Studies on substituted benzo[h]quinazolines, benzo[g]indazoles, pyrazoles, 2,6-diarylpyridines as anti-tubercular agents

Article abstract of DOI:10.1016/j.bmcl.2013.08.101

Various substituted 5,6-dihydro-8-methoxybenzo[h]quinazolin-2-amine, 1-(3-(4-alkoxyphenyl)-7-methoxy-3,3a,4,5-tetrahydro-2H benzo[g]indazol-2-yl) ethanone, pyrazole and 2,6-diarylpyridine derivatives have been synthesized in good yields by an efficient me

Full text of DOI:10.1016/j.bmcl.2013.08.101

Accepted Manuscript
Studies on substituted benzo[h]quinazolines, benzo[g]indazoles, pyrazoles, 2,6-
diarylpyridines as anti-tubercular agents
Hardesh K. Maurya, Ruby Verma, Saba Alam, Shweta Pandey, Vinay Pathak,
Sandeep Sharma, Kishore K. Srivastava, Neelam S. Sangwan, Arvind S. Negi,
Atul Gupta
PII:
S0960-894X(13)01050-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2013.08.101
BMCL 20839
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
10 July 2013
24 August 2013
27 August 2013
Please cite this article as: Maurya, H.K., Verma, R., Alam, S., Pandey, S., Pathak, V., Sharma, S., Srivastava, K.K.,
Sangwan, N.S., Negi, A.S., Gupta, A., Studies on substituted benzo[h]quinazolines, benzo[g]indazoles, pyrazoles,
2,6-diarylpyridines as anti-tubercular agents, Bioorganic & Medicinal Chemistry Letters (2013), doi: http://
dx.doi.org/10.1016/j.bmcl.2013.08.101
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Bioorganic & Medicinal Chemistry Letters - (2013) -–-
Studies on substituted benzo[h]quinazolines, benzo[g]indazoles, pyrazoles, 2,6-diarylpyridines as anti-
tubercular agents
Hardesh K. Maurya,a Ruby Verma,a Saba Alam,a Shweta Pandey,a Vinay Pathak,a Sandeep Sharma,b Kishore K Srivastava,b
Neelam S. Sangwan,c Arvind S. Negi,a Atul Guptaa,*
a,Medicinal Chemistry Department and bMetabolic & Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow-226015, India
c Division of Microbiology, CSIR-Central Drug Research Institute,Sector-10, Jankipuram Extension, Lucknow 226 031, India
ARTICLE INFO
Article History
Received
ABSTRACT
Various substituted 5,6-dihydro-8-methoxybenzo[h]quinazolin-2-amine, 1-(3-(4-alkoxyphenyl)-7-methoxy-3,3a,4,5-tetrahydro-2H
benzo[g]indazol-2-yl)ethanone, pyrazole and 2,6-diarylpyridine derivatives have been synthesized in good yields by an efficient
methodology. The synthesized compounds (4-23) were evaluated for their in vitro anti-tubercular activity against Mycobacterium
tuberculosis H37Rv strain. Compounds 6a, 6c, 8a, 19a and 19e exhibited significant anti-tubercular activity at MIC values 50, 100,
50, 25 and 100 µM concentration. In vitro cytotoxicity data using THP-1 cells indicated that most active compound 19a is safe as
its MIC value is much lower than the cytotoxic value.
Revised
Accepted
Available Online
Keywords
Quinazoline
Indazole
©2013 Elsevier Ltd. All rights reserved
antitubercular
pyrazole
diarylpyridine
In coincidence with the spread of HIV infection,1 tuberculosis is
than two fold high lipophilicity as comparison with Rifampicin (ii,
Figure 1).17 These findings7-17 inspired us to synthesize 2-
(sec.amines)ethoxy chain containing benzo[h]quinazolines (6) and
analogs (8,9,11) in anticipation to display anti-tubercular activity with
better efficacy.
today amongst the universal health threats. Approximately 13 million
new cases of tuberculosis each year worldwide; about one fifth of them
are in India.2 In 2011, there were an estimated 8.7 million new cases of
TB and 1.4 million people died from TB. TB is one of the top killers of
women, with 5,00,000 deaths among HIV women in 2011. India, China,
the Russian Federation and South Africa have almost 60% of the
world’s cases of MDR-TB.3 It is estimated that nearly 5,00,000 people
die from the disease - more than 1000 per day.5 As resistant strains of
Mycobacterium tuberculosis (MTB) have slowly emerged, treatment
failure is a main reality.4 However, various drugs such as streptomycin
(i), rifampicin (ii), pyrazinamide (iii), isoniazid (iv), ethionamide (v) and
ethambutol (vi) etc (Figure 1) are used for the treatment of TB. Since,
these are taking six month long time treatment,6 therefore it becomes
imperative for the discovery of some new chemical entity.
