Synthesis and antitubercular evaluation of novel substituted aryl and thiophenyl tethered dihydro-6H-quinolin-5-ones

Article abstract of DOI:10.1016/j.bmcl.2010.12.082

A series of novel aryl and thiophenyl tethered dihydro-6H-quinolin-5-ones have been synthesized in very good yields through CeCl₃· 7H₂O-NaI catalyzed one-pot condensation of β-enaminones derived from the respective methyl ketones; 1,

Full text of DOI:10.1016/j.bmcl.2010.12.082

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1214–1217
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antitubercular evaluation of novel substituted aryl
and thiophenyl tethered dihydro-6H-quinolin-5-ones
Srinivas Kantevari a, , Santhosh Reddy Patpi a, Balasubramanian Sridhar b, Perumal Yogeeswari c,
⇑
Dharmarajan Sriram c
a Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 007, India
c Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad 500 078, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel aryl and thiophenyl tethered dihydro-6H-quinolin-5-ones have been synthesized in very
good yields through CeCl3Á7H2O–NaI catalyzed one-pot condensation of b-enaminones derived from the
respective methyl ketones; 1,3-cyclohexanedione & 5,5-dimethyl-1,3-cyclohexanedione and ammonium
acetate refluxing in 2-propanol. Dihydro-6H-quinolin-5-ones 3a–f was further derivatized to the respec-
tive hydroxymethyl analogs using proline as an organocatalyst in aqueous media. Among the all 18 com-
pounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB),
Received 1 October 2010
Revised 7 December 2010
Accepted 16 December 2010
Available online 24 December 2010
Keywords:
Thiophene
b-Enaminone
dihydro-6H-quinolin-5-ones 4e and 4f were found to be most active with MIC 3.13 lg/mL.
Ó 2010 Elsevier Ltd. All rights reserved.
Dihydro-6H-quinolin-5-ones
Antimycobacterial activity
Mycobacterium tuberculosis
Tuberculosis is a chronic infectious disease caused mainly by
Mycobacterium tuberculosis (MTB).1 It claims over two million lives
worldwide each year and dwells hidden in as many as two billion
people. It is estimated that between 2005 and 2020, one billion
people will be newly infected, over 125 million people will get sick
and 30 million will die of tuberculosis if control is not further
strengthened.1–3 In addition, the evolution of its new virulent
forms like multi drug resistant (MDR-TB) and extremely drug resis-
tant (XDR-TB) has become a major threat to human kind.2 Among
HIV infected people, the resurgence of TB is alarming due to the
development of pathogenic synergy.2,3 The worsening situation
has prompted the world health organization (WHO) to declare
tuberculosis a global public health crisis.3 All the above facts also
stressed an urgent need for development of fast acting new antitu-
bercular drugs with diverse and unique structural features.4
In recent years, the quinolinone nucleus has gained considerable
attention among medicinal chemists.5 It is a key unit in several syn-
thetic and natural products possessing wide range of biological
activities. Streptonigrin, Lavendamycin and Ascidiathiazones
(Fig. 1) are among the few quinolinone based successful drug candi-
dates in the treatment of various diseases.6 Thiophene is also an
emerging pharmacophoric unit to induce variable pharmacological
activities.11 For instance, thienoquinolones display antitumour
activity,7 while thieno pyrimidones possess analgesic and anti-
inflammatory activities.8 Our quest for obtaining biologically more
potent antitubercular agents prompted us to synthesize new aryl
and thiophene embodied nitrogen heterocycles with quinolinone
O
O
OCH3
HOOC
RO2C
H3C
N
NH2
N
NH2
O
O
H3C
HO
NH2
NH
H3CO
OCH3
Lavendamycin
Streptonigrin
O
O
O
S
O
R1
R2
N
N
O
N
N
H
O
Synthetic antitubercular agent
Ascidiathiazones A & B
⇑
Corresponding author. Tel.: +91 4027191437; fax: +91 4027198933.
E-mail addresses: kantevari@yahoo.com, kantevari@gmail.com (S. Kantevari).
Figure 1. Representative bio-active quinolinones.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.082

S. Kantevari et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1214–1217
1215
R1 R1
O
O
O
O
O
N
N
R1
R1
O
O
R
R
2a-c
N
N
DMF-DMA
R1
R1
R
R
S
1a-c
CeCl3.7H2O
NH4OAc, i-PrOH
Xylene
Reflux
O
R
3d-f: R1=H
4d-f: R1=CH3
3a-c: R1=H
R
S
S
4a-c: R1=CH3
2d-f
1d-f
Scheme 1. Synthesis of dihydro-6H-quinoline-5-ones 3a–f and 4a–f.
