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A convenient new synthesis, characterization and antibacterial activity of double headed acyclo-C-nucleosides from unprotected d-glucose
⁎Corresponding author. adelaliothman@gmail.com (Adil A. Othman)
-
Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
Double headed acyclo-C-nucleosides, 1,4-bis(3-mercapto-1H-1,2,4-triazol-5-yl)butane-1,2,3,4-tetrol (6), 5,5′-(1,2,3,4-tetrahydroxybutane-1,4-diyl)bis(1,3,4-oxadiazole-2(3H)-thione) (7), and 1,4-bis(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)butane-1,2,3,4-tetrol (8) have been synthesized from d-glucose (1) without protecting hydroxyl groups. Two steps synthesis leading to formation of 2,3,4,5-tetrahydroxyhexanedihydrazide (4) which is regarded as starting intermediates for the synthesis of 6,7 and 8. Synthetic intermediates and final products were appropriately characterized by IR, 1H NMR and 13C NMR. The products were tested in vitro against gram positive bacteria Staphylococcus aureus, Listeria inovanii and gram negative bacteria Klebsiella pneumoniae, Salmonella sp., Escherichia coli and compared with the known antibiotic: amoxicillin + clavulanic acid (AMC) and showed variable effects.
Keywords
Double headed acyclo-C-nucleosides
5-Mercapto-1,2,4-triazole
1,3,4-Oxadiazole-2-thione
4-Amino-5-mercapto-1,2,4-triazole
Antibacterial activity
1 Introduction
The modern structural features of nucleosides are somewhat different from those present in poly-ribonucleotides RNA and DNA (see Fig. 1), by means of variations in sugar, heterocyclic moieties and the various modes of attachments between the two major components (sugar and heterocycle) (Watson and Crick, 1954).
A classical structural representation of nucleosides.
The cyclic sugar residues have shown a lot of variations such as the ring size (Nakamura et al., 1986; Furuta et al., 1979; Singha et al., 2003) and oxygen’s ring has been replaced by N, S, Se, CH2 and other elements (Evans et al., 2003; Prichard et al., 2009; Brown et al., 2001). Moreover the open chain sugars are now appearing quite often in the literature (Poonian and Nowoswiat, 1977; Yosuzawa et al., 1987; Tsuchiya et al., 1995) since the discovery of acyclovir (Schaeffer et al., 1978) as acyclic (Rashad et al., 2005; Rybak et al., 2000) and seco-acyclo-nucleosides (Ashry and Kilany, 1998) to expand the scope of the terms: nucleosides and nucleosides analogues may be schematically presented in Fig. 2.
A proposed classification for nucleosides and nucleoside analogues.
In a second structural modification concerning the heterocyclic. In addition to pyrimidine and purine derivatives, the heterocyclic part is now including almost all kinds of heterocycles such as oxadiazoles (Belkadi and Othman, 2006), thiadiazoles (Paolo et al., 1996), triazoles (Awad and El Ashry, 1998) and others (Cappellacci et al., 1997) are utilized at present in the synthesis of various nucleosides due to the biological effects of various kinds of heterocycles (Kalluraya et al., 1996; Holla et al., 1996).
The third emergent feature in structural modification is the different modes of attachments between sugar and heterocyclic residues. The classical sugar –N-heterocyclic bridge is known to comprise –C-heterocyclic (Jin and Hong, 2005), –S-heterocyclic (Talukdar et al., 2007), –O-heterocyclic (Mariño and Marino, 2005) functions and others (Lu et al., 2009).
The fourth modified structural feature includes the number of the nucleobases attaching to sugar(s) molecule(s). A lot of variations and kinds of nucleosides with dinuclear nucleosides (Kašnar et al., 1993; Casiraghi et al., 1992), double-headed nucleosides (Klein and Steglich, 1989) and others were also reported (Jaffer et al., 2010; Shuto et al., 1999) (see for instance Fig. 3).
Nucleosides with multiple fragments.