NH
HO
NH2
H2
HO
N
N
N
O
O
OH
OH
O
O
OH
OH
HN
NH
H3CO
HN
OH
O
O
O
H
NH2
Pyrazinamide (iii)
NHNH2
CHO
O
HO
C
O
N
O
HOH2
HO
O
O
N
OH
NHCH3
HO
N
N
Isonizid (iv)
Streptomycin (i)
Rifampicin (ii)
O
In the recent past, several benzo[h]quinazoline derivatives have been
reported to exhibit antiplatelet combined with anti-inflammatory
activity,7 antimicrobial activity,8 as well as protein kinase inhibitors,9
antivirals,10 antiproliferative,11 histamine H4 receptor (H4R)
antagonists,12 human methionine aminopeptidase inhibitor-1,13
thymidylate synthase inhibitors,14 neoplasm inhibitors.15 Some
pyrimidine derivative ( vii, Figure 1) and pyrazole analog (ix) are
reported to be highly effective against Mycobacterium tuberculosis in in
vitro model at 0.78 and 0.35 µg/mL concentration respectively.16 4-(2-
(Piperidin-1-yl)ethoxy)styryl chain containing chalcone has shown in
vitro 3.5 µg/mL activity against Mycobacterium tuberculosis with more
________________
Cl
O
CN
N
S
NH2
OH
H
S
N
N
H3CO
F
O
N
H
F
N
OH
Ethambutol (vi)
N
ethionamide (v)
Chalcone (viii)
Chloropyrimidine (vii)
F
O
O
N
N
Cl
N
H
N
NH
N
Pyrazole analog (ix)
Figure 1. Lead anti-tubercular agents
Corresponding author. Tel.:+91-522-2718556, E-mail:atisky2001@yahoo.co.in
In our synthetic strategy, 6-methoxy-3,4-dihydronaphthalen-1(2H)-
one (1) and 4-hydroxybenzaldehyde (2) were selected as starting

materials. Reaction of
1
with 4-hydroxybenzaldehyde (2) using
compound 9, compounds 8 (1.0 eq) was subjected to amidation reaction
using hydrazine hydrate (1.5 eq, 95%) in ethanol at reflux temperature
which yielded compound 9 in 91-96% yields.
BF3.OEt2 in dioxane at room temperature with stirring for 72 h produced
precursor 2-(4-hydroxybenzylidene)-6-methoxy-3,4-dihydronaphthalen
-1(2H)-one (3) which on further reaction with guanidine hydrochloride
in the presence of sodium hydride and DMF gave 4-(2-amino-5,6-
dihydro-8-methoxybenzo[h]quinazolin-4-yl)phenol (4) in 89% yield,
In our strategy to see the effect of size of ring C on biological
efficacy of compound 6,
we further synthesized 1-(3-(4-
hydroxyphenyl)-7-methoxy-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-2-
yl)ethanone (10) from the reaction of 2-(4-hydroxybenzylidene)-6-
methoxy-3,4-dihydro- naphthalen-1(2H)-one (3) with hydrazine hydrate
in the presence of sodium hydride and DMF, Scheme 3. Further,
reaction of 1-(3-(4-hydroxyphenyl)-7-methoxy-3,3a,4,5-tetrahydro-2H-
benzo[g]indazol-2-yl)ethanone (10) with various sec-amine substituted
ethyl chlorides (5) gave final product 11 in 72-80% Yields, Scheme 3.
Scheme 1.
Further, alkylation of 4-(2-amino-5,6-dihydro-8-
methoxybenzo[h]quinazolin-4-yl)phenol (4) with sec.amine substituted
ethyl chloride (5) in presence of anhydrous potassium carbonate in dry
acetone/chloroform
gave
4-(4-(2-(sec.amine)ethoxy)phenyl)-5,6-
dihydro-8-methoxybenzo[h]quinazolin-2-amine (6) in 75-96% yields.
