A green expedient synthesis of pyridopyrimidine-2-thiones and their antitubercular activity

Article abstract of DOI:10.1016/j.bmcl.2011.03.045

The pseudo four-component domino reactions of N-substituted-4-piperidones, substituted aromatic aldehydes and thiourea in the presence of solid sodium ethoxide under solvent-free conditions afforded pyridopyrimidine-2-thiones in almost quantitative yields

Full text of DOI:10.1016/j.bmcl.2011.03.045

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3012–3016
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A green expedient synthesis of pyridopyrimidine-2-thiones and their
antitubercular activity
Stephen Michael Rajesh a, Raju Suresh Kumar a, Lawzer Arun Libertsen a, Subbu Perumal a,
,
⇑
Perumal Yogeeswari b, Dharmarajan Sriram b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science—Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad
500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The pseudo four-component domino reactions of N-substituted-4-piperidones, substituted aromatic
aldehydes and thiourea in the presence of solid sodium ethoxide under solvent-free conditions afforded
pyridopyrimidine-2-thiones in almost quantitative yields by simply grinding for 1–2 min. at ambient
temperature. The synthesized compounds were screened for their in vitro activity against Mycobacterium
tuberculosis H37Rv. Among them, (E)-6-benzyl-8-(2,4-dichlorobenzylidene)-4-(2,4-dichlorophenyl)-
Received 12 January 2011
Revised 10 March 2011
Accepted 11 March 2011
Available online 17 March 2011
3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidine-2(1H)-thione (MIC 2.8 lM) displays the maximum
Keywords:
activity, being 2.7 and 1.7 times more active than the first line antitubercular drugs ethambutol and
ciprofloxacin, respectively, and less active than rifampicin and isoniazid, by 28 and 7 times, respectively.
Ó 2011 Elsevier Ltd. All rights reserved.
Pyridopyrimidinethiones
Pseudo four-component reactions
Green synthesis
Antitubercular activity
Pyrimidinone sub-structure is prevalent in many natural/syn-
thetic biologically active compounds, which find applications in
pharmaceutical and biochemical arena.1 Dihydropyrimidinethi-
ones (DHPMs) or 2-thiopyrimidines (2-TP)2 find applications as
and antitumour agents.15b,c Structure–activity studies disclose that
anticancer activity of pyrimidinones and pyrimidinethiones is
ascribable to the presence of (i) nitrogen heterocyclic ring and
(ii) thione functionality, which generally enhance the activity. This
has kindled substantial interest of researches in synthesis of new
pyrimidinones and pyrimidinethiones.
antihypertensive (SQ 32926) (I),3
a1a-adrenergic receptor antago-
nists,4 antibacterial, antiinflammatory and antitumour agents.5 In
2-TP, the sulfur atom serves as an interesting replacement for the
oxygen atom bonded to C-2 in uridine base.6 DHPMs can be con-
verted into either 1,3-diamines or guanidines, which constitute
the core structural elements commonly present in natural products
(Fig. 1), exemplified by the polycyclic marine alkaloids such as
crambines (II), ptilomycalin (III) and batzelladine.7 Ptilomycalin
(III) displays significant activity against a series of cancer cell lines
and DNA polymerase activity of the reverse transcriptase of human
immunodeficiency virus type 1 (HIV-1 RT).8 Batzelladines A and B
(IV and V) are the first low molecular weight natural products re-
ported in the literature to inhibit the binding of HIV-gp120 to the
CD4 cell surface receptor protein on T-cells.9 Monastrol (VI), with
the pyrimidine-2-thione motif, specifically inhibits the motility of
the mitotic kinesin Eg5.10
Tuberculosis (TB) is the leading cause of infectious disease mor-
tality in the world. According to World Health Organization report
(WHO),16 in 2008, there were an estimated 8.9–9.9 million inci-
dent cases of TB, 9.6–13.3 million prevalent cases of TB, 1.1–1.7
million deaths from TB among HIV-negative people and an addi-
tional 0.45–0.62 million TB deaths among HIV-positive people.