The wide occurrences of heterocyclic compounds in bioactive natural products and pharmaceuticals have made them as important synthetic targets. The 1,3,4-oxadiazoles and 1,2,4-triazoles represent classes of heterocyclic compounds of great importance in biological chemistry (Demirbas, 2005; Amir and Shikha, 2004; El Ashry et al., 2000; Demirbas et al., 2004).
The literature of the new kinds of nucleosides is increasing particularly after the discovery of antiviral agent “acyclovir” as well as those acting against herpes simplex virus infection (Gold and Corey, 1987; McKendrick, 1986).
Various approaches to the synthesis of nucleosides from carbohydrate moieties were reported in the literature such as fusion of sugar moieties to functionalized nucleobases (Diekmann et al., 1993) or linking a metal salt of the heterocycle with a sugar halide (Kazimierczuk et al., 1984) or combination of a heterocycle and sugar in the presence of a Lewis acid (Wittenburg, 1964). Most of these methods involve protection and deprotection of the OH groups.
In this communication we would like to present a convenient method for the synthesis of double headed nucleoside using the spontaneous lactonization reaction as a step protecting method within the synthetic pathway.
2 Experimental
2.1 General
All reactions were monitored by TLC analysis (silica gel for TLC supplied by MERCK), iodine was used for visualization. The melting points were measured with a BÜCHI 540 melting point apparatus and are uncorrected. The IR spectra exhibited as wave number (ν cm−1) were recorded using KBr discs in a JASCO V-530 spectrophotometer at the University of Oran, Es-Senia, Algeria. The 1H NMR and 13C NMR (250 MHz) spectra in DMSO-d6 exhibited as ppm, were recorded at the University of Oran, Es-Senia (Algeria). Microorganisms in this study were supplied by the university hospital of Oran and identified by the laboratory of applied microbiology, University of Oran Es-Senia (Algeria). The Mueller Hinton medium was supplied by Difco.
2.2 Chemical synthesis
2.2.1 d-Glucaro-1,5:6,3-dilactone (3)
Fuming nitric acid (31.0 mL) was heated to 55–60 °C and d-Glucose (1) (10.0 g, 55.5 mmol) was added in small batches over a period of 10 min with an aid of magnetic stirring. A vigorous exothermic reaction started taking place. The reaction vessel was immerged into an ice-bath until vigorous reaction seized. The reaction mixture then heated to 55–60 °C for 90 min. After cooling, the excess of nitric acid was removed under vacuum and ether was added to the remainder of the solution. A crystalline material was formed, filtered and washed with ether/dichloromethane 3:1 (v:v). The solid was recrystallized from methanol to give d-glucaro-1,5:6,3-dilactone (3). Colourless crystals, yield 45%, mp 80 °C, IR (νmax, cm−1): 3490 (OH), 1783 (C⚌O, γ-lactone), 1747 (C⚌O, δ-lactone). 1H NMR (250 MHz, DMSO-d6), δH 4.47 (d, 1H, C-5–H), 4.42 (dd, 1H, C-3–H), 4.32 (d, 1H, C-2–H), 4.25 (dd, 1H, C-4–H), 4.21 (s, 1H, OH), 4.18 (s, 1H, OH). 13C NMR (250 MHz, DMSO-d6), δC 176.42 (C-6), 172.18 (C-1), 80.51 (C-5), 72.49 (C-3), 70.74 (C-2), 69.86 (C-4).
2.2.2 2,3,4,5-Tetrahydroxyhexanedihydrazide (4)
The dilactone (3) (1.0 g, 5.74 mmol) was dissolved in ethanol (40.0 mL). Hydrazine hydrate 64% (5.0 mL) was added drop wise, a precipitate was formed immediately. The colloidal mixture was agitated for further 30 min. The precipitate was filtered, washed with an iced cooled ethanol and recrystallized from water. Yellow crystals, yield 86%, mp 122 °C, IR (νmax, cm−1): 3431 (OH), 3362 (NH), 1629 (O⚌C–N), 1616 (O⚌C–N).
