystallized from ethanol as pale yellow crystals; mp 147 °C; Rf: 0.62 (chloroform–methanol; 5:1; v/v); IR (KBr) cm−1: 3307 (OH), 1646 (C=N); 1H-NMR (DMSO-d6); δ: 2.64 (s, 3H, CH3(furan)), 3.39–3.43 (m, 1H, H-4'b), 3.47–3.52 (m, 1H, H-3'), 3.54–3.56 (m, 1H, H-2'), 3.57–3.61 (m, 1H, H-4'a), 4.37 (t, 1H, 4'-OH, J4',OH = 6.10 Hz, D2O-exchangeable), 4.62 (d, 1H, 3'-OH, J3',OH = 6.90 Hz, D2O-exchangeable), 4.66 (d, 1H, 2'-OH, J2',OH = 5.35 Hz, D2O-exchangeable), 4.81 (d, 1H, H-1', J1',2' = 6.85 Hz), 5.23 (d, 1H, 1'-OH, J1',OH = 7.65 Hz, D2O-exchangeable), 6.73 (s, 1H, CH(furan)), 8.27 (d, 2H, Ar-H(b), J = 8.40 Hz), 8.39 (d, 2H, Ar-H(a), J = 8.40 Hz); MS: m/z (%), 393 (28.16, M++2), 392 (30.58, M++1), 391 (37.86, M+), 356 (43.20), 307 (48.54), 300 (100.00), 295 (39.81), 284 (49.51), 279 (44.66), 237 (40.78), 236 (41.75), 228 (40.78), 222 (42.23), 154 (57.77), 147 (43.69), 144 (45.63), 139 (30.58), 137 (75.73), 127 (38.35), 120 (39.32), 104 (67.96), 95 (46.12), 90 (49.51), 79 (43.69), 76 (94.17), 75 (61.65), 57 (48.54), 56 (93.69), 50 (60.19); Anal. Calcd for C17H17N3O8: C, 52.18; H, 4.38; N, 10.74%; found: C, 52.24; H, 4.17; N, 10.76%.

Tetrahydro-1'-[(5-methyl-4-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)furan-2-yl)]-furan-2',3'-diol (9). A solution of compound 8 (0.767 mmoL) was heated with aqueous acetic acid (150 mL, 10%) under reflux for 8 h After cooling the 2',3'-diol 9 that separated out was filtered off, washed with water and dried. Yield 63%; recrystallized from ethanol as a yellow powder; mp 199–200 °C; Rf: 0.88 (chloroform–methanol; 5:1; v/v); IR (KBr) cm−1: 3372 (OH), 1637 (C=N); 1H-NMR (DMSO-d6); δ: 2.66 (s, 3H, CH3(furan)), 3.62–3.64 (dd, 1H, H-4'b, J4'b,3' = 2.30 Hz, J4'b,4'a = 9.15 Hz), 4.02–4.05 (dd, 1H, H-4'a, J3',4'a = 4.55 Hz, J4'b,4'a = 9.20 Hz), 4.10–4.17 (m, 2H, H-3', H-2'), 4.54 (d, 1H, H-1', J1',2' = 7.60 Hz), 5.03 (d, 1H, 3'-OH, J3',OH = 3.85 Hz, D2O-exchangeable), 5.16 (d, 1H, 2'-OH, J2',OH = 6.1 Hz, D2O-exchangeable), 6.93 (s, 1H, CH(furan)), 8.28 (d, 2H, Ar-H(b), J = 8.40 Hz), 8.39 (d, 2H, Ar-H(a),J = 9.20 Hz); MS: m/z (%), 374 (41.04, M++1), 373 (42.54, M+), 328 (48.51), 327 (52.99), 284 (64.93), 257 (79.10), 254 (54.48), 247 (56.72), 238 (67.16), 211 (52.99), 208 (50.75), 206 (50.75), 170 (66.42), 165 (54.48), 154 (52.99), 148 (62.69), 127 (72.39), 109 (52.24), 104 (73.13), 103 (58.96), 77 (56.72), 76 (100.00), 75 (58.96), 65 (92.54), 64 (60.45), 56 (62.69), 50 (47.01); Anal. Calcd for C17H15N3O7: C, 54.69; H, 4.05; N, 11.26%; found: C, 54.70; H, 4.00; N, 11.21%.

4-(9b-Acetyl-5,9b-dihydro-5-oxo-[1,3,4]oxadiazolo[2,3-a]isoindol-2-yl)-5-methylfuran-2-yl acetate (10b). A solution of compound 3a (0.765 mmoL) was boiled with acetic anhydride (4 mL) in the presence of anhydrous sodium acetate (0.25 g) for 7 h. The acetyl derivative that separated was filtered off and dried. Yield 59%; recrystallized from methanol as colourless crystals; Rf: 0.47 (n-hexane-ethyl acetate, 4:1, v/v); mp 168–169 °C; IR (KBr) cm−1: 1744 (OAc), 1725 (COCH3), 1712 (CO-isoindolone), 1618 (C=N); 1H-NMR (CDCl3); δ: 2.14 (s, 3H, OAc), 2.27 (s, 3H, COCH3), 2.56 (s, 3H, CH3(furan)), 7.00 (s, 1H, CH(furan)), 7.53 (d, 1H, Ar-H(d), J = 7.65 Hz), 7.56 (t, 1H, Ar-H(c), J = 7.65 Hz), 7.65 (t, 1H, Ar-H(b), J = 7.65 Hz), 7.84 (d, 1H, Ar-H(a), J = 7.65 Hz); MS: m/z (%), 356 (2.50, M++2), 355 (2.33, M++1), 354 (3.54, M+), 248 (9.62), 189 (15.92), 188 (31.58), 148 (10.09), 147 (23.86), 146 (100.00), 133 (29.25), 118 (10.27), 105 (24.07), 104 (10.66), 89 (33.82), 77 (24.16), 76 (16.31), 63 (12.12), 60 (9.15), 51 (13.03); Anal. Calcd for C18H14N2O6: C, 61.02; H, 3.98; N, 7.91%; found: C, 61.00; H, 4.00; N, 7.99%.