Further, HIV-infected patients have an elevated risk of primary or
reactivated tuberculosis which may enhance HIV replication and
the risk of death. The WHO has estimated that, if the present trend
continues, TB could claim more than 30 million lives between 2000
and 2020.17 In the last 50 years, only a few drugs have been
approved by the Food and Drug Administration to treat TB. This
discloses the difficulties associated with the discovery and clinical
testing of new candidates and the absence of pharmaceutical
industry research in this area. Hence, the discovery of fast-acting
new drugs to effectively cure TB is imperative. As continuation of
our research programme embarked on to discover potent
antitubercular candidates by 1,3-dipolar cycloaddition18 and
multi-component or domino reactions,19 we now report an atom
economic, four-component, green synthesis of pyrido[4,3-d]pyrim-
idine-2-thiones and their antimycobacterial activities.
Pyridopyrimidine analogues constitute a novel class of adeno-
sine kinase inhibitors,11 besides being the most highly potent
and selective antagonists of cholecystokinin receptor subtype-1
(CCK1R),12 tyrosine kinase inhibitors,13 diuretics,14 antiviral15a
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.045

S. M. Rajesh et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3012–3016
3013
NH2
HN
NH
X
(CH2)nCH3
CO2(CH2)n
O
S
H
H
O
O
N
N
iPrO2C
H3C
N
NH2
N
O
HN
NH2
NH2
R
N
H
O
(I)
Crambines (II)
(antihypertensive)
Ptilomycalin (III)
NH
NH
NH
N
O
NH
O
N
O
O
H
H
H
H
O
N
O
N
8
8
H
H
H
O
H
H2N
N
H2N
N
H3C
N
N
C9H19
O
H3C
N
N
C7H15
3
3
H
H
NH
NH
Batzelladine B (V)
Batzelladine A (IV)
EtO2C
H3C
NH
N
S
H
Monastrol (mitotic kinase inhibitor)(VI)
Figure 1. Biologically important compounds containing DHPM and related structural units.
Ar
H
O
S
N
S
Solid NaOEt
1-2 min
+
+
2ArCHO
H2N
NH2
N
N
NH
R
R
H
Ar
1 R = CH3
2 R = CH
3
4
5 R = CH3
2C6H5
6 R = CH
2C6H5
Scheme 1. Synthesis of pyridopyrimidine-2-thiones 5 and 6.
Multi-component reactions (MCRs) constitute a highly valuable
synthetic tool for the construction of polyfunctionalized heterocy-
clic compounds required for drug discovery programmes,20 as
ꢀ60% of drug candidates either in pipeline or currently in market
are heterocycles. They provide convergent, atom economic and
eco-friendly synthesis of molecules of high levels of complexity
and diversity enabling the assembly of three or more simple and
flexible building blocks in practical one-pot operations,21 besides
being amenable for combinatorial library generation.
ent temperature afforded the pyrimidine-2-thiones 5 and 6 in
almost quantitative yields (93–98%; Scheme 1). In a typical exper-
iment, a mixture of 1 or 2 (1 mmol), aromatic aldehydes (2 mmol),
thiourea (1 mmol) and solid sodium ethoxide (3 mmol) was
ground well uniformly in a semimicro boiling tube at ambient tem-
perature for about 1–2 min during which period the reaction went
to completion (TLC). Then water was added to the mixture, the
product was filtered and dried in vacuo.22
In the present investigation, pseudo four-component domino
reactions of N-substituted-4-piperidones (1 and 2), aromatic alde-
hydes (3) and thiourea (4) under solvent-free conditions at ambi-
6.61, s
119.4
Cl
Cl
3.28, d
3.44, d
51.3
H
7.80, s, NH
J = 13.8 Hz
H
N
Cl
Cl
H
S
8a
8
1
H
2
7
6
174.4
9
H
110.4
6.99-7.42, m
NH and aromatic
N
NH
5
4
4a
H
H
N
H
H
3
8
H
1
S
8a
4a
H
H
2
3.49, s
60.6
7
6
3
NH
Cl
Cl
N
2.82, d
3.11, d
J = 16.8 Hz
H
5
4
H
5.46, s
54.5
H
51.7
Cl
Cl
Figure 2. Selected HMBCs of 6k.