CHO
O
O
BF3.OEt2
Dioxane, rt
H3CO
OH
H3CO
OH
1
3
2
NH2NH2
NaH/DMF
O
O
RCl (5)
N
N
N
N
dry K2CO3
acetone:Chloroform (8:5)
MeO
OR
R
MeO
OH
11
10
(85%)
10/11
Yield of 11
a
70
N
75
b
c
N
N
70
75
N
N
Scheme 1. Synthesis of 4-(substituted)-5,6-dihydro-8-methoxybenzo[h]quinazolin-2-
amine (6) 21
d
e
80
In anticipation to study structure activity relationship (SAR) of
methoxybenzo[h]quinazolin-2-amine (6), we have also synthesized ethyl
(4-(2-amino-8-methoxy-5,6-dihydrobenzo[h]quinazolin-4-yl)phenoxy
)alkanoate (8) and (4-(2-amino-8-methoxy-5,6-dihydrobenzo[h]
quinazolin-4-yl)phenoxy)alkanehydrazide (9) in excellent yields
(Scheme 2).
Scheme 3. Synthesis 1-(3-(4-alkoxyphenyl)-7-methoxy-3,3a,4,5-tetrahydro-2H- benzo[g]
indazol-2-yl)ethanone (11) 21
Furthermore, the potential anti-tubercular activity of pyridine6 and
pyrazole18 derivatives viz. isonized (iv) and ethionamide (v) (Figure 1),
prompted us to explore anti-tubercular activity of 2,6-diarylpyridines
(16 and 17), 2-cyano-5-oxo-5-phenyl-3-piperidin-1-yl-pent-2-enoic acid
ethyl ester (18),19 and pyrazole derivatives (19-23).20
CHO
O
O
BF3.OEt2
Dioxane, rt
H3CO
H3CO
OH
X
X
OH
X
H2N
1
3
2
SMe
N
H2N
NH2
N
O
CN
O
13
CN
O
N
H
15
NH.HCl
CN
MeOH, reflux
O
NaOH, DMSO, rt
O
NaH/DMF
NH2
12
N
14
NH2
R
R
a) R=Br, b) R=Cl,
c) R=Me, d) R=OMe
e) R=H
16
O
NaOH
EtOH, rt
R
n
N
B
N
C
Br
N
N
H2SO4
120 o
7 (n=3,4,5)
O
NH2NH2.H2O,
MeOH reflux
14/16
R
X
C
A
K2CO3, DMF, 80oC, 5 h
a.
b.
c.
d.
e.
f.
Br CH2
Cl CH2
Me CH2
OMe CH2
H
Me
H
O
n
MeO
O
CN
8
O
N
O
MeO
OH
O
CN
N2H4.H2O
EtOH, reflux, 7 h
(89%)
4
N
CH2
O
O
N
N
N
H
OCH2CH3
O
CONH2
g
.
8/9
8a
8b
8c
9a
9b
9c
n
3
4
5
3
4
5
Mp (oC)
148-149
109-110
147-148
228-229
221-222
164-165
Yields (%)
NH2
18
19
R
90
94
93
92
96
91
DMFDMA,
THF, reflux
N
N
N
N
N
21
NH2
Br
H
N
17
22
NC
N
N
n
MeO
O
NH2
N
amberlist 50,
TFA, reflux
9
H
O
N
N
N
N
H
N
15
Scheme 2. Synthesis of ethyl (4-(2-amino-8-methoxy-5,6-dihydrobenzo[h]quinazolin-4-
yl)phenoxy)alkanoate (8) and (4-(2-amino-8-methoxy-5,6-dihydrobenzo[h]quinazolin-4-
yl)phenoxy)alkanehydrazide (9)21
R
MeO
20
23
amberlist 50,
TFA, reflux
Scheme 4. Method of synthesis of 12,14,16-18 refer to reference [19] and method of
synthesis of 19,20,22,23 refer to reference [20].