3.2.5. General Procedures for the Preparation of the Aromatic C-Nucleosides 1214

Method A. A solution of compounds 3b and 3e (2.544 mmoL) was heated with aqueous acetic acid (150 mL, 10%) under reflux for 5 h. After cooling the 3-carbohydrazones 12, 13 that separated out were filtered off, washed with water and dried.

Method B. A solution of 5-(2',3'-dihydroxytetrahydrofuran-1'-yl)-2-methylfuran-3-carbohydrazide (11) [4] in ethanol containing a few drops of acetic acid was treated with carbonyl compound, and the reaction mixture was refluxed on water bath for 30 min. After cooling the 3-carbohydrazones 1214 that separated out were filtered off, washed with a little ethanol, and dried.

N-(4-Nitrobenzylidene)-5-(tetrahydro-2',3'-dihydroxyfuran-1'-yl)-2-methylfuran-3-carbohydrazide (12). Obtained in 90% yield from 11 (0.413 mmol) and 4-nitrobenzaldehyde (0.413 mmol); recrystallized from ethanol as yellow needles; mp 239–240 °C; Rf: 0.69 (chloroform–methanol; 5:1; v/v); IR(KBr) cm−1: 3292–3245 (OH, NH), 1660 (CO-amide), 1614 (C=N); 1H-NMR (DMSO-d6); δ: 2.52 (s, 3H, CH3(furan)), 3.61–3.63 (dd, 1H, H-4'b, J3',4'b = 2.30 Hz, J4'b,4'a = 9.20 Hz), 4.01–4.04 (dd, 1H, H-4'a, J3',4'a = 4.60 Hz, J4'b,4'a = 9.20 Hz), 4.06–4.11(m, 2H, H-3', H-2'), 4.49 (d, 1H, H-1', J1',2' = 6.85 Hz), 5.02 (d, 1H, 3'-OH, J2',OH = 3.80 Hz, D2O-exchangeable), 5.12 (d, 1H, 2'-OH, J1',OH = 6.10 Hz, D2O-exchangeable), 6.88 (s, 1H, CH(furan)), 7.93 (d, 2H, Ar-H(b), J = 8.45 Hz), 8.26 (d, 2H, Ar-H(a), J = 8.45 Hz Hz), 8.44 (s, 1H, CH=N), 11.67 (s, 1H, NH, D2O-exchangeable); MS: m/z (%), 376 (4.69, M++1), 375 (11.01, M+), 317 (7.58), 212 (12.18), 211 (100.00), 153 (7.94), 151 (51.35), 137 (12.55), 123 (16.52), 115 (9.03), 105 (8.30), 95 (11.10), 81 (13.63), 79 (14.53), 77 (4.15), 70 (9.75), 63 (8.03), 61 (12.36), 55 (12.82), 53 (10.29), 52 (11.82); Anal. Calcd for C17H17N3O7: C, 54.40; H, 4.57; N, 11.20%; found: C, 54.50; H, 4.60; N, 11.11%.

5-(Tetrahydro-2',3'-dihydroxyfuran-1'-yl)-2-methyl-N-(2-oxoindolin-3-ylidene)furan-3-carbohydrazide (13). Obtained in 91% yield from 11 (0.413 mmol) and isatin (0.413 mmol); recrystallized from ethanol as yellow needles; mp 263–264 °C; Rf: 0.69 (chloroform–methanol; 5:1; v/v); IR (KBr) cm−1: 3420 (OH), 3166 (2NH), 1703 (CO-oxoindoline), 1673 (CO-amide), 1619 (C=N); 1H-NMR (DMSO-d6); δ: 2.57 (s, 3H, CH3(furan)), 3.62 (d, 2H, H-4'b, J4'b,4'a = 9.00 Hz), 4.01–4.06 (dd, 1H, H-4'a, J3',4'a = 6.00 Hz, J4'b,4'a = 9.00 Hz), 4.10 (bs, 2H, H-3', H-2'), 4.53 (d, 1H, H-1', J1',2' = 9.00 Hz), 4.94 (bs, 1H, 3'-OH, D2O-exchangeable), 5.09 (bs, 1H, 2'-OH, D2O-exchangeable), 6.64 (s, 1H, CH(furan)), 6.93 (d, 1H, Ar-H(d), J = 9.00 Hz), 7.07 (t, 1H, Ar-H(c), J = 9.00 Hz), 7.35 (t, 1H, Ar-H(b), J = 9.00 Hz), 7.55 (d, 1H, Ar-H(a), J = 9.00 Hz), 11.25 (bs, 1H, NH(2), D2O-exchangeable), 13.35 (bs, 1H, NH(1), D2O-exchangeable); MS: m/z (%), 372 (33.14, M++1), 371 (44.57, M+), 340 (37.14), 335 (37.14), 294 (40.00), 286 (49.14), 276 (40.00), 268 (37.14), 187 (40.57), 167 (44.57), 141 (40.57), 138 (40.00), 135 (49.71), 126 (43.43), 125 (44.57), 94 (100.00), 88 (46.86), 87 (49.71), 85 (46.86), 83 (55.43), 81 (62.86), 80 (77.14), 79 (48.00), 77 (45.14), 73 (66.29), 72 (42.29), 71 (60.00), 69 (85.71), 64 (69.14), 61 (43.43), 60 (65.14), 57 (82.86), 55 (72.57); Anal. Calcd for C18H17N3O6: C, 58.22; H, 4.61; N, 11.32%; found: C, 58.15; H, 4.65; N, 11.44%.

