Synthesis and antitubercular activity of nucleoside analogs based on L-ascorbic acid and bases

Article abstract of DOI:10.1007/s00044-007-9036-5

5,6-O-isopropylidene-2,3-di-O-methyl ascorbic acid (2), obtained by reaction of acetone with ascorbic acid (1) followed by methylation with methyl iodide, on 1,8-Diazabicyclo[5.4.0]undec-7-ene-catalyzed elimination of acetone moiety led to the formation of respective 2,3-di-O-methyl didehydro-L-ascorbic acid (4) in good yield. The latter, on methanesulfonylation with methanesulfonyl chloride and subsequent reaction of the crude methanesulfonyloxy derivative with imidazole, benzimidazole, and adenine resulted in the corresponding tetronolactonyl nucleoside analogs 5, 6, and 7. Compound 5 on reaction with benzyl amine led to the N-benzylated teramyl nucleoside analog, while compounds 6 and 7 did not react under similar conditions. All the synthesized compounds were evaluated for their antitubercular activity against M. tuberculosis H ₃₇R_a and H₃₇R_v, exhibiting a minimum inhibitory concentration (MIC) of more than12.5 μg/mL.

Full text of DOI:10.1007/s00044-007-9036-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2008) 17:53–61
DOI 10.1007/s00044-007-9036-5
ORIGINAL RESEARCH
Synthesis and antitubercular activity of nucleoside
analogs based on L-ascorbic acid and bases
R. P. Tripathi Æ Namrata Dwivedi Æ Nimisha Singh Æ
Mridul Misra
Received: 22 October 2007 / Accepted: 31 October 2007 / Published online: 20 December 2007
¨
Ó Birkhauser Boston 2007
Abstract 5,6-O-isopropylidene-2,3-di-O-methyl ascorbic acid (2), obtained by
reaction of acetone with ascorbic acid (1) followed by methylation with methyl
iodide, on 1,8-Diazabicyclo[5.4.0]undec-7-ene-catalyzed elimination of acetone
moiety led to the formation of respective 2,3-di-O-methyl didehydro-L-ascorbic
acid (4) in good yield. The latter, on methanesulfonylation with methanesulfonyl
chloride and subsequent reaction of the crude methanesulfonyloxy derivative with
imidazole, benzimidazole, and adenine resulted in the corresponding tetronolactonyl
nucleoside analogs 5, 6, and 7. Compound 5 on reaction with benzyl amine led to
the N-benzylated teramyl nucleoside analog, while compounds 6 and 7 did not react
under similar conditions. All the synthesized compounds were evaluated for their
antitubercular activity against M. tuberculosis H37Ra and H37Rv, exhibiting a
minimum inhibitory concentration (MIC) of more than12.5 lg/mL.
Keywords Ascorbic acid Á Vitamin C Á Nucleosides Á Adenine Á
Tetramic acid
Introduction
Ascorbic acid, commonly known as vitamin C, has served as an excellent scaffold for
the synthesis of many biologically active compounds (Cinatl et al., 1995; Bram et al.
1980; Grdisa et al., 1995). Its antioxidant activity and the immunomodulatory
activities of many of its O-alkyl derivatives have been studied extensively (Olabisi and
Wimalasena, 2004). Ascorbic acid is basically a tetranolactone and the two enols at the
2- and 3- positions play a crucial role both in organic synthesis and in eliciting the
R. P. Tripathi (&) Á N. Dwivedi Á N. Singh Á M. Misra
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001,
India
e-mail: rpt.cdri@gmail.com