2.2.3 2,2′-(2,3,4,5-Tetrahydroxy-1,6-dioxohexane-1,6-diyl)dihydrazinecarbothioamide (5)
The dihydrazide (4) (1.0 g, 4.2 mmol) was dissolved in H2O with stirring. Ammonium thiocyanate (1.40 g, 18.6 mmol) and HCl (30 mL, 37%) were added to the mixture. The solution was refluxed on a water bath for 8 h at 80 °C. Excess solvent was evaporated to almost dryness and the crystalline solid was filtered off and recrystallized from methanol to afford compound 5. Brown crystals, yield 88.6%, mp 100 °C, IR (νmax, cm−1): 3442 (OH), 3196 (NH), 1624 (CO–N), 1382 (C⚌S).
2.2.4 1,4-Bis(3-mercapto-1H-1,2,4-triazol-5-yl)butane-1,2,3,4-tetrol (6)
2.2.4.1 Method A: Synthesis in ethanol
Dihydrazinecarbothioamide (5) (1.0 g, 2.8 mmol) was dissolved in ethanol (40.0 mL) and added to solution of NaOH (0.33 g, 8.25 mmol) in ethanol (40 mL). A precipitate was formed immediately. The colloidal mixture was agitated for further 30 min. The precipitate was filtered, and recrystallized from water. Yellow crystals, yield 84.4%, mp 72 °C, IR (νmax, cm−1): 3414 (OH), 3300 (NH), 2536 (SH), 1619 (C⚌N).
2.2.4.2 Method B: synthesis in water
Dihydrazinecarbothioamide (5) (1.0 g, 2.8 mmol) was dissolved in water (40.0 mL) and added to solution of NaOH (0.33 g, 8.25 mmol) in water (10 mL) .The mixture was refluxed for 8 h on a water bath at 80 °C. After cooling, excess solvent was removed in vacuum. The product was collected and crystallized from ethyl acetate and recrystallized from methanol to afford compound 6. Yellow crystals, yield 88.0%, mp 72 °C, IR (νmax, cm−1): 3427 (OH), 3311 (NH), 2529 (SH), 1638 (C⚌N). 1H NMR (250 MHz, DMSO-d6), δH 13.93 (s, 1H, –NH), 12.01 (s, 1H, –NH), 8.66 (s, 1H, OH), 8.21 (s, 1H, OH), 4.45 (s, 1H, –SH), 4.30 (s, 1H, OH), 4.21 (s, 1H, OH), 4.08 (d, 1H, C-1–H or C-4–H); 3.96 (dd, 1H, C-2–H or C-3–H); 3.90 (d, 1H, C-1–H or C-4–H); 3.83 (dd, 1H, C-2–H or C-3–H). 13C NMR (250 MHz, DMSO-d6), δC 182.01 (C–SH); 173.52 (C⚌N); 161.37 (C-2 and C-3); 140.87 (C-1 and C-4).
2.2.5 5,5′-(1,2,3,4-Tetrahydroxybutane-1,4-diyl)bis(1,3,4-oxadiazole-2(3H)-thione) (7)
Dihydrazide (4) (1.0 g, 4.2 mmol) dissolved in water (40.0 mL) was added to a solution of NaOH (1.0 g, 25 mmol) in water (10.0 mL) and CS2 (30.0 mL). The reaction mixture was heated under reflux at 80 °C for 8 h. After cooling, excess solvent was removed under vacuum and the remainder of the solution was acidified with dil. HCl (10%) to pH 5. A solid was filtered off and washed with ethyl acetate to dissolve the organic products. The washing solution upon standing overnight at room temperature gave crystals which were recrystallized from chloroform/methanol (2:1, v:v) to afford compounds (7). Yellow crystal, yield 76.3%, mp 159 °C, IR (νmax, cm−1): 3424 (OH), 3241(NH), 1618 (C⚌N), 1381(C⚌S), 1042 (C–O–C). 1H NMR (250 MHz, DMSO-d6), δH 8.90 (s, 1H, –NH), 4.31 (s, 1H, OH), 4.21 (s, 1H, OH), 3.92 (d, 1H, C-1–H or C-4–H), 3.73 (dd, 1H, C-2–H or C-3–H), 3.63 (d, 1H, C-1–H or C-4–H), 3.50 (s, 1H, OH), 3.43 (dd, 1H, C-2–H or C-3–H), 3.16 (s, 1H, OH). 13C NMR (250 MHz, DMSO-d6), δC 173.18 (C⚌S), 151.88 (C⚌N), 73.11 (C-2 and C-3), 65.98 (C-1 and C-4).