Synthesis of compound 8 was performed though alkylation reaction of 4
using long chain esters (7, n = 3,4,5) in presence of anhydrous K2CO3 in
dry DMF or acetone which yielded 8 in 90-94% yields. For synthesis of
Synthesis of compound 16 and 17 was done starting from 12
through amination followed by base catalyzed condensation reaction
2

with 5 using reported methodology. Whereas compound 20 and 22 was
synthesized via transformation of 12 into 19 using hydrazine hydrate in
methanol at reflux. Compound 19 was converted into 20 using DMF-
DMA in THF at reflux which yielded 20 in 76-85% yield. Compound 20
on condensation with 2-aminopyridine (21) and benzamide (15) in TFA
at reflux temperature gave 22 and 23 in 31% and 36% yields
respectively19,20 Scheme 4.
Synthesized compounds 4-23 were evaluated for their anti-
tubercular activity against Mycobacterium tuberculosis H37Rv strain
using micro plate alamar blue assay (MABA) and results are reported in
Table 1. Lipophilicity of the synthesized derivatives (4-23) were
calculated using ChemBioDraw Ultra 11.0 and is expressed in the terms
their log P value, Table 1.
value 200 µM. The long chain ester analog of 4 (8a) exhibited activity at
MIC value 50 µM, while alkanoate derivatives (8b and 8c) and
alkanylhydrazide derivatives (9a-c) showed activity at 200 µM.
Structure activity relationship (SAR) reveled that piperidine substituted
analog (6a) and propanoate chain containing analog (8a) had better
activity as compared with other related analogs. It is notworthy that
alkanylhydrazide (9a-c) had only moderate activity, although these
derivatives contain –CONHNH2 group similar to the clinically useful
drug isonizied (iv, Figure 1).
As similar to benzo[h]quinazoline (4), the five membered ring
containing precursor benzo[g]indazole (10) was found inactive at 200
µM, whereas 2-(sec.amine)ethoxy chain containing analogs (11b-e)
were found active at MIC 200 µM. Another analog 11a was found
inactive at MIC 200 µM. From biological activity of compounds 6 and
10 derivatives, it is evident that size of ring-C in compound 6 has
detrimental role in its biological activity.
Table 1.
In vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain using
micro plate alamar blue assay (MABA) and in vitro cytotoxicity in THP-1 cells (CC50
)
In case of 2,6-diarylpyridine derivatives, compounds (16a-f)19
tested for anti-tubercular activity showed the MIC level more than 200
µM and therefore were considered to be inactive in this study.
Biological activity results of pyrazole derivatives (19-23) showed
that 4-bromophenyl ring containing pyrazole (19a) had significant anti-
tubercular activity at MIC value 25 µM. Other pyrazole derivatives 19e
and 19d exhibited anti-tubercular potential at MIC values 100 and 200
µM, while 19b and 19c were found inactive at 200µM. The
corresponding enamine analoges of pyrazoles, 20d and 20e showed
activity at MIC values 100 and 200 µM respectively whereas, 20a-c, 22
and 23 were found inactive at 200 µM. However, Horrocks, P. et. al.
have reported MIC value 0.35 µg/mL of a pyrazole analog (ix, Figure
1).16b
In view of good anti-tubercular activity of compounds 6a, 6c, 8a,
19a and 19e, their cytoxicity was evaluated in vitro MTT assay using
non cancerous hepatic monocytes (THP-1) cells.17 Cytotoxicity
concentration (CC50) values of 6a, 6c and 8a was 200 µM, whereas
compounds 19a, 19e and 20d presented CC50 values more than 200 µM
(Table 1).
Compounds
MIC (µM)
Log Pa
CC50
4
>200
50
3.96
4.96
-
200
6a
200
4.54
4.23
4.55
4.67
5.08
5.50
2.82
3.28
3.74
2.88
3.88
3.46
3.15
3.47
3.82
6.77
6.50
6.43
5.82
5.95
5.03
5.65
1.82
3.10
2.82
2.75
2.14
2.27
3.19
2.92
2.85
2.23
2.36
2.74
3.94
-0.60
2.6117
-4.1117
4.74
3.40
-
6b
6c
100
200
200
-
6d
8a
50
200
200
-
8b
8c
200
-
200
-
9a
200
-
9b
9c
200
-
>200
>200
200
-
10
-
11a
11b
11c
11d
11e
-
200
-
200
-
200
-
Since, theoretically, MIC value represents IC100 or CC100 and is
approximately double of the CC50 value. Therefore, comparing in vitro
anti-tubercular and cytotoxicity activities of compounds 6a, 6c, 8a, 19a
and 19e showed selectivity towards tubercular versus healthy cells. The
most active compound 19a was found to approximately eight times safer
with respect to its MIC value.
