Synthesis and biological evaluation of pyridin-2-one nucleosides

Article abstract of DOI:10.1081/NCN-100002361

The synthesis of 1-(β -D-ribofuranosyl)pyridin-2-one-3-carboxylic acid and the 3-carboxamide as well as a short series of 3N-carboxamides, prepared by TPTU/HOBt coupling of primary amines with 1- (β-D-ribofuranosyl)pyridin-2-one-3-carboxylic acid, and the

Full text of DOI:10.1081/NCN-100002361

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SYNTHESIS AND BIOLOGICAL EVALUATION OF
PYRIDIN-2-ONE NUCLEOSIDES
Caroline M. Huntley a , Ann S. Cotterill a , Jean-Yves Maillard a , Jan Balzarini b & Claire
Simons c
a Welsh School of Pharmacy, Cardiff University , Medicinal Chemistry, King Edward VII
Avenue, Cardiff, CF10 3XF, United Kingdom
b Rega Institute, Katholieke Universiteit Leuven , Minderbroedersstraat 10, Leuven,
B-3000, Belgium
c Welsh School of Pharmacy, Cardiff University , Medicinal Chemistry, King Edward VII
Avenue, Cardiff, CF10 3XF, United Kingdom
Published online: 07 Feb 2007.
To cite this article: Caroline M. Huntley , Ann S. Cotterill , Jean-Yves Maillard , Jan Balzarini & Claire Simons (2001)
SYNTHESIS AND BIOLOGICAL EVALUATION OF PYRIDIN-2-ONE NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids,
20:4-7, 731-733, DOI: 10.1081/NCN-100002361
To link to this article: http://dx.doi.org/10.1081/NCN-100002361
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 731–733 (2001)
SYNTHESIS AND BIOLOGICAL EVALUATION
OF PYRIDIN-2-ONE NUCLEOSIDES
Caroline M. Huntley,1 Ann S. Cotterill,1 Jean-Yves Maillard,2
Jan Balzarini,3 and Claire Simons1,∗
1Medicinal Chemistry and 2Microbiology Divisions, Welsh School
of Pharmacy, Cardiff University, King Edward VII Avenue,
Cardiff CF10 3XF, United Kingdom
3Rega Institute, Katholieke Universiteit Leuven,
Minderbroedersstraat 10, B-3000 Leuven, Belgium
ABSTRACT
The synthesis of 1-(β-D-ribofuranosyl)pyridin-2-one-3-carboxylic acid and the
3-carboxamide as well as a short series of 3N-carboxamides, prepared by
TPTU/HOBt coupling of primary amines with 1-(β-D-ribofuranosyl)pyridin-2-
one-3-carboxylic acid, and their evaluation as anti-infective agents is described.
The interest in pyridin-2-one nucleosides stems from the activity exhibited
bythepseudobaseofthesenucleosides. 2-Hydroxynicotinicaciddisplaysinhibitory
activity against nicotinate phosphoribosyltransferase (1) and cholesterol and
fatty acid synthesis (2), the mechanism of action of which involves conversion
to the corresponding ribofuranoside (3). More recently a series of 2-mercapto-
3N-alkyl-thiocarboxamides have been described by Pagani et al. which display
significant activity against Mycobacterium tuberculosis and Mycobacterium avium
complex (4).
Based on the results obtained by Pagani et al. (4) a series of 1-(β-D-
ribofuranosyl)pyridin-2-one-3N-carboxamideswerepreparedforevaluationasanti-
infectives, using acylated 1-(β-D-ribofuranosyl)pyridin-2-one-3-carboxylic acid 3
as the precursor nucleoside.
∗Corresponding author.
731
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C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
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732
HUNTLEY ET AL.
CO
O
CO2H
2H
CO2H
O
N
N
O
O
O
ii
i
AcO
HO
N
H
AcO OAc
HO OH
(2)
(3)
(1)
iii, iv
O
O
O
O
NH2
NH2
O
N
O
N
O
NH2
vi
v
BzO
HO
N
O
H
BzO OBz
HO OH
(4)
(5)
(6)
Scheme 1. Reagents and conditions: (i) (a) BSA, CH3CN, 1 h (b) 1,2,3,5-tetra-O-acetyl-β-D-
ribofuranose, TMSOTf, 24 h, 88% over 2 steps (ii) NH3, CH3OH, o/n, 100% (iii) CH3OH, H2SO4,
reflux, o/n, 45% (iv) NH3, CH3OH, 24 h, 98% (v) (a) BSA, CH3CN, 1 h (b) 1-O-acetyl-2,3,5-tri-O-
benzoyl-β-D-ribofuranose, TMSOTf, 48 h, 67% over 2 steps (vi) NH3, CH3OH, 24 h, 52%.
1-(β-D-Ribofuranosyl)pyridin-2-one-3-carboxylic acid 1 was prepared, as
previously described (5), by Vorbru¨ggen coupling of 2-hydroxynicotinic acid 2
with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose with subsequent acyl deprotection.
Using the same method the 3-carboxamide derivative (5) 6 was prepared using
pyridin-2-one-3-carboxamide 4, prepared in two steps from 2-hydroxynicotinic
acid 2 (Scheme 1).
A short series of 3 N-carboxamides 7–10 (Table 1) were then prepared, in
low to moderate yields, by reaction of 3 with a series of primary amines employing
O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,Nꢁ,Nꢁ-tetramethyluronium tetrafluoroborate
(TPTU) as the coupling agent (Scheme 2).
The pyridin-2-one nucleosides 1, 6 and 7–10 were evaluated against My-
cobacterium tuberculosis however they exhibited negligible inhibitory activity.
Table 1. HRMS/Microanalysis (MA) Data for the 3N-carboxamide Nucleosides 7–10
Compound
n
HRMS/MA Data
7
8
9
2
3
4
5
HRMS (CI, C14H20N2O6): 313.1399 [M + H]+
MA (C15H22N2O6): C, 55.08%; H, 6.96%; N, 8.51%
MA (C16H24N2O6 · H2O): C, 55.01%; H, 7.49%; N, 7.88%
MA (C17H26N2O6 · H2O): C, 54.71%; H, 7.78%; N, 7.41%
10

