Synthesis and antimicrobial screening of some new 4-imino-3,5,7- trisubstituted pyrido[2,3-d]pyrimidines and their ribofuranosides as potential chemotherapeutic agents

Article abstract of DOI:10.1080/10426500490262342

Some new nucleosides, viz. 4-imino-3,5,7-trisubstituted-1-(2′, 3′,5′-tri-O-benzyl-β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin / e-2(1H)-ones / thiones(VII/VIII), have been synthesized by condensation of trimethylsilyl derivatives of 4-imino-3,5,7-trisubstitu

Full text of DOI:10.1080/10426500490262342

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SYNTHESIS AND ANTIMICROBIAL SCREENING OF SOME
NEW 4-IMINO-3,5,7-TRISUBSTITUTED PYRIDO[2,3-
d]PYRIMIDINES AND THEIR RIBOFURANOSIDES AS
POTENTIAL CHEMOTHERAPEUTIC AGENTS
Shabana Khatoon a & Ashok K. Yadav a
a University of Rajasthan , Jaipur, India
Published online: 11 Aug 2010.
To cite this article: Shabana Khatoon & Ashok K. Yadav (2004) SYNTHESIS AND ANTIMICROBIAL SCREENING OF SOME NEW 4-
IMINO-3,5,7-TRISUBSTITUTED PYRIDO[2,3-d]PYRIMIDINES AND THEIR RIBOFURANOSIDES AS POTENTIAL CHEMOTHERAPEUTIC
AGENTS, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:2, 345-352, DOI: 10.1080/10426500490262342
To link to this article: http://dx.doi.org/10.1080/10426500490262342
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Phosphorus, Sulfur, and Silicon, 179:345–352, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490262342
SYNTHESIS AND ANTIMICROBIAL SCREENING
OF SOME NEW 4-IMINO-3,5,7-TRISUBSTITUTED
PYRIDO[2,3-d]PYRIMIDINES AND THEIR
RIBOFURANOSIDES AS POTENTIAL
CHEMOTHERAPEUTIC AGENTS
Shabana Khatoon and Ashok K. Yadav
University of Rajasthan, Jaipur, India
(Received April 22, 2003)
Some new nucleosides, viz. 4-imino-3,5,7-trisubstituted-1-(2ꢁ,3ꢁ,5ꢁ-tri-
O-benzyl–β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin/e–2(1H)-ones/
thiones(VII/VIII), have been synthesized by condensation of
trimethylsilyl derivatives of 4-imino-3,5,7-trisubstituted pyrido[2,3-
d]pyrimidin/e-2(1H)-ones/thiones (III/IV) with β-D-ribofuranosyl-
1-acetate-2,3,5-tribenzoate. Compounds III/IV have been synthesized
by refluxing 2-amino-3-cyano-4,6-disubstituted pyridine (II) with
substituted an arylisocyanate or an isothiocyanate respectively. The
structure of all the synthesized compounds have been established
by IR and 1H NMR studies. These compounds have been screened
for antimicrobial activities in order evaluate. The possibility of the
derivatives to be used as potential chemotherapeutic agents.
Keywords: Antimicrobial activities; nucleosides; pyrido[2,3-d]
primidines; spectral studies
The pyrido[2,3-d]pyrimidine derivatives have been well recognized and
documented by a large number of patents, as chemotherapeutic agents,
viz. antibacterial,1,2 anticancer,3−4 antiulcer,5 anticonvulsant,6,7
antihypertensive,8 antitumor,9 antifungal,10,11 antiAIDS,12 anti-
herpes,13 antiviral,14 and antineuplastic.15 With a recent patent, e.g.,
Martin et al.16 have demostrated that pyrido[2,3-d]pyrimidines are ac-
tive against P38 kinase; Reinhard et al.17 have synthesized pyrido[2,3-d]
pyrimidine derivatives as analogs of the antifolates methotrexate.
Financial support of this work (including a fellowship to S.K.) from UGC, New Delhi
is gratefully acknowledged.
Address correspondence to A. K. Yadav, Department of Chemistry, University of
Rajasthan, Jaipur-302004, India. E-mail: draky@sify.com
345