>200
>200
>200
>200
>200
>200
>200
>200
25
-
16a
16b
-
16c
16d
16e
16f
17
-
-
-
In conclusion, we have synthesized various substituted 5,6-dihydro-8-
-
methoxybenzo[h]quinazolin-2-amine,
1-(substituted)-4,5-dihydro-7-
-
methoxybenzo[g]indazol-2-yl)ethanone, pyrazole and 2,6-diarylpyridine
derivatives in good yields by an efficient methodology. Compounds 6a,
6c, 8a, 19a and 19e exhibited significant anti-tubercular activity at MIC
values 50, 100, 50, 25 and 100 µM respectively in in- vitro assay against
Mycobacterium tuberculosis H37Rv strain. The biological activity
profile of most active derivative 19a showed beside significant anti-
tubercular activity and was found to be eight times safe with respect to
its MIC value.
Overall, out of four pharmacophores studied viz 4, 10, 16, 19,
pyrimidine 4 and pyrazole 19 derivatives have scope for further
investigation in the quest of novel anti-tubercular agents for better
treatment of MTB.
-
18
19a
>200
19b
19c
19d
19e
>200
>200
200
-
-
-
100
>200
>200
>200
>200
100
-
20a
20b
-
20c
20d
20e
22
-
>200
200
-
-
-
-
-
-
>200
>200
0.2
Acknowledgements
23
Isonizid
Rifampicin
H.K.M. acknowledges DST, New Delhi, India for financial support as
DST fast track young scientist fellowship [No SR/FT/CS-20/2011].
Authors are also thankful to Director, CSIR-CIMAP and CSIR-CDRI.
2.0
Streptomycin
vii (Figure 1)16a
ix (Figure 1)16b
6.0
0.78 b
0.35 b
References and Notes:
aliphophilicity was calculated using ChemBioDraw Ultra 11.0, b µg/mL
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4-(4-(2-
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3

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was dissolved in the mixture of acetone (40 mL) and chloroform (25 mL) at 80 0C.
After stirring for ten minutes, anhydrous K2CO3 (0.4 g) and substituted amine
ethylchloride hydrochloride 5 (0.13 g, 1.07 mmol) was added in reaction mixture.
The progress of reaction was monitored by thin layer chromatography. After the
completion of reaction, solvent was evaporated and residue was diluted with
chloroform and extracted with water. The organic phase was filtered, evaporated and
dried. The crude was purified by silica gel column chromatography with a mixture of
chloroform-hexane (10%) to give the desired product 6. 4-(4-(2-(piperidin-1-
yl)ethoxy)phenyl)-5,6-dihydro-8-methoxybenzo[h] quinazolin-2-amine (6a): off-
white colored solid; Rf: 0.23 (10% methanol in chloroform); mp 152-155 oC; IR
(KBr, νmax/cm-1): 3396 (NH2); 1H NMR (CDCl3, 300 MHz, δ ppm): 1.26 (bs, 2H,
CH2), 1.46 (bs, 4H, 2xCH2), 2.54 (bs, 4H, 2xNCH2), 2.77-2.86 (bs, 6H, NCH2
&
2xCH2), 3.85 (s, 3H, OCH3), 4.17 (t, 2H, OCH2), 5.00 (s, 2H, NH2), 6.73 (d, 1H,
J=2.1 Hz, Ar-H), 6.86 (d, 1H, J=2.4 Hz, Ar-H), 6.89 (d, 2H, J=2.1 Hz, Ar-H), 7.50
(d, 2H, J=8.7 Hz, Ar-H), 8.20 (d, 1H, J=8.7 Hz, Ar-H); 13C NMR (CDCl3, 100 MHz,
δ ppm): 24.52, 24.73, 26.24 (2C), 29.16, 55.43 (2C), 55.72, 58.20, 66.41, 112.95,
113.24, 114.72 (2C), 115.43, 126.67, 127.83, 130.54 (2C), 131.41, 141.92, 159.79,
161.36, 161.94, 161.98, 165.04; m/z : 431.5 [M+1]+.