Figure 3. 1H and 13C chemical shifts of 6k.

3014
S. M. Rajesh et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3012–3016
S
S
O
O
S
N
NH
Ar
HN
NH
Ar
2 ArCHO
Ar
Ar
H2N
NH2
Ar
Ar
3
4
H
N
R
N
R
-H2O
NaOEt
N
R
N
R
9 R = CH
10 R = CH32C6H5
5 R = CH3
6 R = CH2C6H5
1 R = CH3
2 R = CH2C6H5
7 R = CH3
8 R = CH2C6H5
Scheme 2. Mechanistic proposal for the formation of pyridopyrimidine-2-thiones 5 and 6.
It is pertinent to note that in a previous study El-Subbagh et
al.15a reported the formation of pyrido[4,3-d]pyrimidine-2-thiones
(5d, 5g and 5s), respectively, in 80%, 91% and 83% yields from the
reaction of equimolar amounts of 1-methyl-3,5-bis[(E)-arylmeth-
ylidene]tetrahydro-4(1H)-pyridinones 7 with thiourea 4 with two
molar equivalents of sodium in n-butanol under reflux for 10 h.
Rostom et al.15b reported 5c in 27% yield from the reaction of equi-
molar amounts of 7, thiourea and sodium hydroxide in ethanol.
Consequently, the present solvent-free expedient protocol, requir-
ing only water to work up the product, completed in 1–2 min
affording an excellent yield of the product (93–98%), is clearly
more advantageous than the literature methods in terms of yield,
reaction time and eco-friendliness. It is pertinent to note that sim-
ilar pseudo four-component synthesis has been reported only for
pyrimidinones fused to carboyclic ring bearing arylidene function
in lower yields (50–92%) and longer reaction times (3–10 h) from
the reaction of cyclopentanone with aromatic aldehydes and urea/
thiourea in the presence of YbCl3.15g In another related study, the
above reactants in presence of TMSCl15h in DMF–CH3CN mixture
displayed aryl substituent-mediated product selectivity with
inconsistent yields of the bicyclic pyrimidinone for the range of
substituents studied.
hibit MTB. Among them, four compounds, viz 6k, 6n, 5q, 6m are
found to be 2.7, 2.2, 1.4 and 1.1 times, respectively, more active
than ethambutol (MIC = 7.6
respectively, are 1.7 and 1.4 times as active as the first line antitu-
bercular drug, ciprofloxacin (MIC = 4.7 M). When compared to the
MIC values of standard drugs, rifampicin (MIC: 0.1 M) and isoni-
azid (MIC: 0.4 M), all the compounds are less active against MTB.
lM). Two compounds 6k and 6n,
l
l
l
From the viewpoint of structure–activity, the following trends
emerge (Table 1 and Chart 1):
(i) In general, the N-benzylpyridopyrimidine-2-thiones 6 show
better activity than their N-methyl analogs 5 suggesting that
lipophilicity could be an important factor for activity.
(ii) In both the series 5 and 6, compounds with aryl ring bearing
halogens exhibit enhanced activity, the order of activity in
series
5 being: 4-F < 2-Cl = 4-Cl < 3-Br = 4-Br < 3-F < 2,4-
Cl2 < 2,6-Cl2 and in series 6 the order of activity is found to
be:4-(CH3)2N < 1-naphthyl < 2,5-(CH3O)2 = 3,4-
(CH3O)2 < 3,4,5-(CH3O)3 < 2-Cl = 4-Cl < 4-(CH3)2CH < 2-
Br < 3-F < 4-F < 2,4-Cl2.
Table 1
Yield and MICa
(lM) values of pyridopyrimidine-2-thiones 5 and 6 against MTB
Structural elucidation of the pyridopyrimidine-2-thiones was
accomplished from 1D and 2D NMR spectroscopic data as de-
scribed for 6k as a representative case. The 1H NMR spectrum of
6k has a singlet at 5.46 ppm readily assignable to H-4. The H-4
shows H,H-COSY correlations with the doublets at 2.82 and
3.11 ppm (J = 16.8 Hz) enabling their assignment to H-5a and H-
5b. The other doublets at 3.28 and 3.44 ppm (J = 13.8 Hz) can be
readily assigned to H-7a and H-7b. The 1H singlet at 6.61 ppm is
due to H-9 and the 2H singlet at 3.49 ppm is due to CH2 of N-
CH2Ph. One of the NH hydrogens of the pyrimidine ring appears
as a singlet at 7.80 ppm, while the other merges with the signal
of the aromatic hydrogens in the region 6.99–7.42 ppm. The
assignment of signals of carbon bearing hydrogens has been done
from the chemical shifts of hydrogens and C,H-COSY correlations.
