3968
D. Chanda et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3966–3969
Table 1
oral toxicity. A detailed structure activity relationship study is
needed for this class of compounds to get a better candidate in
future.
Antimycobacterial activity of tetralene and indene analogues against M. tuberculosis
H37Rv strain by BACTEC assay
S. No. Compd No. MIC (
l
g/mL) S. No. Compd no.
MIC (lg/mL)
1
2
3
4
5
6
7
8
12
13
14
15
16
17
18
19
20
21
22
60
12
13
14
15
16
17
18
19
20
21
—
23
24
25
26
27
28
29
30
30
Acknowledgments
125
125
naa
250
125
125
125
125
250
naa
500
naa
30
500
125
500
500
2.0
The authors are thankful to the Director, CIMAP for constant
encouragement and providing necessary facilities and also to the
Director, National JALMA Institute for Leprosy and other
Mycobacterial Diseases (ICMR), Agra, India for providing the
Mycobacterial strain. The financial support from CSIR is duly
acknowledged.
9
10
11
Rifampicin
Streptomycin 2.0
—
—
a
na = Inactive at 500
lg/mL.
References and notes
1. Negi, A. S.; Kumar, J. K.; Luqman, S.; Saikia, D.; Khanuja, S. P. S. Med. Res. Rev.
2010, 30, 603.
2. World Health Organization; In ‘Epidemiology’. Global tuberculosis control:
epidemiology, strategy, financing. ISBN 978 92 4 156380 2, 2009, pp 6.
3. WHO fact sheet N°104, March 2010: Tuberculosis.
4. van der Kooy, F.; Meyer, J. M. J.; Lall, N. S. Afr. J. Bot. 2006, 72, 349.
5. Lin, W. Y.; Peng, C. F.; Tsai, I. L.; Cheng, J. J.; Chen, I. S. Planta Med. 2004, 71, 171.
6. Vilsmeier, A.; Haack, A. Chem. Ber. 1927, 60, 119.
7. Meth-Cohn, O. Heterocycles 1993, 35, 539.
8. Guzman, A.; Ronero, M.; Maddox, M. L.; Machowski, J. M. J. Org. Chem. 1990, 55,
5793.
Compounds 13, 14, 17–20, and 28 exhibited moderate level of
activity (MIC = 125 g/mL), while compounds 12, 23, and 26 pos-
sessed higher level of activity (MIC range 60–30 g/mL). Rest of
the compounds, that is, 15, 22, and 25 were found inactive at
500 g/mL concentration.
l
l
l
Compound 12 having a 1-chloro-2-formyl arrangement in the
tetralin system exhibited antitubercular activity (MIC at 60
9. Sreenivasulu, M.; Krishna Rao, G. S. Indian J. Chem., Sect. B 1989, 28, 584.
10. Mahata, P. K.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. J. Org.
Chem. 2003, 68, 3966.
11. Chupp, J. P.; Metz, S. J. Heterocycl. Chem. 1979, 16, 65.
12. Katrtizky, A. R.; Arend, M. J. Org. Chem. 1998, 63, 9989.
13. Arnold, Z.; Zemlicka, J. Collect. Czech. Chem, Commun. 1959, 24, 2385.
14. Saxena, H. O.; Faridi, U.; Srivastava, S.; Kumar, J. K.; Darokar, M. P.; Luqman, S.;
Chanotiya, C. S.; Krishna, V.; Negi, A. S.; Khanuja, S. P. S. Bioorg. Med. Chem. Lett.
2008, 18, 3914.
l
g/mL). On introducing a methoxy group in the aromatic ring
at 6-position (i.e., 13), antitubercular activity was reduced (MIC
at 125 g/mL). Similarly, on attaching a methyl group at 4-posi-
tion of aliphatic ring (i.e., 14) antitubercular activity was reduced
(MIC at 125 g/mL). The five membered 1-chloro-2-formyl
l
l
indene derivatives exhibited moderate level of antitubercular
activity. When the 5-methyl derivative (16) was replaced with
a methoxy group (17), activity was enhanced by two fold. Simi-
larly, 5,6-methylenedioxy indene analogue (18) exhibited better
activity than the analogue 16. Replacement of 5-methyl group
15. General procedure for the synthesis of 1-chloro-2-formyl indenes and tetralenes:
Indanone Or tetralone (2 mmol) was taken in dry dimethylformamide (1 mL)
and stirred at 0–10 °C in an ice bath. To this phosphorus oxychloride (0.5 mL,
836 mg, 5.43 mmol) was added and further stirred for 1 h. On completion, the
reaction mixture was poured in crushed ice, extracted with ethyl acetate,
washed with water. The organic layer was dried over anhydrous sodium
sulphate and evaporated in vacuo. The desired 1-chloro-2-formyl indenes/
tetralenes were obtained either solid or oil. In some of the cases
chromatographic purification was done through silica gel column and
hexane–ethyl acetate as eluents.