d) General procedure for the synthesis of ethyl (4-(2-amino-8-methoxy-5,6-
dihydrobenzo[h]quinazolin-4-yl)phenoxy)alkanoate (8): In a 100 mL R.B. flask, 4-
(2-amino-5,6-dihydro-8-methoxybenzo[h]quinazolin-4-yl)phenol (4) (319 mg,
1
mmol) was dissolved in dimethylformamide (DMF, 9 mL) at 80 0C. After stirring for
five minutes, anhydrous K2CO3 (1.1 mmol) and substituted ethyl bromoalkanoate 7
(1.5 mmol) was added in reaction mixture and stirred the reaction for 5 h. The
reaction mixture was poured in cold water with vigorous stirring and neutralized it
with N/5 HCl solution. The precipitate was filtered and dried. The crude was purified
by column chromatography using basic alumina and a mixture of chloroform-
methanol (0.5 to 1.0%) to give the desired product 8. Ethyl 5-(4-(2-amino-8-
methoxy-5,6-dihydrobenzo[h]quinazolin-4-yl)phenoxy)pentanoate (8b): off white
colored solid; Rf: 0.40 (30% acetone in hexane); mp 109-110 oC; 1H NMR (DMSO-
d6, 300 MHz, δ ppm): 1.19 (t, 3H, J=7.2 Hz, CH3), 1.40 (bs, 4H, 2xCH2), 2.38 (t, 2H,
J=6.9 Hz, CH2), 2.77 (bs, 4H, 2xCH2), 3.82 (s, 3H, OCH3), 4.05 (m, 4H, 2xOCH2),
6.34 (s, 2H, NH2), 6.86 (s, 1H, Ar-H), 6.92 (d, 1H, J=8.7 Hz, Ar-H), 7.01 (d, 2H,
J=8.4 Hz, Ar-H), 7.52 (d, 2H, J=8.4 Hz, Ar-H), 8.11 (d, 1H, J=8.4 Hz, Ar-H); 13C
NMR (CDCl3, 100 MHz, δ ppm): 14.98, 22.07, 24.65, 28.86, 34.02, 35.00, 56.10,
60.59, 68.01, 113.41, 113.53, 113.85, 114.65 (2C), 126.81, 127.66, 131.08 (2C),
131.49, 142.20, 159.85, 160.59, 161.83, 162.86, 164.77, 173.65; m/z : 448.2 [M+1]+.
e)
yl)ethanone (10): In a 250 mL R.B. flask 8.94 mL hydrazine hydrate and of 2-(4-
hydroxybenzylidene)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (3, g, 21.35
1-(3-(4-hydroxyphenyl)-7-methoxy-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-2-
6
mmol )) in acetic acid (40 mL) were refluxed with vigorous stirring for 48 hrs. The
progress of reaction was monitored by thin layer chromatography. After the
completion of reaction, reaction mixture was diluted with ethyl acetate and extracted
with water. The organic phase was separated, dried over anhydrous sodium sulphate
and concentrated to give crude material which on column chromatography on silica
gel using chloroform as eluent gave desired compound as off-white colored solid; Rf:
0.26 (10% methanol in chloroform); mp 242-244oC; IR (KBr, νmax/cm-1): 1627
(C=O), 3256 (NH2), 3490 (OH); 1H NMR (DMSO-d6, 300 MHz, δ ppm): 1.83 (q,
1H, J=5.7 Hz, CH2), 2.06 (q, 1H, J=9.6 Hz, CH), 2.20 (s, 3H, COCH3), 2.82 (bs,
2H, CH2), 3.09 (bs, 1H, CH2), 3.75 (s, 3H, OCH3), 4.75 (d, 1H, J=9.6 Hz, NCH),
6.69 (d, 2H, J=7.8 Hz, Ar-H), 6.79 (s, 1H, Ar-H), 6.85 (d, 1H, J=8.7 Hz, Ar-H), 7.03
(d, 2H, J=8.1 Hz, Ar-H), 7.74 (d, 1H, J=8.4 Hz, Ar-H), 9.35 (s, 1H, OH); 13C NMR
(DMSO-d6, 100 MHz, δ ppm): 22.99, 27.94, 29.76, 56.12 (2C), 67.10, 114.14,
114.41, 116.05 (2C), 120.56, 126.74, 127.83 (2C), 133.36, 142.69, 155.55, 157.16,
161.66; m/z : 337.1 [M+1]+.