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Med Chem Res (2008) 17:53–61
biological response. Replacement of the ring oxygen atom with sulfur in the
tetranolactone results in thionotetranolactone, a pharmacophore in compounds
exhibiting antimalarial and antitubercular activities via Fatty acid synthetase-II
inhibition. One of such compounds possessing the thiotetranolactone moiety,
thiolactomycin, is under preclinical development as a new antitubercular drug
(Miyakawa et al., 1982; Kremer et al., 2000). However, replacement of the ring
oxygen with nitrogen atom results in tetramates, another moiety found in a variety of
antibiotics (Royles, 1995; Ley et al., 1992; Wang et al., 2003; Elbe et al., 1956) and
anti-HIV (Roggoet et al., 1994), anticancer, and antitumor agents (Holtzel et al., 2000;
Iwata et al., 2005). Very recently a few reports have come to light where ascorbic-
based nucleosides were prepared as antiviral and antitumor agents (Malic et al., 2000).
Nucleoside analogs themselves are known for their diverse range of biological
activities (Mishra et al., 2005). Ascorbic acid has also been used in the synthesis of
pyrano[3,4-b]indoles and a variety of other heterocycles by Preobrzhenskaya and co-
workers (Larvrenov et al., 2005; Preobrzhenskaya and Korolev 2000).
In our continuing program aimed towards the development of new antitubercular
agents we were curious to synthesize certain teramic-acid-based nucleosides and
investigate their antitubercular activity. Our curiosity arose due to the fact that many
purines, nucleoside analogs, and thiolactomycins have displayed significant
antitubercular activity (Miyakawa et al., 1982; Kremer et al., 2000; Somu, 2006).
Thus herein we describe the methodology to synthesize tetranolactonyl and tetramyl
nucleoside analogs. The synthesized compounds were evaluated for their antitu-
bercular activities.
Results and discussion
The synthetic strategy involves the reaction of ascorbic acid (1) with acetone in the
presence of a catalytic amount of acetyl chloride, leading to selective protection of
the 5,6-diol to give 5,6-O-isopropylidene-L-ascorbic acid (2) in quantitative yield.
This compound (2) was methylated with methyl iodide in dimethyl sulfoxide
(DMSO)/acetone (1:4) as the solvent in the presence of K2CO3 and tetrabutylam-
monium bromide (TBAB) to give 2,3-O-bis-methyl-5,6-O-isopropylidene ascorbic
acid (3) (Khan and Adams, 1999). The latter was reacted with DBU (50 mol%)
using Tetrahydrofuran as the solvent, leading to the elimination of a molecule of
acetone to give 3,4-bis-methyl-5-(2-hydroxyethylidene)-5H-furan-2-one (4) (Singh
et al., 2006). Compound 4 was treated with methanesulfonyl chloride in dry CH2Cl2
in the presence of a catalytic compound of triethylamine, resulting in the
intermediate methanesulfonyloxy derivative (5), which was used as such in the
subsequent steps of the desired synthesis.
The intermediate methanesulfonyloxy derivative (4) was reacted with imidazole
and a catalytic amount of DBU (25 mol%) in dry toluene at 120°C to give (Z)-5-[2-
(imidazol-1-yl)ethylidene]-3,4-dimethoxy-5H-furan-2-one (5) at 65.7% yield.
A similar reaction of compound 5 with benzimidazole gave the corresponding
(Z)-5-[2-(benzimidazol-1-yl) ethylidene]-3,4-dimethoxy-5H-furan-2-one (6) in
good yield.

Med Chem Res (2008) 17:53–61
55
To prepare the adenine derivative of thiotetranolactone, the adenine was
persilylated by refluxing it with 1,1,1,3,3,3-Hexamethyldisilazane in anhydrous
toluene in the presence of a catalytic amount of (NH4)2SO4 under a nitrogen
atmosphere for 3–4h. The silyated adenine thus obtained was reacted with
methanesulfonyloxy tetranolactone derivative 5 as above using DBU (25 mol%) in
refluxing toluene to give (Z)-5-[2-(adenin-9-yl) ethylidene]-3,4-dimethoxy-5H-
furan-2-one (7) at 10% yield (Scheme 1).
The reaction of the imidazolyl tetranolactone 6 with benzyl amine in ethanol
gave the corresponding tetramate, 1-benzyl-5-hydroxy-5-(2-imidazol-1-yl-ethyl)-
3,4-dimethoxy-1,5-dihydro-pyrrol-2-one (8) at very good yield. Similar reactions of
OH
OH
O
O
O
OH
O
O
O
O
O
O
O
O
O
(i)
(ii)
(iii)
OH
HO
OH
OCH3
HO
H3CO
OCH3
(iv)
H3CO
1
2
4
3
N
N
N
N
OMs
O
(v)
O
O
O
O
O
OCH3
H3CO
H3CO
H3CO
OCH3
OCH3
6
5
(vi)a,b
(vii)
(vii)
NH2
N
N
N
N
N
N
No Reaction
N
O
O
O
HO
H3CO
H3CO
OCH3
OCH3
8
7
(vii)
No reaction
Scheme 1 (i)Acetone, Acetylchloride,30°C, 4 h (ii) MeI, TBAB, DMSO:Acetone (1:4), K2CO3, 30°C,
18h (iii) THF , DBU, 30°C, 7 h (iv) Methanesulphonyl chloride, CH2Cl2, Et3N, 0–30°C, 5h (v) imidazole
or benzimidazole,Toluene, DBU, 120°C, 3–6 h.(vi) a. adenine, HMDS, (NH4)2SO4, reflux, 3h; b. DBU,
120°C, 3–4h (vii) Ethanol, benzyl amine 3–4 h