5-(Tetrahydro-2',3'-dihydroxyfuran-1'-yl)-N-2,3,4,5,6-pentahydroxyhexylidene)-2-methylfuran-3-carbohydrazide (14). Obtained in 93% yield from 11 (0.413 mmol) and d-galactose (0.826 mmol); recrystallized from ethanol as pale yellow syrup; Rf: 0.44 (chloroform–methanol, 1:1, v/v); IR (KBr) cm−1: 3380–3150 (OH, NH), 1648 (CO), 1612 (C=N); MS: m/z (%), 406 (18.88, M++2), 405 (23.08, M++1), 404 (19.93, M+), 395 (24.83), 363 (26.57), 362 (25.87), 354 (23.78), 313 (25.52), 305 (24.48), 294 (23.78), 282 (24.48), 262 (28.67), 250 (26.57), 236 (24.48), 235 (28.67), 228 (28.67), 225 (23.78), 219 (28.67), 209 (24.83), 208 (30.07), 205 (25.87), 175 (25.52), 173 (25.52), 158 (24.83), 157 (26.57), 122 (27.62), 107 (28.67), 73 (100.00), 71 (39.16), 61 (40.91), 60 (81.82), 56 (26.57), 52 (26.57).

3.2.6. General Procedure for the Acetylation of the Aromatic C-Nucleosides 12 and 13

A solution of 2',3'-dihydroxyfurans 12 and 13 (0.809 mmoL) in dry pyridine (15 mL) was treated with acetic anhydride (15 mL) and the mixture was kept overnight with occasional shaking at room temperature. Then it was poured onto crushed ice, the acetyl derivatives 15 and 16 that separated out were filtered off, washed with water and dried.

N-(4-Nitrobenzylidene)-5-(tetrahydro-2',3'-diacetoxyfuran-1'-yl)-2-methylfuran-3-carbohydrazide (15). Obtained in 79% yield from 12 (0.809 mmoL); recrystallized from ethanol as yellow crystals; mp 173–174 °C; Rf: 0.61 (n-hexane–ethyl acetate; 1:1; v/v); IR (KBr) cm−1: 3235 (NH), 1753 (OAc), 1654 (CO), 1600 (C=N); 1H-NMR (CDCl3); δ: 2.00, 2.06 (2s, 6H, 2OAc), 2.52 (s, 3H, CH3(furan)), 3.81–3.84 (dd, 1H, H-4'b, J4'a,4'b = 10.70 Hz, J4'b,3' = 2.30 Hz), 4.25–4.29 (dd, 1H, H-4'a, J4'a,4'b = 10.70 Hz, J4'a,3' = 5.35 Hz), 4.88 (d, 1H, H-3', J2',3' = 6.10 Hz), 5.34–5.37 (m, 1H, H-2'), 5.40–5.42 (m, 1H, H-1'), 6.98 (s, 1H, CH(furan)), 7.93 (d, 2H, Ar-H(b), J = 6.85 Hz), 8.26 (d, 2H, Ar-H(a), J = 7.65 Hz), 8.43 (s, 1H, CH=N), 11.72 (s, 1H, NH, D2O exchangeable); MS: m/z (%), 460 (12.29, M++1), 459 (16.74, M+), 400 (28.39), 380 (24.15), 340 (74.79), 323 (19.49), 296 (25.21), 295 (100.00), 265 (19.92), 260 (15.47), 258 (17.16), 235 (19.92), 193 (26.91), 192 (25.21), 175 (35.17), 151 (44.28), 150 (26.69), 147 (24.58), 138 (25.00), 137 (54.03), 123 (28.39), 115 (79.87), 105 (27.54), 95 (40.89), 91 (26.27), 85 (25.64), 27 (23.31), 76 (23.52), 63 (25.64), 55 (27.54), 52 (28.39); Anal. Calcd for C21H21N3O9: C, 54.90; H, 4.61; N, 9.15%; found: C, 54.79; H, 4.69; N, 9.24%.

5-(Tetrahydro-2',3'-diacetoxyfuran-1'-yl)-2-methyl-N-(N'-acetyl-2-oxoindolin-3-ylidene)furan-3-carbohydrazide (16). Obtained in 67% yield from 13 (0.809 mmoL); recrystallized from ethanol as yellow crystals; mp 162–163 °C; Rf: 0.51 (n-hexane–ethyl acetate; 5:1; v/v); IR (KBr) cm−1: 3273 (NH), 1745 (OAc), 1708 (3CO), 1603 (C=N); 1H-NMR (CDCl3); δ: 2.06, 2.11 (2s, 6H, 2OAc), 2.67 (s, 3H, CH3(furan)), 2.73 (s, 3H, N-Ac), 3.93–3.98 (dd, 1H, H-4'b, J4'a,4'b = 12.00 Hz, J4'b,3' = 3.00 Hz), 4.36–4.41 (dd, 1H, H-4'a, J4'a,4'b = 12.00 Hz, J4'a,3' = 3.00 Hz), 4.93 (d, 1H, H-3', J2',3' = 6.00 Hz), 5.48–5.55 (m, 2H, H-2', H-1'), 6.74 (bs, 1H, CH(furan)), 7.27 (t, 1H, Ar-H(d), J = 9.00 Hz), 7.42 (t, 1H, Ar-H(c), J = 9.00 Hz), 7.82 (d, 1H, Ar-H(b), J = 6.00 Hz), 8.23 (d, 1H, Ar-H(a), J = 9.00 Hz), 13.03 (bs, 1H, NH, D2O exchangeable); MS: m/z (%), 499 (5.52, M++2), 498 (7.88, M++1), 496 (4.73, M+-1), 434 (8.23), 379 (11.03), 378 (31.35), 296 (21.54), 295 (100.00), 235 (10.16), 193 (13.66), 192 (10.42), 175 (18.83), 151 (13.84), 149 (13.40), 148 (11.30), 147 (14.19), 137 (34.68), 121 (16.20), 115 (40.72), 109 (13.84), 105 (17.86), 104 (17.43), 95 (34.85), 80 (14.89), 79 (15.06), 77 (23.64), 76 (11.56), 55 (13.22), 52 (12.00), 51 (14.36); Anal. Calcd for C24H23N3O9: C, 57.95; H, 4.66; N, 8.45%; found: C, 57.88; H, 4.52; N, 8.50%.