Table 1
Synthesis of b-enaminones 2a–f
b-enaminones 2a–f formed from 1a–f were fully characterized by
1H and 13C NMR, IR and mass spectral data.
On the basis of our recent work,10 initially, b-enaminone 2a was
reacted with 5,5-dimethylcyclohexane-1,3-dione (dimedone) and
ammonium acetate in the presence of 20 mol % of CeCl3Á7H2O–
NaI catalyst (Scheme 1). The reaction was facile when CeCl3Á7H2O
in combination with NaI was used and no reaction took place with
NaI alone. The reaction with CeCl3Á7H2O alone requires 24 h to give
product 4a in 35% yield. Screening various solvents (DMF, metha-
nol, 2-propanol, acetonitrile, water and neat) resulted optimum
yield (89%) of target product 4a in 2-propanol at reflux tempera-
ture. Having succeeded with the reaction, the enaminones 2a–f
in 2-propanol were refluxed with 1,3-cyclohexanedione or 5,5-di-
methyl cyclohexane-1,3-dione and ammonium acetate in the pres-
ence of 20 mol % of CeCl3Á7H2O–NaI catalyst (Table 2). All the
products 3a–f and 4a–f obtained in excellent yields (68–89%) were
fully characterized by 1H and 13C NMR, IR and mass (ESI and HRMS)
spectral data.
S. no.
Ketone
R
b-Enaminone
Ref.
1
2
Yielda (%)
mp (°C)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
2a
2b
2c
2d
2e
2f
90
86
83
88
82
85.5
87–88
90–91
99
101
106
10a
10a
10a
11
—
12
CH3
OCH3
H
Cl
Br
110
a
Isolated yields.
backbone. We herein report an efficient synthesis of novel aryl and
thiophenyl tethered dihydro-6H-quinolin-5-ones 3a–f, 4a–f, in
excellent yields through CeCl3Á7H2O–NaI catalyzed one-pot conden-
sation of b-enaminones (derived from aryl and thiophenyl methyl
ketones 1a–f), cyclic-1,3-dicarbonyls and ammonium acetate. The
dihydro-6H-quinolin-5-ones 3a–f were further derivatized to
hydroxymethyl analogs 5a–f using proline as an organocatalyst in
aqueous media. Screening all new compounds 3a–f, 4a–f and 5a–f
for in vitro activity against M. tuberculosis H37Rv (MTB) resulted
dihydro-6H-quinolin-5-ones 4e and 4f as most potent antitubercu-
Further to obtain compounds with enhanced lipophobic nature,
the dihydro-6H-quinolin-5-ones 3a–f was subjected to hydrox-
ymethylation at
a-position to the carbonyl group. After series
experiments, the reaction of dihydro-6H-quinolin-5-ones 3a–f
was successful with paraformadehyde in aqueous media using pro-
line as an organocatalyst12 under modified reaction conditions,13
resulted products 5a–f in very good yields (Scheme 2). The com-
pounds 5a–f was characterized14 by 1H and 13C NMR, IR and mass
(ESI and HRMS) spectral data. The single crystal X-ray diffraction
studies of 5b unambiguously confirmed structure (Fig. 2).
The antimycobacterial activity of the synthesized dihydroquin-
olinones 3a–f, 4a–f and 5a–f has been screened in triplicate
against M. tuberculosis H37Rv (MTB) by agar dilution method for
lar agents with MIC of 3.13 lg/mL.
b-Enaminones,9 being versatile substrates in the synthesis of
heterocyclic compounds and drug intermediates, were chosen as
starting material for the synthesis of dihydro-6H-quinolin-5-ones.
They were prepared in excellent yields by the conversion of respec-
tive aryl and thiophenyl methyl ketones 1a–f using dimethylform-
amide dimethylacetal refluxing in xylene (Scheme 1,Table 1). All
Table 2
Physical data and antitubercular evaluation of 3a–f and 4a–f against M. tuberculosis H37RV
Entry
Enaminone
2
Product
R
Yielda (%)
mp (°C)
Log P/C Log Pb
MIC (lg/mL)
R1
3
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
—
H
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
82
80
76
73
70
71
89
85
80
68
75
72
—
115
88
96
3.04/1.975
3.52/3.621
2.91/3.140
3.02/3.014
3.39/3.748
3.73/3.898
3.84/3.013
4.32/4.659
3.71/4.179
3.82/4.052
4.19/4.786
4.53/4.936
—
12.5
12.5
12.5
12.5
6.25
6.25
12.5
6.25
12.5
6.25
3.13
3.13
0.1
CH3
OCH3
H
Cl
Br
98
116
119
67
119
126
85
96
114
—
H
CH3
OCH3
H
Cl
Br
—
—
—
9
10
11
12
13
14
15
Isoniazid
Ethambutol
Pyrazinamide
—
—
—
—
—
—
—
—
—
—
—
3.13
50.0
a
Isolated yields.