346
S. Khatoon and A. K. Yadav
The manifold of diverse pharmacological activities shown by
pyrido[2,3-d]pyrimidines and our interest in this area18,19 led us
to synthesize some new 4-imino-3,5,7-trisubstituted pyrido[2,3-d]
pyrimidin/e-2-(1H)-ones/thions and their nucleosides, viz. 4-imino-3,5,
7-trisubstituted-1-(2ꢁ,3ꢁ,5ꢁ -tri-O-benzoyl-β-D-ribofuranosyl)pyrido[2,3-
d]pyrimidine-2(1H)ones/thiones.
RESULTS AND DISCUSSION
2-Amino-3-cyano-4,6-disubstituted pyridines II were prepared via
cyclisation20 of chalcones I, on treatment with ammonium acetate
in ethanol, via a Michael type condensation reaction. Compound II,
on refluxing with phenyl isocyanate/isothiocyanate, afforded 4-imino-
3,5,7-trisubstituted pyrido[2,3-d]pyrimidin/e-2(1H)-ones/thiones. Com-
pound III/IV on treatment with hexamethyldisilazane in toluene, gave
the corresponding trimethylsilyl derivatives V/VI, which, subsequently,
on stirring with β-D-ribofuranose-1-acetate-2,3,5-tribenzoate in vacua,
at 155–160◦C for 10 h, afforded 4-imino-3,5,7-trisubstituted(2ꢁ,3ꢁ,5ꢁ -
tri-O-benzoyl-β -D-ribofuranosyl)pyrido[2,3-d]
pyrimidin/e-2(1H)-
ones/thiones respectively (Scheme 1).
Characterization Data
The structure of synthesized compounds were well supported by their
spectral data (Table I).
IR Spectra
In IR spectra bands due to the CN and the NH2 groups in compound
II appeared in the region 2230–2130 cm−1, 3450–3315 cm−1 respec-
tively. Disappearance of −CN group and appearance of band due to
>C O group in the region 1750–1665 cm−1 in compound (IIIa–d and
VIIa–d) and >C S groups in the region 1235–1200 cm−1 in compounds
(IVa–e and VIIIa–e) and observation of bands, due to >NH and >C NH
in the region 3410–3345 cm−1 and 3230–3140 cm−1, respectively, are
supportive of their formation. Three characteristic bands of NHCS
moiety in the region 1560–1320 cm−1 has also been observed in com-
pound IVa, IVb, IVc, IVd, IVe and VIIIa, VIIIb, VIIIc, VIIId, VIIIe.
The absorption band, due to the >NH moiety in the region 3410–
3345 cm−1 was found to be absent in compounds VII–VIII, suggesting
that this was the site of ribosylation. The symmetric and asymmetric

Pyrimidines and Their Ribofuranosides
347
SCHEME 1
stretching vibrations due of C O C linkage of the sugar moiety in
compound VII–VIII has appeared in the region 1180 and 1020 cm−1
.
1H NMR
1
The H NMR spectra of compounds III and IV exhibit a multiplet in
the region δ 6.66–8.12 due to aromatic protons. The >NH protons in
compounds III and IV showed as a singlet at δ 8.09–8.26. In compound
IIIa, IIb/IVa, IVb, and VIIa, VIIb/VIIIa, VIIIb the protons of the NH2
group appeared as a broad peak, in the region δ 3.88–4.52. In compound
III/IV and VII/VIII protons of the >C NH appeared δ 8.09–8.50, as a
singlet. In the protons of the OCH3 group appeared a singlet between