5-(Tetrahydroj-2,2-dimethylfuro[2',3'-d][1,3]dioxol-1'-yl)-2-methyl-N-(2-oxoindolin-3-ylid-ene)furan-3-carbohydrazide (17). Compound 13 (0.485 mmol) was treated with FeCl3 (0.035 g) in dry acetone (30 mL). The reaction mixture was heated under reflux for 30 min. After cooling it was poured onto cold water, the separated yellow crystals 17 was filtered off and dried. Yield 88%; recrystallized from ethanol as yellow needles; mp 220 °C; Rf: 0.75 (chloroform–methanol; 20:1; v/v); IR (KBr) cm−1: 3178 (2NH), 1684 (2CO), 1615 (C=N); 1H-NMR (DMSO-d6); δ: 1.26, 1.39 (2s, 6H, CMe2, Δδ = 0.13), 2.54 (s, 3H, CH3(furan)), 3.74–3.69 (dd, 1H, H-4'b, J4'a,4'b = 12.00 Hz, J4'b,3' = 3.00 Hz), 3.87 (d, 1H, H-4'a, J4'a,4'b = 12.00 Hz), 4.88–4.95 (m, 2H, H-3', H-2'), 4.98 (s, 1H, H-1', J1',2' = 0 Hz ), 6.63 (bs, 1H, CH(furan)), 6.92 (d, 1H, Ar-H(d), J = 9.00 Hz), 7.06 (t, 1H, Ar-H(c), J = 9.00 Hz), 7.36 (t, 1H, Ar-H(b), J = 6.00 Hz), 7.53 (d, 1H, Ar-H(a), J = 9.00 Hz), 11.28 (s, 1H, NH(2), D2O exchangeable), 13.35 (bs, 1H, NH(1), D2O exchangeable); MS: m/z (%), 413 (0.88, M++2), 412 (5.26, M++1), 411 (20.24, M+), 383 (9.26), 252 (16.46), 251 (100.00), 160 (24.84), 159 (10.29), 151 (8.40), 137 (23.36), 132 (16.47), 123 (6.97), 121 (12.88), 110 (8.02), 109 (6.21), 105 (6.89), 104 (15.66), 95 (14.58), 80 (10.20), 79 (18.26), 78 (6.11), 77 (22.12), 76 (6.12), 69 (7.01), 65 (6.34), 59 (14.57), 57 (6.78), 55 (12.70), 53 (8.67), 52 (10.78), 51 (11.09); Anal. Calcd for C21H21N3O6: C, 61.31; H, 5.14; N, 10.21%; found: C, 61.26; H, 5.19; N, 10.18%.

(5-(1',2',3',4'-Tetrahydroxybutyl)-2-methylfuran-3-yl)(3,5-dimethyl-1H-pyrazol-1-yl)-methanone (18). A mixture of 3-carbohydrazide 1 (5 mmoL) and acetylacetone (5 mmoL) was heated under reflux in ethanol (10 mL) containing a few drops of acetic acid for 5 h. After cooling the solid 18 that separated was filtered off and dried. Yield 100%; recrystallized from ethanol as colorless needles; mp 142–143 °C; Rf: 0.55 (chloroform–methanol; 5:1; v/v); IR (KBr) cm−1: 3314 (OH), 1689 (CO), 1560 (C=N); 1H-NMR (DMSO-d6); δ: 2.16 (s, 3H, CH3(b-pyrazole)), 2.48 (s, 6H, CH3(furan) and CH3(a-pyrazole)), 3.39–3.43 (m, 1H, H-4'b), 3.47–3.58 (m, 3H, H-3', H-2', H-4'a), 4.30 (bs, 1H, 4'-OH, D2O-exchangeable), 4.48 (d, 1H, 3'-OH, J3',OH = 6.00 Hz, D2O-exchangeable), 4.56 (bs, 1H, 2'-OH, D2O-exchangeable), 4.76 (d, 1H, H-1', J1',2' = 6.00 Hz), 5.11 (d, 1H, 1'-OH, J1',OH = 6.00 Hz, D2O-exchangeable), 6.18 (s, 1H, CH(pyrazole)), 6.90 (s, 1H, CH(furan)); MS: m/z (%), 325 (0.17, M++1), 324 (0.30, M+), 306 (17.49), 234 (9.75), 233 (32.42), 211 (26.86), 210 (75.30), 203 (23.37), 182 (23.85), 151 (6.04), 138 (6.24), 137 (41.72), 123 (6.09), 122 (7.28), 121 (12.20), 110 (13.35), 109 (12.02), 103 (8.55), 97 (100.00), 96 (10.91), 95 (18.16) 81 (11.08), 79 (11.69), 56 (6.59), 55 (9.48), 53 (11.53), 51 (7.48); Anal. Calcd for C15H20N2O6: C, 55.55; H, 6.22; N, 8.64%; found: C, 55.56; H, 6.20; N, 8.59%.