2.2.6 1,4-Bis(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)butane-1,2,3,4-tetrol (8)
The compound 7 (1.0 g, 3.1 mmol) dissolved in EtOH (80.0 mL) and hydrazine hydrate 64% (5.0 mL) were heated under reflux on a water bath for 8 h at 90 °C. Excess solvent was evaporated and the remaining solid/liquid mixture was filtered off and washed with ethyl acetate to give 8 which was recrystallized from MeOH/H2O (2:1, v:v). Brown crystals, yield 72.2%, mp 142.7 °C, IR (νmax, cm−1): 3432 (OH), 3315 (NH), 2621 (SH), 1622 (C⚌N). 1H NMR (250 MHz, DMSO-d6), δH 8.878 (s, 1H, NH), 8.828 (s, 1H, NH), 8.408 (s, 1H, NH), 8.223 (s, 1H, NH), 5.646 (s, 4H, 4 OH), 4.198 (s, 2H, 2 SH), 4.031 (d, 1H, C-1–H or C-4–H); 3.870 (t, 1H, C-2–H or C-3–H); 3.462 (d, 1H, C-1–H or C-4–H); 3.403 (dd, 1H, C-2–H or C-3–H). 13C NMR (250 MHz, DMSO-d6), δC 181.598 (C–SH); 165.942 (C⚌N); 142.457 (C-2 and C-3); 140.917 (C-1 and C-4).
2.3 Antibacterial susceptibility testing
A disc diffusion assay according to the standard protocols (CLSI, 2006; NCCLS, 2003, 2005) was used to determine the susceptibility of two gram positive bacteria Staphylococcus aureus ATCC 25923, Listeria inovanii ATCC 19119 and gram negative bacteria Klebsiella pneumoniae ATCC 700603, Salmonella sp., Escherichia coli ATCC 25922 and using the known antibiotic amoxicillin + clavulanic acid combination (AMC 20/10 μg) as the reference. The bacterial suspension turbidity was adjusted to 0.5 McFarland, and then the suspensions were spread with a sterile cotton swab confluent over the entire surface of Mueller Hinton agar (Merck, Germany).
The filter paper disc method was performed in duplicate using fresh Mueller Hinton agar medium. This agar medium was inoculated with 0.5 mL of cultures containing about 106 CFU mL−1. Filter paper discs (5 mm diameter) saturated with solution of each compound (concentration 30 μg/mL) were placed on the indicated agar media. The incubation time was 24 h at 37 °C. The blank test disc with DMSO was used. Inhibitory activity was evaluated by measuring the diameter of clear zone observed around the disc (in mm).
The minimum inhibition concentrations (MIC) test. Each 1 mL of the original concentration (30 μg mL−1) in DMSO of the compounds 4, 6, 7 and 8 was diluted with DMSO for five times in test tubes to 15, 7.50, 3.75, 1.875, and 0.94 μg mL−1. The optical density at 600 nm was measured at 0 h, 18 h, 24 h and 48 h.
3 Results and discussion
3.1 Synthesis
The double headed acyclo-C-nucleosides 6, 7 and 8 have been synthesized by a common pathway as described in scheme 1. Oxidation of d-glucose (1) by fuming nitric acid revealed the formation of d-glucaro-1,5:6,3-dilactone (3) as shown by IR spectrum. It exhibited two carbonyl absorption bands at 1783 cm−1 attributed to five member ring lactone and another one at 1747 cm−1 assigned to six member ring lactone (Pretch et al., 2000a,b,c p. 265) occurred from spontaneous lactonization of d-glucaric acid (2) between C-1–C-5 and C-6–C-3. There is another hypothetical possibility of forming two lactone rings in 2 which may take place between C-1–C-4 and C-6–C-3 leading to double five member ring lactone (3′) which expected to show only one carbonyl absorption in IR at the region ≈1800 cm−1 (Pretch et al., 2000a,b,c, p. 265). However, 13C NMR showed two signals at 176.43 and 172.19 ppm attributed to C6 and C1 respectively (Pretch et al., 2000a,b,c, p. 104). These differences in IR and 13C NMR suggested that there is a formation of two lactone rings of different sizes. Results of the oxidation reaction of d-glucose was realized to be sensitive to the concentration of nitric acid, heating temperature and time length of the reaction, since oxalic acid was resulted in several cases.