with a chloro substituent (19, MIC = 125 lg/mL) doubled the
activity. However, introduction of a phenyl unit at 3-position
of the indene unit did not improve the activity (compounds 21
and 22). Further modifications of compound 13 were not found
beneficial, as most of the analogues exhibited lower activity than
the parent compound. However, modification of 2-aldehyde of
analogue 13 to its corresponding 2-formate ester 23, activity
16. Selected physical data: 13: Yield = 83%, mp = 76–78 °C. 1H NMR (CDCl3,
300 MHz) d 2.56(t, 2H, 4-CH2, J = 7.78 Hz), 2.76 (t, 2H, 3-CH2, J = 7.86 Hz),
3.79 (s, 3H, OCH3), 6.68 (d, 1H, 5-CH, J = 2.25 Hz), 6.77 (dd, 1H,7-CH,
J = 8.7 Hz, 2.5 Hz), 7.74 (d, 1H, 8-CH, J = 8.7 Hz), 10.27 (s, 1H, CHO). 13C NMR
was increased by four folds (MIC = 30 lg/mL). Thus, although
(CDCl3, 75 MHz)
d 21.99, 27.94, 55.76, 112.55, 114.01, 125.31, 128.62,
130.28, 141.59, 146.02, 162.68, 190.34; EI mass (MeOH): 223 [M+], 208[M-
CH3]+, 180 [M-CO-CH3]+; IR (KBr, cmÀ1): 2932, 1655, 1606, 1486, 1180.
Compound 23: Yield = 39%, mp = oil. 1H NMR (CDCl3, 300 MHz) d 2.86 (br s,
2H, 4-CH2), 3.13 (br s, 2H, 3-CH2), 3.91(s, 3H, OCH3), 6.62 (s, 1H, 5-CH), 6.83
(dd, 1H, 8-CH), 7.32 (br s, 1H, 7-CH), 8.05 (s, 1H, OCHO); ESI mass (MeOH):
247 [M+H]+, 262 [M+Na]+, 285 [M+K]+. IR (KBr, cmÀ1): 2925, 1727, 1632,
most of the indene analogues possessed moderate level of anti-
tubercular activity, tetralene analogues were better candidates
for higher potency.
The most active analogue of 13, that is, 2-formyl ester 23 was
further evaluated for in vivo acute oral toxicity in Swiss albino
mice at 5, 50 and 300 mg/kg single oral dose.22 No observational
changes, morbidity and mortality were observed throughout the
experimental period. Blood and serum samples upon analysis
showed nonsignificant changes in all the parameters studied like
total RBC, WBC count, differential leukocyte count, hemoglobin,
serum total cholesterol, triglycerides, creatinine level, SGPT and
SGOT activity. Similarly, animals on gross pathological study
showed no changes in any of the organs studied including their
absolute and relative weights. Thus, the experiment showed that
compound 23 was well tolerated by the Swiss albino mice up to
the dose level of 300 mg/kg body weight as a single acute oral
dose. However, sub-acute and chronic experiments with the test
drug need to be carried out to look for any adverse effect on re-
peated exposure to the test drug compound 23 for its future
development.
1504, 1257. Compound 26: Yield = 89%, oil, 1H NMR (CDCl3, 300 MHz)
d
1.78–1.80 (m, 2H, 3-CH2), 1.90–1.93 (m, 2H, 2-CH2), 2.06 (s, 3H, OCOCH3),
2.73–2.79 (m, 2H, 4-CH2), 3.78 (s, 3H, OCH3), 5.95 (t, 1H, 1-CH, J = 3.52 Hz),
6.63(d, 1H, 5-CH, J = 2.14 Hz), 6.72–6.76 (dd, 1H, 7-CH, J = 8.49 and 2.51 Hz),
7.22–7.86 (d, 1H, 8-CH, J = 8.51 Hz); ESI mass (MeOH): 191.9 [M+H]+, 213.8
[M+Na]+, 381.1[2 M–H]+.
The structure of 30: In 1H NMR, two distinct singlets at d 10.6 and 10.87 ppm
for two aldehydic protons were further supported in 13C NMR. Further, one
singlet, two doublets and two triplets in aromatic region each integrating for
one proton clearly indicated that the second aldehyde was also present in the
A ring. 13C NMR and DEPT 135 spectra confirmed presence of seven methines
(two aldehydic) and five quaternary carbons and hence, total 12 carbons. HR-
MS indicated its molecular formulae as
C12H7ClO2. Further, in HMBC
experiment, both the aldehydic protons showed long range correlations
with the carbonyl carbons of each other. Further, one of the aldehydes
showed strong correlation with an aromatic CH, while another aldehyde
showed correlations with two quaternary carbons. Thus, suggesting both the
aldehydes ortho to each other. All this confirmed the structure of 30 as 1-
chloro-naphthalene 2,3-dicarboxaldehyde. Compound 30: Yield = 46%;
mp = 129-131 °C. 1H NMR (CDCl3, 300 MHz) d 7.57–7.62 (t, 1H, –CH), 7.71–
7.77 (t, 1H, –CH), 7.91–7.93 (d, 1H, –CH), 8.50 (s,1H, –CH), 8.92–8.95 (d, 1H, –
CH), 10.60 (s, 1H, CHO), 10.87 (s, 1H, CHO); 13C NMR (CDCl3, 75 MHz) d
125.30, 128.39, 128.58, 129.73, 130.95, 131.57, 132.92, 133.82, 137.01,
140.09, 188.94, 192.02; DEPT 135: 13C NMR (CDCl3, 75 MHz): d 125.30 (CH
aromatic), 128.39 (CH aromatic), 130.95 (CH aromatic), 132.92 (CH aromatic),
In conclusion, both tetralone and indanone based 1-chloro-2-
formyl analogues have exhibited antimycobacterial activity against
M. tuberculosis H37Rv strain. The most active analogue 23 was
found to be safe up to 300 mg/kg dose in Swiss albino mice in acute