(5-(1',2',3',4'-Tetraacetoxybutyl)-2-methylfuran-3-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (19). A solution of compound 18 (1.543 mmoL) in dry pyridine (15 mL) was treated with acetic anhydride (15 mL) and the mixture was kept overnight with occasional shaking at room temperature. Then it was poured onto crushed ice and the acetyl derivative 19 that separated out was filtered off, washed with water and dried. Yield 68%; recrystallized from ethanol as colorless needles; mp 101–102 °C; Rf: 0.74 (n-hexane–ethyl acetate; 2:1; v/v); IR (KBr) cm−1: 1751 (OAc), 1683 (CO), 1591 (C=N); 1H-NMR (CDCl3); δ: 2.03, 2.04, 2.06, 2.12 (4s, 12H, 4OAc), 2.23 (s, 3H, CH3(pyrazole-b)), 2.54 (s, 3H, CH3(furan)), 2.57 (s, 3H, CH3(pyrazole-a)), 4.09–4.14 (dd, 1H, H-4'b, J4'a,4'b = 12.00 Hz, J4'b,3' = 3.00 Hz), 4.19–4.24 (dd, 1H, H-4'a, J4'a,4'b = 12.00 Hz, J4'a,3' = 3.00 Hz), 5.14–5.19 (m, 1H, H-3'), 5.60–5.64 (dd, 1H, H-2',J1',2' = 3.00 Hz, J2',3' = 6.00 Hz), 5.97 (s, 1H, CH(pyrazole)), 6.08 (d, 1H, H-1', J1',2' = 3.00 Hz), 7.15 (s, 1H, CH(furan)); 13C-NMR (CDCl3); δ: 13.86, 14.47 and 14.58 for (2CH3(pyrazole), CH3(furan)), 20.74, 20.80 (2 lines for 4 OCOCH3), 61.65, 65.70, 68.66 and 69.86 for (C-4', C-3', C-2' and C-1'), 110.97, 113.77, 116.00, 144.72, 145.84, 151.87, 162.89 for (pyrazole and furan carbons), 169.50 (CO-N), 169.70, 169.80, 169.95, 170.60 (4 OCOCH3); MS: m/z (%), 494 (4.19, M++2), 493 (7.52, M++1), 492 (18.80, M+), 433 (9.49), 432 (10.73), 397 (13.56), 396 (27.19), 373 (11.47), 372 (9.25), 336 (27.99), 330 (11.96), 275 (10.91), 235 (16.40), 234 (60.30), 233 (86.68), 203 (33.48), 193 (19.36), 192 (30.83), 180 (09.00), 179 (10.11), 175 (12.08), 151 (10.97), 150 (09.25), 138 (19.79), 137 (75.71), 136 (09.49), 123 (09.12), 122 (10.42), 121 (13.69), 115 (23.06), 110 (19.30), 109 (17.02), 103 (09.99), 98 (10.60), 97 (100.00), 96 (17.32), 95 (25.77), 83 (10.42), 81 (16.83), 80 (10.79), 79 (15.84), 73 (11.59), 71 (11.41), 69 (16.71), 67 (10.23), 61 (10.48), 57 (19.17), 55 (22.32), 54 (09.80), 53 (11.47), 51 (10.30); Anal. Calcd for C23H28N2O10: C, 56.09; H, 5.73; N, 5.69%; found: C, 56.00; H, 5.62; N, 5.77%.

1-(5-(1',2',3',4'-Tetrahydroxybutyl)-2-methylfuran-3-carbo-3-yl)-4-phenyl thiosemicarbazide (20) [24]. A mixture of 5-(1',2',3',4'-tetrahydroxybutyl)-2-methylfuran-3-carbohydrazide 1 (3.846 mmoL) and phenyl isothiocyanate (3.846 mmoL) are heated under reflux in ethanol (10 mL) for 2 h. After cooling the thiosemicarbazide that separated was filtered off, washed with little ethanol, and dried. Yield (100%); recrystallized from ethanol as white crystals; mp 133–134 °C; Rf: 0.35 (chloroform–methanol; 5:1; v/v); IR(KBr) cm−1: 3415–3264 (OH, 3NH), 1659 (CO); 1H-NMR (DMSO-d6); δ: 2.47 (s, 1H, CH3-furan with DMSO), 3.34–3.41 (m, 1H, H-4'b), 3.45–3.48 (m, 1H, H-4'a), 3.50–3.57 (m, 2H, H-3', H-2'), 4.34 (t, 1H, 4'-OH, J4',OH = 6.15 Hz, D2O-exchangeable), 4.42 (d, 1H, 3'-OH, J3',OH = 6.85 Hz, D2O-exchangeable), 4.59 (d, 1H, 2'-OH, J2',OH = 6.15 Hz, D2O-exchangeable), 4.73 (d, 1H, H-1', J1',2' = 7.65 Hz), 5.12 (d, 1H, 1'-OH, J1',OH = 8.40 Hz, D2O-exchangeable), 6.72 (s, 1H, CH (furan)), 7.11 (t, 1H, Ar-H(f), J = 8.40 Hz), 7.28 (t, 2H, Ar-H(e), J = 9.15 Hz), 7.42 (bs, 2H, Ar-H(d)), 9.54 (s, 1H, NH(c), D2O exchangeable), 9.72 (s, 1H, NH(b), D2O exchangeable), 9.97 (s, 1H, NH(a), D2O exchangeable); Anal. Calcd for C17H21N3O6S: C, 51.64; H, 5.35; N, 10.63%; found: C, 51.70; H, 5.20; N, 10.60%.