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Med Chem Res (2008) 17:53–61
compounds 6 and 7 did not afford the desired tetramates. The possible reason for the
inertness of (Z)-5-[2-(benzimidazol-1-yl)ethylidene]-3,4-dimethoxy-5H-furan-2-one
(6) and (Z)-5-[2-(adenin-9-yl)ethylidene]-3,4-dimethoxy-5H-furan-2-one (7)
towards benzyl amine may be due the steric hindrance offered during reaction by
the bulky benzimidazole and adenine moieties. Thus among the compounds 5, 6,
and 7 described above only (Z)-5-[2-(imidazol-1-yl)ethylidene]-3,4-dimethoxy-5H-
furan-2-one (5) undergoes a ring-opening reaction with the benzyl amine to give the
enol-keto-amide, leading to compound 8. The structures of all the products
synthesized were established on the basis of their spectroscopic data and analysis
(see the Experimental Section).
Biological activity
The ascorbic-acid-based nucleosides 5, 6, 7, and 8 were evaluated for their
antitubercular activity against M. Tuberculosis H37Ra by Micro alamar blue essay
technique (Collins and Franzblan, 1997); while the agar microdilution method (Saito
et al., 1991) was used against H37Rv. As evident from Table 1 none of the compounds
showed significant activity against M. tuberculosis H37RA and the virulent H37RA
strains since the MIC values for them are greater than 25 lg/mL as compared to the
standard drug Isoniazid. One of the possible reasons for their inactivity against
mycobacterium may be their transport or instability in the cellular medium.
In summary, we have developed a simple method for the synthesis of
tetranolctonyl nucleosides which can be manipulated to tetramyl nucleoside
analogs. The compounds have been screened against M. tuberculosis and exhibited
MIC values above 25 lg/mL.
Experimental section
5,6-O-isopropylidene-L-ascorbic acid (2)
To a magnetically stirred solution of ascorbic acid (30 g, 170.4 mmol) in acetone
(120 mL), acetyl chloride (3 ml, 42.6 mmol) was added and the reaction mixture
stirred for 2–3 h at ambient temperature. The reaction mixture was kept for 7–8 h in
Table 1 Antimycobacterial activity of synthesized compounds 5–8
Sample number
Compound
H37Ra MIC (lgmL-1
)
H37Rv MIC (lgmL-1
)
1
5
6
7
8
–
[12.5
[12.5
[12.5
[12.5
–
[25
[25
[25
[25
0.65
2
3
4
INH
MIC = minimum inhibitory concentration

Med Chem Res (2008) 17:53–61
57
freezer, the solid separated was filtered and washed with cold acetone and was dried
to give compound 2 as colorless granules (27 g, 73.7%), m.p. 195–198°C. lit m.p.
2,3-Dimethoxy-5, 6-O-isopropylidene-L-ascorbic acid (3)
A mixture of compound 2 (25 g, 115.7 mmol) and anhydrous K2CO3 (32 g, 231.4
mmol) in acetone:dimethyl sulfoxide (4:1, 250 mL) was magnetically stirred for 25
min. A solution of methyl iodide (14.9 mL, 231.4 mmol) was dissolved slowly in
acetone (30 mL) for 30 min, followed by the addition of tetrabutylammonium
bromide (2.0 g) and stirring overnight at ambient temperature. The result was
filtered and the filtrate thus obtained was evaporated under reduced pressure to give
the crude mass, which was dissolved in ethyl acetate and washed with water. The
organic layer was dried (Na2SO4) and evaporated under reduced pressure to afford a
crude solid, which was chromatographed over silica gel (230–400 mesh) using a
gradient of hexane-EtOAc (17:3) as eluent to give the compound 3 as a colorless
solid (22 g, 78%).
(Z)-3,4-Dimethoxy-5-(2-hydroxyethylidene)-5H-furan-2-one (4)
To a magnetically stirred solution of compound 3 (20 g, 81.96 mmol) in THF (80
mL), DBU (6.2 mL, 50 mol%) was added slowly and the reaction mixture was
stirred for 18 h at room temperature. The solvent was evaporated under reduced
pressure and the residue thus obtained was dissolved in ethyl acetate (100 mL) and
washed with water (25 mL). The organic layer was dried (Na2SO4) and concentrated
under reduced pressure to afford a crude mass, which was chromatographed over
silica gel (230–400 mesh) using hexane:ethyl acetate (9:1) as eluent to give the
above compound 4 as a colorless solid (10 g, 65.7%), m.p. 60°C, infrared(IR) (neat)
3391, 1688 cm-1, MS (FAB) 187(M + H)+ 1H NMR (200 MHz, CDCl3) dH 1.39 (bs,
1H), 3.92 (s, 3H, OCH3 ), 4.16 (s, 3H, -OCH3), 4.41 (d, J = 7.0, 2H, OCH2), 5.50 (t,
J = 7.0 Hz, 1H, = CH-); 13C NMR (50 MHz, CDCl3): d 56.6, 59.9, 60.6, 108.1,
125.0, 142.3, 149.1, 164.7.
Preparation of the intermediate 5-(2-methanesulfonyloxy ethylidene)-3,4-
dimethoxy-5H-furan-2-one
To a stirring solution of compound 4 (2 g, 10.65 mmol) and triethylamine (1 mL) in
anhydrous dichloromethane (10 mL) a solution of methanesulfonyl chloride (1.11
mL, 10.65 mmol) in CH2Cl2 (2 ml) was added slowly at 0°C during 5 min. The
reaction mixture was brought to 30°C and stirring continued for a further hour. The
solvent was evaporated under reduced pressure and the residue thus obtained was
dissolved in ethyl acetate (100 mL) and washed with water (25 mL). The organic
layer was dried (Na2SO4) and concentrated under reduced pressure to give a crude
mass of the title compound, which was used as such in the subsequent reactions.