20.
a) Mishra, P.; Kumar, S.; Maurya, H. K.; Gautam, S. K.; Kumar, B.;
Tandon, V. K.; Ram, V. J. Heterocycles 2012, 82, 189; b) Ram, V. J.; Verma, M.;
Hussaini, F. A.; Shoeb, A. Chem Res (s) 1991, 98.
21. a) Representative procedure for synthesis of (E)-2-(4-hydroxybenzylidene)-6-
methoxy-3,4-dihydronaphthalen-1(2H)-one (3): In a 250 mL R.B. flask 6-methoxy-
3,4-dihydronaphthalen-1(2H)-one (1, 3 g, 17 mmol) was stirred in dioxane (20 ml)
and afterward, BF3.Et2O (0.69 ml) was added in the reaction mixture. After stirring
for ten minute, 4-hydroxybenzaldehyde (2, 2.5 g, 8.9 mmol) was added in the
reaction mixture. The reaction mixture was allowed to stir at room temperature for
72 hrs. The progress of reaction was monitored by thin layer chromatography. After
the completion of reaction, the mixture was diluted with ethyl acetate and extracted
with water. The organic layer was separated, dried over anhydrous sodium sulphate
and concentrated to give crude material which on column chromatography on silica
gel using 4% ethyl acetate-hexane as eluent gave desired compound (3) as yellow
solid; yield 71%; Rf: 0.3 (30% EtOAc in hexane); mp 172-173 oC; IR (KBr,
νmax/cm-1): 3357 (NH2), 3489 (OH); 1H NMR (acetone-d6, 300 MHz, δ ppm): 2.92
(t, 2H, J=6.0 Hz, CH2), 3.11 (t, 2H, J=6.0 Hz, CH2), 3.88 (s, 3H, OCH3), 6.90 (m,
4H, Ar-H), 7.39 (d, 2H, J=8.4 Hz, Ar-H), 7.68 (s, 1H, CH), 7.97 (d, 1H, J=8.4 Hz,
Ar-H), 9.35 (s, 1H, OH); 13C NMR (acetone-d6, 100 MHz, δ ppm): 27.60, 29.30,
55.58, 112.66, 113.87, 116.05 (2C), 127.50, 127.64, 130.49, 132.36 (2C), 133.54,
136.02, 146.27, 159.04, 164.03, 185.96; m/z; 281 [M+1]+.
e) General procedure
for the synthesis of 1-(substituted)-4,5-dihydro-7-
methoxybenzo[g]indazol-2-yl)ethanone (11): In a 100 mL R.B. Flask, 1-(3,3a,4,5-
tetrahydro-3-(4-hydroxyphenyl)-7-methoxybenzo[g]indazol-2-yl)ethanone (10, 0.2 g
, 0.6 mmol ) was stirred in the mixture of acetone (40 mL) and chloroform (25 mL)
at 80 0C. After stirring for ten minutes, anhydrous K2CO3 (0.4 g) and substituted
amine ethylchloride hydrochloride 5 (0.13 g, 1.07 mmol) was added in reaction
mixture. The progress of reaction was monitored by thin layer chromatography.
After the completion of reaction, solvent was evaporated and residue was diluted
with chloroform and extracted with water. The organic phase was filtered,
evaporated and dried. The crude was purified by column chromatography with a
mixture of chloroform-hexane (10%) to give the desired product 11. 1-(3-(4-(1-
(dimethylamino)propan-2-yloxy)phenyl)-4,5-dihydro-7-methoxybenzo[g]indazol-2-
yl)ethanone (11d): Off-white colored oil; Rf: 0.26 (10% methanol in chloroform); IR
(neat, νmax/cm-1): 1626 (C=O); 1H NMR (CDCl3, 300 MHz, δ ppm): 1.15 (d, 3H,
J=6.6 Hz, CH3), 1.59 (s, 9H, CH2 & 2xNCH3), 1.94 & 2.31 (m, 2H, CH2), 2.45 (bs,
4H, CH2), 2.87 (m, 1H, CH), 3.80 (s, 3H, OCH3), 4.05 (bs, 1H, OCH), 4.85 (m, 1H,
CH), 6.66 (s, 1H, Ar-H), 6.80-6.86 (m, 3H, Ar-H), 7.19 (d, 2H, J=5.1 Hz, Ar-H),
7.88 (d, 1H, J=8.1 Hz, Ar-H); 13C NMR (CDCl3, 100 MHz, δ ppm): 18.87, 22.62,
28.20, 30.05, 41.72, 46.32, 55.70, 67.24, 70.03, 109.93, 113.68, 113.96, 115.24,
116.41, 120.57, 126.87, 127.47 (2C), 134.42, 134.53, 141.68, 155.55, 158.46,
161.68, 170.62; m/z : 420.4 [M+1]+.