1'-(5-Methyl-4-(5-(phenylamino)-1,3,4-oxadiazol-2-yl)furan-2-yl)butane-1',2',3',4'-tetraol (21). To a suspension of thiosemicarbazide 20 (5.063 mmol) in ethanol (50 mL), sodium hydroxide solution (4 N, 5 mL) was added with shaking. A solution of iodine and potassium iodide was added dropwise with stirring till the color of iodine persisted. The precipitate 21 was filtered off, washed with sodium thiosulphate solution, then with water, and dried. Yield (95%); recrystallized from ethanol as white crystals; mp 223–224 °C; Rf: 0.71 (chloroform–methanol; 4:1; v/v); IR(KBr) cm−1: 3421–3318 (OH), 3242 (NH), 1673 (C=N); 1H-NMR (DMSO-d6); δ: 2.54 (s, 3H, CH3(furan)), 3.41–3.55 (m, 4H, H-4'b, H-3', H-2', H-4'a,), 4.37 (t, 1H, 4'-OH, J4',OH = 6.00 Hz, D2O-exchangeable), 4.62 (d, 1H, 3'-OH, J3',OH = 9.00 Hz, D2O-exchangeable), 4.65 (d, 1H, 2'-OH, J2',OH = 3.00 Hz, D2O-exchangeable), 4.77 (d, 1H, H-1', J1',2' = 6.00 Hz), 5.19 (d, 1H, 1'-OH, J1',OH = 6.00 Hz, D2O-exchangeable), 6.53 (s, 1H, CH(furan)), 6.96 (t, 1H, Ar-H(c), J = 9.00 Hz), 7.32 (t, 2H, Ar-H(b), J = 9.00 Hz), 7.55 (d, 2H, Ar-H(a), J = 9.00 Hz), 10.50 (s, 1H, NH, D2O-exchangeable); MS: m/z (%), 361 (14.29, M+), 360 (27.07), 359 (18.30), 312 (19.05), 287 (17.04), 283 (26.32), 247 (19.80), 241 (17.04), 229 (177.79), 221 (23.06), 204 (18.55), 181 (17.04), 173 (20.30), 172 (17.54), 167 (17.54), 152 (20.55), 148 (16.54), 141 (21.05), 137 (15.54), 135 (24.56), 120 (21.80), 117 (18.30), 111 (27.57), 110 (19.05), 109 (20.30), 103 (19.80), 99 (21.55), 98 (26.57), 97 (35.84), 96 (31.08), 95 (30.58), 93 (25.56), 85 (34.59), 84 (29.07), 83 (51.13), 82 (24.31), 81 (37.59), 80 (39.60), 77 (26.32), 76 (18.55), 75 (17.79), 73 (29.82), 71 (49.62), 70 (32.58), 69 (67.67), 68 (29.57), 67 (38.60), 64 (28.57), 61 (19.05), 60 (39.60), 57 (100.00), 56 (27.57), 55 (93.98), 54 (30.58), 53 (26.32), 52 (19.80), 51 (23.06); Anal. Calcd for C17H19N3O6: C, 56.51; H, 5.30; N, 11.63%; found: C, 56.47; H, 5.41; N, 11.70%.

1'-[5-Methyl-4-(5-(phenylamino)-1,3,4-oxadiazol-2-yl)furan-2-yl]butane-1',2',3',4'-tetrayl tetraacetate (22). A solution of compound 21 (1.108 mmoL) in dry pyridine (10 mL) was treated with acetic anhydride (10 mL) and the mixture was kept overnight with occasional shaking at room temperature. Then it was poured onto crushed ice, and the acetyl derivative 22 that separated out was filtered off, washed with water and dried. Yield (85%); recrystallized from ethanol as white crystals; mp 180–181 °C; Rf: 0.5 (n-hexane–ethyl acetate; 2:1; v/v); IR(KBr) cm−1: 3136 (NH), 1747 (OAc), 1622 (C=N); 1H-NMR (CDCl3); δ: 2.04, 2.06, 2.08, 2.09 (4s, 12H, 4OAc), 2.60 (s, 3H, CH3(furan)), 4.09–4.15 (dd, 1H, H-4'b, J4'a,4'b = 12.00 Hz, J4'b,3' = 6.00 Hz), 4.22–4.27 (dd, 1H, H-4'a, J4'a,4'b = 12.00 Hz, J4'a,3' = 3.00 Hz), 5.16–5.21 (m, 1H, H-3'), 5.59–5.63 (dd, 1H, H-2', J1',2' = 3.00 Hz, J2',3' = 6.00 Hz), 6.06 (d, 1H, H-1', J1',2' = 3.00 Hz), 6.69 (s, 1H, CH(furan)), 7.07 (t, 1H, Ar-H(i), J = 9.00 Hz), 7.35 (t, 2H, Ar-H(h), J = 9.00 Hz), 7.48 (d, 2H, Ar-H(g), J = 9.00 Hz), 8.01 (bs, 1H, NH, D2O-exchangeable); 13C-NMR (CDCl3); δ: 13.72 (CH3(furan)), 20.72, 20.78, 20.84 (3 lines for 4 COCH3), 61.65 (C-4'), 65.86 (C-3'), 68.61 (C-2'), 69.79 (C-1'), 107.45 (j), 108.99 (i), 117.66 (h), 123.17 (g), 129.48 (f), 137.77 (e), 147.91 (d), 154.14 (c), 154.41 (b), 159.51 (a), 169.43, 169.74, 169.84, 170.62 (4 COCH3); MS: m/z (%), 531 (11.12, M++2), 530 (6.24, M++1), 529 (19.12, M+), 496 (10.05), 476 (8.68), 452 (9.46), 428 (11.12), 388 (8.39), 374 (8.98), 368 (21.56), 367 (34.93), 329 (10.34), 325 (28.88), 312 (11.41), 308 (16.29), 307 (10.73), 297 (8.68), 285 (8.98), 274 (9.17), 271 (17.07), 270 (100.00), 249 (8.68), 232 (8.98), 193 (9.46), 185 (8.98), 181 (8.68), 178 (10.34), 167 (13.37), 129 (8.49), 127 (10.73), 122 (11.90), 120 (12.00), 115 (18.83), 93 (9.46), 92 (18.93), 78 (12.59), 77 (12.49), 66 (9.85), 52 (12.68); Anal. Calcd for C25H27N3O10: C, 56.71; H, 5.14; N, 7.94%; found: C, 56.66; H, 5.14; N, 8.01%.