Common pathway to the synthesis of compounds 6, 7 and 8.
The dihydrazide (4) was obtained in 86% yield by treatment of dilactone (3) with hydrazide hydrate 64%. The IR spectra showed two carbonyl bands at 1629 cm−1 and 1616 cm−1 attributed to the two hydrazide groups. The slight difference in carbonyl absorptions may be due to the effect of strong intramolecular hydrogen bonding (Pretch et al., 2000a,b,c, p. 265).
The dihydrazinecarbothioamide (5) was obtained from 4 by treatment with ammonium thiocyanate and HCl under reflux conditions to give the compound 5 in a good yield 88.6%. The IR spectrum exhibited characteristic bands at 1624 cm−1 assigned to (CO–N) and at 1382 cm−1 assigned to (C⚌S) (Pretch et al., 2000a,b,c, p. 265).
The bis-triazole (6) was obtained by reaction of 5 with NaOH in water or ethanol. In water solution the reaction mixture was refluxed for 8 h at 80 °C to give very good yield 88% of 6 while in ethanol the cyclization had taken place spontaneously at room temperature in a yield of about 84.4%. IR and 1H NMR suggested that the compound 6 existed as the ene-thiol form (Pretch et al., 2000a,b,c, p. 186). Further support for the thiol form came from IR and 1H NMR which exhibited a characteristic band at 2536 cm−1 and a signal around 4.46 ppm where the S–H is normally shown.
For the preparation of the bis-oxadiazole (7), the dihydrazide (4) was heated with an aqueous solution of NaOH and CS2 under reflux conditions followed by acidification with HCl to give a yellowish crystalline product 7 in a moderate yield 76.3%. The IR spectrum exhibited the absorptions at 1618 cm−1 for (C⚌N), 1381 cm−1 characteristic of (C⚌S), and 1042 cm−1 for (C–O–C) (Pretch et al., 2000a,b,c, p. 265). The position of the (C⚌N) band suggested that the oxadiazole existed as the thione tautomer rather than the ene-thiol form. Further support for the thione form came from 1H NMR spectrum which showed a singlet at 8.91 ppm assigned to N–H proton (Pretch et al., 2000a,b,c, p. 186).
The bis-4-amino-triazole (8) was prepared in moderate yield 72.2% by heating the compound 7 with hydrazine hydrate under reflux conditions for 8 h. The IR spectrum showed the characteristic band at 3431 cm−1, 3315 cm−1, 2621 cm−1 and 1622 cm−1 for (OH), (NH), (SH) and (C⚌N) respectively (Pretch et al., 2000a,b,c, p. 265). The 1H NMR supported the structure 8 by exhibiting four singlets between 8.87→8.22 ppm attributed to two NH2 groups. (OH) groups appeared as singlet at 5.64 ppm. In addition, SH signal at 4.19 ppm was also present as singlet (Pretch et al., 2000a,b,c, p. 186). 13C NMR confirmed the structure of 8 by revealing signals at 181.59 ppm attributed to (C–SH) and 165.94 ppm for (C⚌N) (Pretch et al., 2000a,b,c, p. 104).