Calculated using Chemdraw Ultra 11.0.
b

1216
S. Kantevari et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1214–1217
O
O
O
OH
OH
O
OH
OH
N
(HCHO)n
N
3a-c
R
N
S
Proline, Water
0.5N NaOH
R
R
5d-f
5a-c
N
S
3d-f
R
Scheme 2. Proline catalyzed synthesis of 5a–f.
Figure 2. ORTEP representation of compound 5b with thermal displacement ellipsoids drawn at the 30% probability.
Table 3
Physical data and antitubercular evaluation of 5a–f against M. tuberculosis H37RV
Entry
3
R
Product 5
Yielda (%)
mp (°C)
Log P/C Log Pb
MIC (lg/mL)
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
H
5a
5b
5c
5d
5e
5f
50.6
66.7
55.8
68.2
62.5
48.2
130
156
152
147
172
185
2.19/0.950
2.67/2.597
2.06/2.116
2.17/1.990
2.54/2.723
2.88/2.873
>25.0
>25.0
>25.0
>25.0
>25.0
>25.0
CH3
OCH3
H
Cl
Br
a
Isolated yields.
Calculated using Chemdraw Ultra 11.0.
b
the determination of MIC. The minimum inhibitory concentration
(MIC) is defined as the minimum concentration of compound re-
quired to completely inhibit the bacterial growth. The MIC values
of 3a–f, 4a–f and 5a–f along with the standard drugs for compar-
ison are furnished in Table 2 and 3. All the eighteen new com-
pounds screened have shown in vitro activity against MTB with
In conclusion, we have synthesized new aryl and thiophenyl
tethered dihydro-6H-quinolin-5-ones in very good yields through
CeCl3Á7H2O–NaI catalyzed one-pot condensation of b-enaminones,
1,3-cyclohexanedione & 5,5-dimethyl-1,3-cyclo hexanedione and
ammonium acetate refluxing in 2-propanol. Proline catalyzed reac-
tion of dihydro-6H-quinolin-5-ones 3a–f with HCHO in aqueous
media resulted hydroxymethyl analogs 5a–f in good yields. Screen-
ing all these new derivatives against M. tuberculosis H37Rv (MTB)
resulted dihydro-6H-quinolin-5-ones 4e and 4f as most potent
MIC ranging from 3.13 to 25.0
and 4d inhibited MTB with MIC of 6.25
4e and 4f inhibited MTB with MIC of 3.13
to one of the first line anti-TB drug ethambutol (MIC 3.13
two compounds 4e and 4f are found to be equally active as etham-
butol. When compared to pyrazinamide (MIC 50.8 g/mL), all the
l
g/mL. Four compounds 3e, 3f, 4b
g/mL and two compounds
g/mL. When compared
g/mL),
l
l
l
antitubercular agents with MIC 3.13 lg/mL.
Acknowledgments
l
18 compounds were found to be more potent, though all the com-
pounds were less potent than another anti-TB drug isoniazid.
Structural correlations of the new compounds with respect to
their antitubercular activity showed that introduction lipophobic
hydroxymethyl groups (Scheme 2,Table 3) profoundly decreased
Authors (S.K., S.R.P. and B.S.) are thankful to Dr. J.S. Yadav, Direc-
tor and Dr. V.V.N. Reddy, Head, Organic Chemistry Division-II, IICT,
Hyderabad for their continuous support, encouragement and finan-
cial assistance from MLP projects. S.R.P. (JRF) is thankful to CSIR for
fellowship.
their MIC values (>25 lg/mL). The result reveals that moderate
lipophilic nature is needed for dihydro-6H-quinolin-5-ones to be
active against M. tuberculosis H37Rv (MTB). In comparison with aryl
tethered dihydro-6H-quinolin-5-ones, thiophenyl tethered dihy-
dro-6H-quinolin-5-ones are better placed to show potent antitu-
bercular activity (Table 2). Dihydro-6H-quinolin-5-ones derived
from dimedone (entries 11 and 12, Table 2) are structurally better
correlates and showed potent activity against M. tuberculosis H37Rv
(MTB).