5-(5-(1',2',3',4'-Tetrahydroxybutyl)-2-methylfuran-3-yl)-4-phenyl-2H-1,2,4-triazole-3(4H)-thione (23). In a round bottom flask thiosemicarbazide 20 (1.823 mmoL) was refluxed with 10% aqueous sodium hydroxide solution (20 mL) for 5 h. The reaction mixture was filtered, cooled, and neutralized by gradual addition of dilute hydrochloric acid; the white precipitate of 23 was filtered off and dried. It was recrystallized from ethanol as white crystals. Yield 83%; mp 217–218 °C; Rf: 0.4 (chloroform–methanol; 5:1; v/v); IR (KBr) cm−1: 3369 (OH, NH), 1624 (C=N); 1H-NMR (DMSO-d6); δ: 2.30 (s, 3H, CH3(furan)), 3.29–3.33 (m, 1H, H-4'b), 3.45–3.47 (m, 3H, H-3', H-2', H-4'a), 4.24–4.29 (m, 2H, 4'-OH, 3'-OH, D2O-exchangeable), 4.45 (bs, 1H, 2'-OH, D2O-exchangeable), 4.55 (d, 1H, H-1', J1',2' = 6.00 Hz), 4.91 (d, 1H, 1'-OH, J1',OH = 6.00 Hz, D2O-exchangeable), 5.48 (s, 1H, CH(furan)), 7.32 (m, 2H, Ar-H(c)), 7.49 (t, 3H, Ar-H(b, a), J = 3.00 Hz), 13.92 (s, 1H, NH, D2O-exchangeable); MS: m/z (%), 379 (5.85, M++2), 378 (10.53, M++1), 377 (22.81, M+), 360 (12.38), 359 (30.12), 298 (8.77), 287 (26.80), 286 (100.00), 285 (30.60), 284 (10.14), 237 (7.60), 211 (7.41), 199 (9.75), 183 (7.70), 170 (7.60), 162 (7.12), 155 (8.19), 144 (8.67), 138 (7.21), 131 (8.38), 128 (8.48), 127 (8.97), 124 (8.67), 118 (9.45), 116 (7.41), 104 (9.26), 95 (9.65), 92 (7.02), 91 (8.87), 77 (31.38), 66 (8.19), 61 (14.52), 60 (7.50); Anal. Calcd for C17H19N3O5S: C, 54.10; H, 5.07; N, 11.13%; found: C, 54.22; H, 5.22; N, 11.00%.

5-(5-(1',2',3',4'-Tetraacetoxybutyl)-2-methylfuran-3-yl)-4-phenyl-2-N-acetyl-1,2,4-triazole-3-(4H)-thione (24). A solution of compound 23 (1.061 mmoL) in dry pyridine (15 mL) was treated with acetic anhydride (15 mL) and the mixture was kept overnight with occasional shaking at room temperature. Then it was poured onto crushed ice, and the acetyl derivative 24 that separated out was filtered off, washed with water and dried. Yield 97%; recrystallized from ethanol as pale yellow needles; mp 168–169 °C; Rf: 0.49 (n-hexane–ethyl acetate; 2:1; v/v); IR (KBr) cm−1: 1747 (OAc, N-Ac), 1622 (C=N); 1H-NMR (CDCl3); δ: 1.97, 1.99, 2.01 (3s, 12H, 4OAc), 2.50 (s, 3H, CH3(furan)), 2.77 (s, 3H, N-Ac), 3.98–4.04 (dd, 1H, H-4'b, J4'a,4'b = 12.00 Hz, J4'b,3' = 6.00 Hz), 4.10–4.16 (dd, 1H, H-4'a, J4'a,4'b = 15.00 Hz, J4'a,3' = 3.00 Hz), 5.03–5.07 (m, 1H, H-3'), 5.39–5.46 (m, 1H, H-2'), 5.48 (s, 1H, CH(furan)), 5.79 (d, 1H, H-1', J1',2' = 3.00 Hz), 7.20–7.30 (m, 2H, Ar-H(c)), 7.53 (t, 3H, Ar-H(b, a), J = 3.00 Hz); MS: m/z (%), 589 (1.52 , M++2), 588 (3.93 , M++1), 587 (10.34, M+), 547 (9.46), 546 (26.15), 545 (79.56), 485 (6.60), 384 (20.24), 383 (57.91), 382 (5.92), 370 (4.92), 342 (12.32), 341 (28.54), 329 (4.49), 328 (15.48), 324 (11.95), 323 (13.76), 299 (8.53), 298 (6.72), 288 (7.01), 287 (21.33), 286 (100.00), 285 (9.11), 284 (5.98), 270 (4.66), 256 (6.60), 115 (10.38), 77 (8.82), 60 (4.34), 51 (2.25); Anal. Calcd for C27H29N3O10S: C, 55.19; H, 4.97; N, 7.15%; found: C, 55.11; H, 4.99; N, 7.00%.

5-(5-(Tetrahydro-2',3'-dihydroxyfuran-1'-yl)-2-methylfuran-3-yl)-4-phenyl-2H-1,2,4-triazole-3-(4H)-thione (25). A solution of compound 23 (1.823 mmoL) was heated with aqueous acetic acid (150 mL, 10%) under reflux for 5 h. After cooling the product 25 that separated out was filtered off, washed with water and dried. Yield 80%; recrystallized from ethanol as off-white needles; mp 217–218 °C; Rf: 0.4 (chloroform–methanol; 5:1; v/v); IR (KBr) cm−1: 3407–3184 (OH, NH), 1625 (C=N); 1H-NMR (DMSO-d6); δ: 2.32 (s, 3H, CH3(furan)), 3.47–3.51 (dd, 1H, H-4'b, J3',4'b = 3.00 Hz, J4'b,4'a = 9.00 Hz), 3.85–3.90 (dd, 2H, H-3', H-4'a, J3',4'a = 6.00 Hz, J4'b,4'a = 9.00 Hz), 3.97(bs, 1H, H-2'), 4.24 (d, 1H, H-1', J1',2' = 9.00 Hz), 4.86 (d, 1H, 3'-OH, J3',OH = 3.00 Hz, D2O-exchangeable), 4.92 (d, 1H, 2'-OH, J2',OH = 6.00 Hz, D2O-exchangeable), 5.53 (s, 1H, CH(furan)), 7.32–7.35 (m, 2H, Ar-H(c)), 7.49 (t, 3H, Ar-H(b, a), J = 3.00 Hz), 13.96 (bs, 1H, NH, D2O-exchangeable); MS: m/z (%), 360 (23.69, M++1), 359 (20.21, M+), 357 (20.21), 341 (20.21, M+-H2O), 326 (20.21, M+-SH), 321 (26.48), 316 (24.74), 314 (24.74), 305 (24.39), 289 (29.97), 255 (20.91, M+-C4H8O3), 225 (26.48), 212 (25.44), 203 (25.78), 167 (25.78), 153 (27.53), 149 (32.06), 141 (27.53), 139 (24.74), 129 (25.78), 118 (24.74), 112 (25.44), 111 (25.44), 97 (30.31), 95 (29.27), 94 (50.52), 93 (27.53), 90 (25.78), 83 (43.21), 81 (33.80), 74 (29.97), 73 (30.31), 71 (56.10), 70 (33.80), 69 (49.48), 67 (24.74), 61 (24.74), 60 (45.99), 57 (100.00), 56 (42.16), 55 (76.66), 54 (24.39), 52 (25.78); Anal. Calcd for C17H17N3O4S: C, 56.81; H, 4.77; N, 11.69%; found: C, 56.77; H, 4.77; N, 11.74%.