The above assignments are also supported by the HMBCs (Fig. 2).
The 1H and 13C chemical shifts of 6k are depicted in Figure 3.
Entry
Compd
Ar
Yield (%)
MIC (lM)
5
6
5
6
5
6
1
2
3
4
5
6
7
8
a
b
c
a
b
c
4-(CH3)2NC6H4
2,5-(CH3O)2C6H3
3,4-(CH3O)2C6H3
4-CH3OC6H4
2-CH3C6H4
4-(CH3)2CHC6H4
4-CH3C6H4
C6H5
1-Naphthyl
2-ClC6H4
2,4-Cl2C6H3
4-ClC6H4
3-FC6H4
4-FC6H4
3-BrC6H4
2-BrC6H4
2-CH3OC6H4
3,4,5-(CH3O)3C6H2
2,6-Cl2C6H3
4-BrC6H4
98
93
97
94
96
97
96
57.7
53.5
53.5
61.4
66.6
57.9
66.6
71.9
55.9
30.0
12.9
30.0
16.3
32.6
24.7
––
49.1
46.0
46.0
51.7
55.4
24.6
55.4
59.0
47.7
25.4
2.8
25.4
6.8
3.4
––
21.5
––
94 (27)b
94 (80)c
98
d
e
d
e
f
f
96
95
97
g
h
i
g
h
i
96 (91)c
95 (96)d
95
96 (49)d
97
9
10
11
12
13
14
15
16
17
18
19
20
21
22
j
j
97
96
98
k
l
k
l
98
97
95
96 (87)d
97
m
n
o
––
p
––
q
r
m
n
––
o
––
p
––
––
––
––
95
96
96
––e
97
The pyridopyrimidine-2-thiones
5
and
6
are presumably
––e
97
––e
98
61.4
––
5.6
formed by multi-step domino reactions (Scheme 2), triggered by
the initial condensation of N-substituted-4-piperidinones and
2 mol of aromatic aldehydes sequentially affording N-substi-
––e
41.4
––
98
95
––e
––e
––e
––e
24.7
69.5
55.9
0.1
––
––
––
s
t
2-Thienyl
95 (83)c
96
tuted-3,5-bis[(E)-1-arylmethylidene]-4-piperidinones
7 and 8.
2-Naphthyl
Rifampicin
Isoniazid
Ciprofloxacin
Ethambutol
These intermediates 7 and 8 react with thiourea furnishing 5 and
6 via Michael addition–condensation–tautormerization domino
sequence.
All the thirty six compounds were screened for their in vitro
antimycobacterial activity against Mycobacterium tuberculosis
H37Rv (MTB) by agar dilution method for the determination of
MIC in duplicate. The MIC (lM) values of the synthesized com-
pounds along with the standard drugs for comparison are pre-
sented in Table 1. Twenty compounds, 5j–5o, 5q, 5r, 6a–6c, 6f,
6i–6p, have MIC ranging from 2.8 to 49.1 lM which effectively in-
0.4
4.7
7.6
a
The MIC is defined as the minimum concentration of the compound required to
inhibit 99% of bacterial growth.
b
Ref. 15b.
Ref. 15a.
Ref. 15f.
c
d
e
These reactions did not proceed.

S. M. Rajesh et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3012–3016
3015
Chart 1. Comparison of MIC (
lM) values of series 5, 6 and standard drugs.