348

Pyrimidines and Their Ribofuranosides
349
δ 3.60–3.90 in compounds IVa, IVb, IVc, IVd/VIIIa, VIIIb, VIIIc, VIIId;
and the protons of the CH3 groups were observed between singlet at
δ 3.40–3.70 in compounds IVe, VIIIe. In the NMR spectra of ribofura-
nosides VII and VIII, a multiplet due to aromatic protons appeared at
δ 6.69–8.20. The peak due to >NH moiety was found to be absent, in-
dicating the site of attachment of the sugar, while, a singlet due to the
OH protons in compounds IIIa, IVa, VIIa, VIIIa was noticed in the
region at δ 9.80–10.09.
Antimicrobial Screening
All the synthesized compounds were screened for their antibacterial
and antifungal activities at the conc. of 100 µg/disc, using strepto-
mycin and mycostatin, respectively, as the reference compounds. The
test organism used included Escherichia coli (gram negative bacteria),
Staphylococcus aureus (gram positive bacteria), Aspergillus flavus, As-
pergillus niger, and Fusarium oxysporium (Fungi). The disc diffusion
method developed by Varma et al.21 has been followed. The results have
been tabulated (Table II) in the form of inhibition zones and activity in-
dices. Although, all the compounds show moderate to fairly good activi-
ties, a closer look on the activity indices reveals that the ribofuranosides
are better antimicrobial agents than their bases.
EXPERIMENTAL SECTION
Melting point of all the synthesized compounds were determined in
open capillary tube and are uncorrected. IR spectra were recorded on
1
NICOLET MEGNA FT-IR 550 spectrometer and H NMR spectra on
a JEOL FX 90Q spectrophotometer using TMS as internal standard
(chemical shifts in δ, ppm). The purity of compounds was checked by
elemental analysis and also by TLC using silica gel “G,” as adsorbent
and visualization was accomplished by UV light /Iodine.
Synthesis of 2-Amino-3-cyano-4,6-disubstituted
Pyridine II
A chalcone (0.05 mmol), malononitrile (0.05 mmol), and ammonium
acetate (0.4 mmol) in ethanol (150 ml) was refluxed on a water bath
for 20–22 h and then the contents were poured onto crushed ice with
constant shaking. The solid, thus obtained, was washed with water sev-
eral times, and finally with ethanol. Recrystallization from ethanol to
gave22 II.