4-(4,5-Dihydro-4-phenyl-5-thioxo-1H-1,2,4-triazol-3-yl)-5-methylfuran-2-carbaldehyde (26). A solution of compound 23 (2.122 mmol) in distilled water (20 mL) was treated dropwise with a solution of sodium metaperiodate (6.366 mmol) in distilled water (20 mL) with continuous stirring for 5 h, the formyl derivative 26 that separated out was filtered off, washed with water, and dried. Yield 48%; recrystallized from ethanol as pale yellow needles; mp 237–238 °C; Rf: 0.77 (chloroform–methanol; 20:1; v/v); IR (KBr) cm−1: 3354 (NH), 1681 (CHO), 1600 (C=N); 1H-NMR (DMSO-d6); δ: 2.46 (s, 3H, CH3(furan) with DMSO), 6.65 (d, 1H, CH(furan)), 7.39 (t, 2H, Ar-H(c), J = 3.00 Hz), 7.50–7.57 (m, 3H, Ar-H(b, a)), 9.32 (s, 1H, CHO), 14.17 (s, 1H, NH, D2O exchangeable); MS: m/z (%), 287 (6.12, M++2), 286 (19.64, M++1), 285 (100.00, M+), 284 (33.49), 256 (19.21), 228 (17.85), 212 (6.13), 169 (9.29), 150 (7.92), 149 (16.37), 135 (6.34), 134 (13.27), 118 (6.39), 109 (7.29), 106 (6.53), 93 (6.00), 91 (11.22), 80 (68.01), 79 (9.20), 78 (13.83), 77 (61.00), 76 (7.14), 69 (6.12), 66 (7.25), 65 (13.54), 64 (43.58), 63 (10.89), 55 (5.63), 53 (6.78), 52 (14.86), 51 (47.93), 50 (13.88); Anal. Calcd for C14H11N3O2S: C, 58.93; H, 3.89; N, 14.73%; found: C, 58.90; H, 4.00; N, 14.88%.

3.3. Antioxidant and Anticancer Screening

3.3.1. Materials

Mammalian cell lines: MCF-7 cells (human breast cancer cell line were obtained from VACSERA Tissue Culture Unit (Cairo, Egypt). Chemicals used: Dimethyl sulfoxide (DMSO), crystal violet and trypan blue dye were purchased from Sigma (St. Louis, MO, USA). Fetal bovine serum, Dulbecco’s Modefied Eagle’s Medium (DMEM), RPMI-1640, HEPES buffer solution, L-glutamine, gentamycin and 0.25% trypsin-EDAT were purchased from Lonza (St. Louis, MO, USA). Crystal violet (1%) was made from 0.5% (w/v) crystal violet and 50% methanol, then made up to volume with dd H2O and filtered through a Whatman No. 1 filter paper.

3.3.2. Cell Line Propagation

The cells were propagated in (DMEM) supplemented with 10% heat-inactivated fetal bovine serum, 1% l-glutamine, HEPES buffer and 50 µg/mL gentamycin. All cells were mentained at 37 °C in humidified atmosphere with 5% CO2 and were subcultured two times a week. Cell toxicity was monitored by determining the effect of the examined compound on cell morphology and cell viability.

3.3.3. Cytotoxicity Evaluation Using Viability Assay

For the cytotoxicity assays, cells were seeded in 96-well plate at a cell concentration of 1 × 104 cell per well in 100 μL of growth medium. Fresh medium containing different concentrations of the test sample was added after 24 h of seeding. The microtiter plates were incubated at 37 °C in a humidified incubator with 5% CO2 for a period of 48 h. Three wells were used for each concentration of the tested sample. Control cells were incubated without test sample and with or without DMSO. After incubation of the cells for 24 h at 37 °C, various concentrations of the sample (50.000, 25.000, 12.500, 6.250, 3.125 and 1.560 μg) were added each separately. The incubation was continued for 48 h and viable cells yield was determined colorimetrically using 3,4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTTB). The water insoluble tetrazolium salt is converted to purple formazan by the mitochondrial dehydrogenase of viable cells. After the end of incubation period, media were aspirated and crystal violet solution (1%) was added to each well for at least 30 min. The stain was removed and plates were rinsed using tap water until all excess stain is removed. Glacial acetic acid (30%) was then added to all wells and mixed thoroughly, then the absorbance of the plates were measured after gently shaken on Microplate Reader (Tecan, Inc., city, country), at 490 nm. All results were corrected for background absorbance detected in wells without added stain. Treated sample was compared with the cell control in the absence of the tested compound. All experiments were carried out in the triplicate. The cell cytotoxic effect of the tested compound was calculated [27,28].

4. Conclusions

Some new aromatic C-nucleosides have been prepared from carbohydrate precursors. Their physical and chemical properties were studied, and some of the compounds showed potential antioxidant activities. One of these compounds has been screened for its antitumor activity.

Acknowledgments

We would like to thank chemistry department, Faculty of Science, Alexandria University, Egypt for providing facilities during this research.

Author Contributions

Author contributions are equally in this work.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds are available from the authors.
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