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Med Chem Res (2008) 17:53–61
(Z)-5-[2-(Imidazol-1-yl)ethylidene]-3, 4-dimethoxy-5H-furan-2-one (5)
A mixture of the above crude methanesulfonyloxy derivative (1 g, 3.78 mmol)
imidazole (0.257 g, 3.78 mmol) and DBU (0.285 mL, 25 mol%) in anhydrous
toluene was stirred at 120°C for 5 h. The solvent was evaporated under reduced
pressure and the residue thus obtained was dissolved in ethyl acetate (100 mL) and
washed with water (25 mL). The organic layer was dried (Na2SO4) and concentrated
under reduced pressure to afford a crude mass, which was chromatographed over
silica gel (230–400 mesh) using a gradient of hexane:ethylacetate (3:2) as eluent to
give the above compound 6 as a light yellow foam (1 g, 65.7%), as foam IR (KBr)
1
tmax 3210, 1775 ; FABMS 237(M + H)+; H NMR (200Mz, CDCl3) d 3.95 (s, 3H,
OCH3), 4.14 (s, 3H, OCH3), 4.81 (d, J = 7.4 Hz, 2H, CH2), 5.73 (t, J = 7.4 Hz, 1H,
= CH), 6.93, 7.07 (2s, 2H, imidazole CH), 7.51 (s, 1H, imidazolyl CH); analysis
calculated for C11H12N2O4 C, 55.92; H, 5.12, N, 11.85; found: C, 55.87; H, 5.08; N,
11.93.
(Z)-5-[2-(Adenin-9-yl)ethylidene]-3,4-dimethoxy-5H-furan-2-one (7)
Adenine (1.5 g, 11.1 mmol) was refluxed in anhydrous toluene with HMDS in the
presence of a catalytic amount of (NH4)2SO4 under an N2 atmosphere for 3–4 h and
the excess reagent and solvent were removed under reduced pressure to give the
silylated adenine derivative. A mixture of this silylated adenine derivative, the
above intermediate methanesulfonyloxy derivative (1 g, 3.78 mmol), and DBU
(0.285 mL, 50 mol%) in anhydrous toluene (5 mL) was stirred at 120°C for 5 h. The
solvent evaporated, and the residue thus obtained was dissolved in chloroform and
washed with water and the organic layer dried (Na2SO4) and solvent-evaporated
under reduced pressure to afford a crude mass. The latter was chromatographed over
an SiO2 column using CH2Cl2:MeOH (9:1) as eluent to give the title compound 7 as
colorless granules (0.32 g) at 10% yield: m.p. 138–140°C; IR (KBr) tmax 3210, 1775
1
; FABMS 304(M + H)+; H NMR (200Mz, DMSO) d 3.82 (s, 3H, OCH3), 4.08 (s,
3H, OCH3), 5.15 (d, J = 7.0 Hz, 2H, CH2), 5.73 (t, J = 7.0 Hz, 1H, = CH), 7.76 (s,
1H, CH), 7.95 (br, 2H, NH2), 8.14 ( s, 1H, CH ); analysis calculated for C13H13N5O4
C, 51.48; H, 4.29, N, 23.10; found: C, 51.40; H, 4.32; N, 23.18.
1-Benzyl-5-hydroxy-5-(2-imidazol-1-yl-ethyl)-3,4-dimethoxy-1,5-dihydro-
pyrrol-one (8)
A solution of compound 5 (0.2 g, 0.847 mmol) and benzylamine (0.09 mL 0.847
mmol) in ethanol (1 mL) was stirred at 40°C for 5 h. The solvent was evaporated to
a crude product which was chromatographed over silica gel (230–400 mesh) using a
gradient of hexane:ethylacetate (3:2) as eluent to give compound 8 as a light yellow
foam. Yield (174 mg, 60 %); IR (KBr) tmax 3210, 1775 cm-1; FABMS
1
343(M + H)+; H NMR (200Mz, CDCl3) d 2.00– 2.24 (m, 2H, H-6), 3.22– 3.40
(m, 2H, H-7), 3.85 (s, 3H, OCH3), 4.00 (s, 3 H, OCH3), 4.21 (d, J = 15.2 Hz, 1 H,