350
S. Khatoon and A. K. Yadav
TABLE II Results of Antimicrobial Study of 4-Imino-3,5,7-trisubstituted
pyrido[2,3-d]pyrimidin/e-2(1H)-ones/thiones and Their Ribofuraosides Zone of
Growth Inhibition (mm) (activity index)a
Bacteria
Fungl
Compd. no.
E. Coli
St. oureus
A. Niger
A. Flavus
F. Oxysporium
IIIa
IIIb
IIIc
IIId
IVa
IVb
IVc
IVd
7.9 (0.96)
8.0 (0.98)
8.3 (1.01)
8.4 (1.02)
8.1 (0.99)
8.2 (1.00)
8.5 (1.04)
8.6 (1.07)
8.7 (1.06)
8.8 (1.07)
9.1 (1.11)
9.9 (1.21)
10.0 (1.22)
9.8 (1.20)
10.1 (1.23)
10.3 (1.26)
10.9 (1.33)
10.6 (1.29)
7.9 (0.90)
8.3 (0.99)
8.4 (0.95)
8.5 (0.97)
8.2 (0.93)
8.6 (0.98)
8.4 (0.95)
8.9 (1.01)
8.7 (0.99)
9.2 (1.05)
8.9 (1.01)
9.3 (1.06)
9.9 (1.1)
8.9 (1.10)
9.2 (1.13)
9.0 (1.11)
9.4 (1.16)
9.1 (1.12)
9.4 (1.16)
9.3 (1.15)
9.9 (1.22)
9.8 (1.21)
9.6 (1.19)
10.1 (1.25)
9.9 (1.22)
10.4 (1.28)
10.2 (1.26)
10.5 (1.30)
10.0 (1.29)
11.2 (1.38)
11.1 (1.37)
9.0 (1.03)
9.4 (1.08)
9.2 (1.06)
9.6 (1.10)
9.3 (1.07)
9.5 (1.09)
9.8 (1.13)
9.9 (1.14)
9.7 (1.11)
9.9 (1.14)
10.1 (1.16)
9.8 (1.13)
10.6 (1.22)
9.6 (1.10)
9.9 (1.14)
10.1 (1.16)
10.5 (1.21)
10.3 (1.18)
9.5 (1.04)
9.6 (1.05)
9.3 (1.02)
9.8 (1.08)
9.6 (1.05)
9.7 (1.07)
9.5 (1.04)
9.9 (1.09)
10.2 (1.12)
9.9 (1.09)
10.2 (1.12)
10.1 (1.11)
10.5 (1.15)
9.8 (1.08)
10.2 (1.12)
10.5 (1.15)
11.1 (1.22)
10.6 (1.16)
IVe
VIIa
VIIb
VIIc
VIId
VIIIa
VIIIb
VIIIc
VIIId
VIIIe
9.5 (1.07)
9.4 (1.07)
10.0 (1.14)
10.3 (1.17)
10.2 (1.16)
a(Activity index) = Inhibition zone of the sample/inhibition zone of the standard.
Following 2-amino-3-cyano-4,6-disubstituted pyrimidines were
synthesized:
IIa 2-amino-3-cyano-4-(2-hydroxynaphthaldehyde)-6-(4-aminophenyl)
pyridine: m.p. 135◦C; yield 60%
IIb 2-amino-3-cyano-4-(3-chlorophenyl)-6-(4-aminophenyl)pyridine:
m.p. 105◦C; yield 82%
IIc 2-amino-3-cyano-4-(3-bromophenyl)-6-(4-bromophenyl)pyridine:
m.p. 110◦C; yield 77%
IId 2-amino-3-cyano-4-(4-chlorophenyl)-6-(4-bromophenyl)pyridine:
m.p. 112◦C; yield 70%
IIe 2-amino-3-cyano-4-(2-chlorophenyl)-6-(4-bromophenyl)pyridine:
m.p. 120◦C; yield 75%
Preparation of 4-Imino-3,5,7-trisubstituted
Pyrido[2,3-d]pyrimidine-2(1 H)-Ones III
A mixture of II (0.01 mmol), an arylisocyanate (0.01 mmol), dioxane
(18.0 ml), and pyridine (2.0 ml) was refluxed at 150◦C for about 18–20 h.

Pyrimidines and Their Ribofuranosides
351
After cooling, the contents of the flask were poured onto crushed ice with
constant stirring. The yellow solid mass, thus obtained, was washed
with water. The dried crude product, so obtained, was recrystallized for
DMF-ethanol (1:10).
Synthesis of 4-Imino-3,5,7-trisubstituted
Pyrido[2,3-d]pyrimidines-2(1H)-thiones IV
Compounds of II (0.01 mmol), appropriate aryl isothiocyanate
(0.01 mmol), dioxane (15.0 ml), and pyridine (2.0 ml), were refluxed
at 150◦C for about 18–20 h. After cooling, the contents of the flask were
poured onto crushed ice with constant stirring. The yellow solid mass,
thus obtained, was washed with water. The dried crude product was
recrystallized form DMF-ethanol (1:10).
Synthesis of 4-Imino-3,5,7-trisubstituted-1-(2ꢀ ,3ꢀ ,5ꢀ -tri-
O-benzoyl- β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin/e-2
(1H)-ones VII/Thiones VIII
Compounds III, IV (0.002 mmol) were refluxed with hexamethyl disi-
lazane (0.0124 mmol) containing few crystals of ammonium sulphate,
in toluene (30 ml) for 4 h. The coloured solution, thus obtained, was
filtered and the solvent was removed in vacuo at 100◦C. To this, β-
D-ribofuranose-1-acetate-2,3,5-tribenzoate (0.02 mmol) was added and
then stirred at 155–160◦C, under vaccuum, for 15 min in the absence
of moisture. The reaction contain was stirred for 10 h. During the re-
action period, the vaccuum was regularly applied for 5 min, at the end
of each hour. The melt so obtained was boiled in methanol for 10 min,
cooled, and filtered. The viscous mass of ribofuranoside, so obtained,
was crystallized with diethyl ether.
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