ORDER
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PYRIDIN-2-ONE NUCLEOSIDES
733
O
O
CO2H
NH(CH2)nCH3
N
O
N
O
i, ii
O
AcO
HO
AcO OAc
HO OH
(7-10)
(3)
Scheme 2. Reagents and conditions: (i) (a) TPTU, HOBt, DIPEA, DMF, 5 min (b) CH3(CH2)nNH2,
o/n, 25–51% (ii) NH3, CH3OH, o/n, 81–98%.
Compounds 1, 6 and 7–10 were also evaluated against a wide range of RNA and
DNA viruses including HIV-1, HIV-2, HSV-1, HSV-2, vaccinia, varicella zoster,
parainfluenza-3, reovirus-1, sindbis, punta toro, coxsackie B4 and echovirus how-
ever, these nucleosides displayed neither cytotoxicity nor any appreciable antiviral
activity.
ACKNOWLEDGMENTS
Antimycobacterial data were provided by the Tuberculosis Antimicrobial
Acquisition and Coordinating Facility (TAACF) through a research and devel-
opment contract with the U.S. National Institute of Allergy and Infectious Disease.
REFERENCES
1. Gaut, Z.N.; Solomon, H.M. J. Pharm. Sci., 1971, 60, 1887–1888.
2. Miller, O.N.; Gutiere, M.; Sullivan, J.G. In Metabolic effects of nicotinic acid and its
derivatives, K.F. Gey and L.A. Carlson (eds). Hans Huber, Bern, 1971, 609.
3. Schwartz, M.A.; Kolis, S.J.; Williams, T.H.; Gabriel, T.F.; Toome, V. Drug Metab.
Dispos., 1973, 1, 557–564.
4. Pagani, G.; Pregnolata, M.; Ubiali, D.; Terrani, M.; Piersimani, C.; Scaglione, F.;
Fraschini, F.; Gascon, A.R.; Munoz, J.L.P. J. Med. Chem., 2000, 43, 199–204.
5. Hanna, N.B.; Joshi, R.V.; Larson, S.B.; Robins, R.K.; Revankar, G.R. J. Heterocycl.
Chem., 1989, 26, 1835–1843.

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