5. Kappe, C. O. Tetrahedron 1993, 49, 6937.
In conclusion, the present investigation describes a one pot,
pseudo four-component, green synthesis of several pyridopyrimi-
dinethiones from the reaction of N-methyl/benzyl-4-piperidinones
(1/2), substituted aromatic aldehydes and thiourea in presence of
solid sodium ethoxide at ambient temperature under solvent-free
conditions. The method described is far more advantageous than
the literature procedures with respect to convergence, eco-friend-
liness, yield and reaction time. The only solvent required for this
synthesis is water to wash the product. The compounds, 6k and
6n, display significant in vitro antimycobacterial activity against
M. tuberculosis H37Rv.
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S.P. thanks the Department of Science and Technology, New
Delhi, for funding for an Indo–Spanish collaborative major research
project (No. DST/INT/SPAIN/P-11/09) and for funds under IRHPA
program for funds for the purchase of a high resolution NMR spec-
trometer and the University Grants Commission, New Delhi. SMR
thanks University Grants Commission, New Delhi for the award
of Junior Research Fellowship.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.03.045.
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22. General procedure for the synthesis of pyrido[4,3-d]pyrimidine-2-thiones.
dC 51.3, 51.7, 54.5, 60.5, 110.4, 119.3, 126.6, 126.7, 127.4, 127.8, 128.2, 128.4,
128.9, 129.4, 129.7, 130.3, 131.1, 132.0, 133.2, 134.1, 134.6, 135.3, 135.9, 136.7,
174.4. Anal. calcd for C27H21Cl4N3S: C, 57.77; H, 3.77; N, 7.49. Found: C, 57.87;
H, 3.86; N, 7.38%.
A
mixture of N-substituted-4-piperidinone (1 mmol), aromatic aldehyde
(2 mmol), thiourea (1 mmol) and sodium ethoxide (3 mmol) were ground
well in a semimicro boiling tube at ambient temperature for about 1–2 min.
After completion of the reaction as evident from TLC, water (50 mL) was added
to the mixture and the product was filtered and dried in vacuo.
(E)-8-(2-Chlorobenzylidene)-4-(2-chlorophenyl)-6-methyl-3,4,5,6,7,8-
hexahydropyrido[4,3-d]pyrimidine-2(1H)-thione 5j. Isolated as white solid.
(0.357 g, 97%). Mp = 145 °C; IR (KBr): 759, 1035, 1195, 1479, 1571,
(E)-6-Benzyl-8-(2,4-dichlorobenzylidene)-4-(2,4-dichlorophenyl)-3,4,5,6,7,8-
hexahydropyrido[4,3-d]pyrimidine-2(1H)-thione 6k. Isolated as pale yellow
solid. (0.487 g, 98%). Mp = 142 °C; IR (KBr): 852, 1285, 1473, 1560,
3376 cmÀ1 1H NMR (300 MHz, DMSO-d6) dH 2.23 (s, 3H, N-CH3), 2.75 (d, 1H,
;
J = 16.7 Hz, H-5a), 3.05 (d, 1H, J = 16.7 Hz, H-5b), 3.22 (d, 1H, J = 13.4 Hz, H-7a),
3.35 (d, 1H, J = 13.4 Hz, H-7b), 5.55 (s, 1H, H-4), 6.85 (s, 1H, H-9), 7.15–7.49 (m,
8H, aromatic), 8.04 (br s, 1H, NH), 8.39 (br s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6) dC 44.4, 53.7, 54.4, 110.6, 119.8, 125.8, 126.1, 127.5, 127.7, 128.6,
129.2, 129.3, 129.4, 130.3, 131.9, 133.5, 133.7, 137.8, 172.7. Anal. calcd for
3388 cmÀ1 1H NMR (300 MHz, DMSO-d6) dH 2.82 (d, 1H, J = 16.8 Hz, H-5a),
;
3.11 (d, 1H, J = 16.8 Hz, H-5b), 3.28 (d, 1H, J = 13.8 Hz, H-7a), 3.44 (d, 1H,
J = 13.8 Hz, H-7b), 3.49 (s, 2H, CH2Ph), 5.46 (s, 1H, H-4), 6.61 (s, 1H, H-9), 6.99–
7.42 (m, 12H, NH and aromatic), 7.79 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6)
C
21H19Cl2N3S: C, 60.58; H, 4.60; N, 10.09. Found: C, 60.65; H, 4.51; N, 10.17%.