b) Synthesis of 4-(2-amino-5,6-dihydro-8-methoxybenzo[h]quinazolin-4-yl)phenol
(4): In a 250 mL R.B. flask NaH (2.2 g) and DMF (7 mL) was stirred on ice bath at
00C for 10 minutes and subsequently, guanidine hydrochloride (3.82 gm, 40 mmol)
was
added.
Afterward,
2-(4-hydroxybenzylidene)-6-methoxy-3,4-
dihydronaphthalen-1(2H)-one (3, 6 g, 21.43 mmol) dissolved in DMF (25 mL) was
added in the reaction mixture and stirred for half hour at 00C, followed by stirring at
120 0C for 36 hour. The progress of reaction was monitored by thin layer
chromatography. After the completion of reaction, the mixture was diluted with ethyl
acetate and extracted with water. The organic phase was separated, dried over
anhydrous sodium sulphate and concentrated to give crude material which on
column chromatography on silica gel using chloroform as eluent gave desired
compound 4 as off-white colored solid, Rf: 0.17 (10% methanol in chloroform); mp
263-265 oC; IR (KBr, νmax/cm-1): 3357 (NH2), 3489 (OH); 1H NMR (DMSO-d6, 300
MHz, δ ppm): 2.74 (bs, 2xCH2), 3.80 (s, 3H, OCH3), 5.74 (s, 1H, OH), 6.31 (s, 2H,
NH2), 6.83-6.92 (m, 4H, Ar-H), 7.42 (d, 2H, J=8.4 Hz, Ar-H), 8.09 (d, 1H, J=8.4 Hz,
Ar-H); 13C NMR (DMSO-d6, 100 MHz, δ ppm): 24.71, 28.94, 56.09, 113.38,
113.50, 113.77, 115.52 (2C), 126.86, 127.63, 129.97, 131.14 (2C), 142.19, 158.86,
160.50, 161.78, 162.81, 165.07; m/z : 320.4 [M+1]+.
c) General procedure for the synthesis of 4-(4-(2-(sec.amine)ethoxy)phenyl)-5,6-
dihydro-8-methoxybenzo[h] quinazolin-2-amine (6): In a 100 mL R.B. Flask, 4-(2-
amino-5,6-dihydro-8-methoxybenzo[h]quinazolin-4-yl)phenol (4, 0.2 g, 0.6 mmol)
4

Tetrahedron Letters
5
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Studies on substituted benzo[h]quinazolines,
benzo[g]indazoles, pyrazoles, 2,6-diarylpyridines
as anti-tubercular agents
Hardesh K. Maurya,a, Ruby Verma,a Saba Alam,a Shweta Pandey,a Vinay Pathak,a Sandeep Sharma,b Kishore K Srivastava,b Neelam.
S. Sangwan,c Arvind S. Negi,a Atul Guptaa,*
b
a,Medicinal Chemistry Department and Metabolic & Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic
Plants, P.O. CIMAP, Kukrail Road, Lucknow-226015, India, c Division of Microbiology, CSIR-Central Drug Research Institute,Sector-10,
Jankipuram Extension, Lucknow 226 031, India
Various substituted 5,6-dihydro-8-methoxybenzo[h]quinazolin-2-amine, 1-(3-(4-alkoxyphenyl)-7-methoxy-3,3a,4,5-tetrahydro-2H-benzo[g]
indazol-2-yl)ethanone, pyrazole and 2,6-diarylpyridine derivatives have been synthesized in good yields by an efficient methodology. The
synthesized compounds (4-23) were evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain.
Compounds 6a, 6c, 8a, 19a and 19e exhibited significant anti-tubercular activity at MIC values 50, 100, 50, 25 and 100 µM concentration.
In vitro cytotoxicity data using THP-1 cells indicated that most active compound 19a is safe as its MIC value is much lower than the
cytotoxic value
X
O
NH2
N
CN
N
N
N
N
N
N
R
CN
N
H
MeO
OR
MeO
OR
R
5