3.2 Antibacterial tests
The inhibitory effect of the compounds 3, 4, 5, 6, 7 and 8 in DMSO (10% v:v) was tested upon in vitro against gram positive bacteria S. aureus ATCC 25923, L. inovanii ATCC 19119 and gram negative bacteria K. pneumoniae ATCC 700603, Salmonella sp., E. coli ATCC 25922. DMSO which is known as bacterial static in the above mentioned concentration was used as negative control and standard discs (Mast Diagnostics, UK) saturated with known antibiotic: amoxicillin + clavulanic acid (AMC) as positive control were applied. After incubation at 37 °C for 24 h, the zone of inhibition of growth around each disc was measured in millimetres and zone diameters were interpreted in accordance with CLSI and NCCLS guidelines (National Committee for Clinical and Laboratory Standards Villanova, 1997; Clinical and Laboratory Standards Institute, 2007).
The experiments were performed in duplicates and the average results are summarized in Table 1.
| Compounds⁎ | Gram positive bacteria | Gram negative bacteri | |||
|---|---|---|---|---|---|
| S. aureus | L. inovanii | K. pneumoniae | Salmonella sp. | E. coli | |
| AMC | 30 | 16 | 18 | 24 | 18 |
| 3 | – | – | – | – | – |
| 4 | 36 | 16 | 18 | 14 | 16 |
| 5 | – | – | – | – | – |
| 6 | – | – | 14 | – | – |
| 7 | 16 | 14 | – | – | – |
| 8 | 22 | – | – | – | 14 |
For: AMC (amoxicillin + clavulanic acid combination) S ⩾ 18 mm; I = 14–17 mm; R ⩽ 13 mm.
The screening results in Table 1 indicate that all compounds under study showed variable effects upon gram positive and gram negative bacteria.
Compounds 3 and 5 were found to be inactive against all tests on bacterial species under study.
Compound 4 has a better inhibition effect than AMC against S. aureus, a similar effect than AMC against L. inovanii, K. pneumoniae and an intermediate activity against the other bacteria tested.
The bis-triazole (6) showed an intermediate effect on K. pneumoniae.
The bis-oxadiazole (7) exhibited an intermediate activity against gram positive bacteria S. aureus and L. inovanii.
The bis-4-amino-triazol (8) has a better inhibition effect than AMC against S. aureus, but less than dihydrazide (4). The compound 8 showed also an intermediate activity against E. coli.
The minimum inhibitory concentrations (MIC) were determined for the active compounds 4, 6, 7 and 8 in triplicates against the tested bacteria. The averages are shown in Table 2.
| Compounds | Gram positive bacteria | Gram negative bacteria | |||
|---|---|---|---|---|---|
| S. aureus | L. inovanii | K. pneumoniae | Salmonella sp. | E. coli | |
| 4 | 0.94 | 1.875 | 1.875 | 1.875 | 1.875 |
| 6 | – | – | 1.875 | – | – |
| 7 | 1.875 | 1.875 | – | – | – |
| 8 | 0.94 | – | – | – | 1.875 |
MIC: Minimum inhibitory concentration.
The dihydrazide (4) has exhibited its MIC at 0.94 μg mL−1 on S. aureus and at 1.875 μg mL−1 on other bacteria under test.
The bis-triazole (6) has exhibited its MIC at 1.875 μg mL−1 on K. pneumoniae.
The bis-oxadiazole (7) has shown its (MIC) at 1.875 μg mL−1 on the two gram positive bacteria S. aureus and L. inovanii.
The bis-4-amino-triazol (8) has exhibited its MIC at 0.94 μg mL−1 on S. aureus, and at 1.875 μg mL−1 on E. coli.
All the newly synthesized compounds showed moderate antibacterial activity, except dihydrazide (4) and bis-4-amino-triazol (8) which observed the highest effect at lowest concentration upon S. aureus. These findings concluded that the titled compounds have the property to kill the microbes in some extent when compared with standard drug; it gives a future scope to study the mechanism of action and would be worthy of further investigation.
4 Conclusion
In conclusion, double headed C-nucleosides from unprotected d-glucose were synthesized and their structures were determined and also assayed for their in vitro antibacterial activity. This study should extend on anti-viral, antifungal and anti-cancer tests because the literature gives enormously interesting results on these subjects. Also tests on other bacteria should also be included to widen the investigation.
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