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opropenone (2e) yield: 82%; mp: 106 °C. 1H NMR (300 MHz, CDCl3) d 7.68
(d, J = 12.2 Hz, 1H), 7.34 (d, J = 3.9 Hz, 1H), 6.86 (d, J = 3.9 Hz, 1H), 5.43
(d, J = 12.2 Hz, 1H), 3.04 (d, br, 6H). 13C NMR (75 MHz, CDCl3) d 179.67, 153.74,
146.12, 135.36, 127.42, 126.94, 90.59, 45.03, 43.73. IR (KBr) 2922, 2803, 1631,
1548, 1413, 1361, 1278, 1031, 881, 761 cmÀ1. MS (ESI) m/z 216 (M+H)+, 218
(M+H+2)+; HRMS (ESI) calcd for C9H10ClNOS (M+H)+: 216.0249, found:
216.0257. 2-Thiophen-2-yl-7,8-dihydro-6H-quinolin-5-one (3d) yield: 63.3%;
mp: 90 °C. 1H NMR (CDCl3,100 MHz)
d 8.22 (d, J = 8.3 Hz, 1H), 7.65 (dd,
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J = 1.33 & 3.77 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.45 (dd, J = 1.33 & 5.09 Hz, 1H),
7.10 (dd, J = 3.77 & 5.09 Hz, 1H), 3.15 (t, J = 6.0 Hz, 2H), 2.66 (t, J = 6.0 Hz, 2H),
2.20 (qt, J = 6.0 Hz, 2H). 13C NMR (CDCl3, 75 MHz) d 197.4, 164.0, 155.5, 143.9,
135.6, 131.9, 129.7, 128.3, 126.5, 117.1, 38.4, 32.5, 21.7. IR (KBr) 3088, 2945,
1677, 1574, 1403, 1268, 1119, 833, 710 cmÀ1. MS(ESI) m/z 230 (M+H)+; HRMS
(ESI) calcd for C13H11NOS (M+H)+: 230.0639, found: 230.0646. 7,7-Dimethyl-2-
thiophen-2-yl-7,8-dihydro-6H-quinolin-5-one (4d) yield: 73%; mp: 75 °C. 1H
NMR (CDCl3,300 MHz) d 8.2 (d, J = 8.1 Hz, 1H), 7.65 (dd, J = 1.3 Hz & 3.7 Hz, 1H),
7.58 (d, J = 8.3 Hz, 1H), 7.45 (dd, J = 1.3 Hz & 5.0 Hz, 1H), 7.11 (dd, J = 3.7 Hz &
5.0 Hz, 1H), 3.04 (s, 2H), 2.51(s, 2H), 1.15 (s, 6H). 13C NMR (CDCl3, 75 MHz) d
197.5, 162.6, 156.0, 144.0, 135.2, 129.6, 128.3, 126.4, 125.2, 117.0, 52.0, 46.3,
32.9, 28.2. IR (KBr) 2943, 2865, 1683, 1573, 1402, 1294, 1108, 829, 717 cmÀ1
MS(ESI) m/z 258 (M+H)+; HRMS (ESI) calcd for C15H15NOS (M+H)+: 258.0952,
.
found:
258.0947.
6,6-Bis-hydroxymethyl-2-thiophen-2-yl-7,8-dihydro-6H-
quinolin-5-one (5d) yield: 68.2%; mp: 142 °C. 1H NMR (DMSO, 300 MHz) d
8.16 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 3.7 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.47
(d, J = 3.7 Hz, 1H), 7.12 (t, J = 3.7 Hz, 1H), 4.20 (br s, 2H), 3.80–3.65 (m, 4H), 3.20
(t, J = 6.4 Hz, 2H), 2.22 (t, J = 6.4 Hz, 2H). 13C NMR (CDCl3, 75 MHz) d 199.1,
162.8, 154.7, 143.5, 135.3, 131.2, 129.2, 128.0, 127.8, 126.0, 63.0, 51.7, 28.9,
27.8. IR (KBr) 3348, 2926, 1669, 1574, 1407, 1234, 1043, 945, 852, 727 cmÀ1
.
MS(ESI) m/z 290 (M+H)+; HRMS (ESI) calcd for C15H15NO3S (M+H)+: 290.0850,
found: 290.0846.