Med Chem Res (2008) 17:53–61
59
NCH2A), 4.90 (d, J = 15.2 Hz, 1 H, NCH2B), 6.30 (s, 1H, imidazole H), 6.85 (m,
2H, imidazole CH), 7.33–7.43 (m, 5H, Ar-H); analysis calculated for C18H21N3O4:
C, 62.93; H, 6.16, N, 12.24; found: C, 62.90; H, 6.16; N, 12.24.
Antitubercular screening
Activity against M. tuberculosis H37Ra strain
All the compounds synthesized were evaluated for their efficacy against M.
tuberculosis H37Ra at concentrations ranging from 100 lg mL-1 to 1.56 lg mL-1
using twofold dilutions in the initial screen. Log phase culture of M. tuberculosis
H37Ra was diluted so as to give a final optical density (OD)550 nm of 0.05 in Sauton’s
medium. In 96-well white plates, 190 ll of culture is dispensed in each well. A
dimethyl sulfoxide (DMSO) solution of test compounds was dispensed into 96-well
plates so as to make the final test concentration 25 lg mL-1 (5 lgtest compound
dispensed in 10 ll of DMSO). Then the plate was incubated at 37°C in 5% CO2 for
5 days. On fifth day 15 ll Alamar blue solution was added to the each well of plate.
The plate was again incubated overnight at 37 °C in 5% CO2. The fluorescence was
read on a BMG Polar Star with an excitation frequency of 544 nm and emission
frequency of 590 nm. The compounds that were found active to be ([90%
inhibition compared with control) at this concentration were then tested at six serial
dilutions from 50 to 1.56 lg mL-1
.
Activity against M. tuberculosis H37Rv strain
Drug susceptibility and determination of MIC of the test compounds/drugs against
M. tuberculosis H37Rv was performed by the agar microdilution method where
twofold dilutions of each test compound added to 7H10 agar supplemented with
oleic acid-albumin-dextrosecatalase and organism. A culture of M. tuberculosis
H37Rv growing on Lowenstein Jensen medium was harvested in 0.85% saline with
0.05% Tween-80. A 1 lg mL-1 concentration suspension of the extracts/com-
pounds was prepared in DMSO. This suspension was added to (in tubes) 7H10
middle Brook’s medium (containing 1.7 ml medium and 0.2 ml OADC supplement)
at different concentrations of compound, keeping the volume constant, i.e., 0.1 mL.
The medium was allowed to cool with the tubes in a slanting position. These tubes
were then incubated at 37°C for 24 h followed by streaking of M. tuberculosis
H37Rv (5 9 104 bacilli per tube). These tubes were then incubated at 37°C. Growth
of bacilli was observed after 30 days of incubation. Tubes containing the
compounds were compared with control tubes in which medium alone was
incubated with H37Rv. The concentration at which complete inhibition of colonies
occurred was taken as the active concentration of test compound.
Acknowledgements The authors would like to thank the Director of the CDRI for his keen interest in
this program. ND would like to thank CSIR New Delhi for the award of a SRF; NS and MM are thankful

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Med Chem Res (2008) 17:53–61
for financial assistance from DRDO (ERIP/ER/050212/M/01/857) and ICMR, respectively. We would
also like to thank the task force members involved in the tuberculosis screening program at our institute.
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