1-Chloro-2-formyl indenes and tetralenes as antitubercular agents

Article abstract of DOI:10.1016/j.bmcl.2011.05.016

1-Chloro-2-formyl indenes and tetralenes have been synthesized using Vilsmeier-Haack-Arnold reaction onto indanones and tetralones. Most of these analogues exhibited antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MICs ranging from 30 to 500 μg/mL. Analogue 13 was further modified to some derivatives. The most active analogue 23 showing MIC at 30 μg/mL was further evaluated for acute oral toxicity in Swiss albino mice and was found to be safe up to 300 mg/kg dose.

Full text of DOI:10.1016/j.bmcl.2011.05.016

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3966–3969
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1-Chloro-2-formyl indenes and tetralenes as antitubercular agents
Debabrata Chanda b, Dharmendra Saikia b, J. K. Kumar c, Jay Prakash Thakur b, Jyoti Agarwal b,
C. S. Chanotiya a, Karuna Shanker a, Arvind S. Negi a,
⇑
a Chemical Sciences Division, Central Institute of Medicinal and Aromatic Plants (CIMAP-CSIR), P.O. CIMAP, Kukrail Picnic Spot Road, Lucknow 226015, U.P., India
b Biotechnology Division, Central Institute of Medicinal and Aromatic Plants (CIMAP-CSIR), P.O. CIMAP, Kukrail, Picnic Spot Road, Lucknow 226015, U.P., India
c CIMAP Research Centre, Hyderabad, A.P., India
a r t i c l e i n f o
a b s t r a c t
Article history:
1-Chloro-2-formyl indenes and tetralenes have been synthesized using Vilsmeier–Haack–Arnold reaction
Received 12 February 2011
Revised 30 April 2011
Accepted 6 May 2011
Available online 14 May 2011
onto indanones and tetralones. Most of these analogues exhibited antitubercular activity against Myco-
bacterium tuberculosis H37Rv strain with MICs ranging from 30 to 500
lg/mL. Analogue 13 was further
modified to some derivatives. The most active analogue 23 showing MIC at 30
l
g/mL was further eval-
uated for acute oral toxicity in Swiss albino mice and was found to be safe up to 300 mg/kg dose.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tetralene
Indene
Antitubercular
Vilsmeier–Haack–Arnold reaction
Acute oral toxicity
Tuberculosis is one of the largest killers in the world from any
single infectious disease.1 One third of the world’s population is
thought to be infected by this pathogen. In 2007, there were an esti-
mated 13.7 million chronic active cases and in 2008, about 1.3 mil-
lion were died of this disease.2,3 Although per capita TB incidence is
stable or declining in all the six WHO regions, number of patients
every year is increasing continuously. Due to the development of
multidrug resistance and extensive drug resistance of Mycobacte-
rium against various antimycobacterial drugs and also a high prev-
alence of it in AIDS patients, the problem has become fiercer. WHO
has targeted the elimination of tuberculosis by 2050 as a public
health problem. The development of resistance to present antitu-
bercular drugs has posed a serious threat to the treatment and man-
agement of the disease. Hence, there is an urgent need to develop a
new, effective and affordable antiTB drug.
Juglandaceae) roots. Encouraged by the efficacy of these tetralone
derivatives, we synthesized several tetralone and indanone deriva-
tives as antimycobacterial agents (Fig. 1), using Vilsmeier–Haack–
Arnold reaction to formylate activated aromatic ring systems.6 The
reaction has got a wide application in synthesizing many heterocy-
clic compounds.7–12 Vilsmeier–Haack–Arnold reaction of 1-inda-
nones and 1-tetralones yield unusual 1-chloro-2-formyl indenes
and tetralenes under mild reaction conditions.13 All the synthe-
sized analogues were evaluated against M. tuberculosis H37Rv
strain by BACTEC method. Analogue, 23 was further evaluated for
acute oral toxicity in Swiss albino mice.
O
OH
O
In the recent past, two naturally occurring tetralones, that is,
shinanolone and hydroxymethoxy tetralone have been reported
as potent antimycobacterial agents.1,4,5 Shinanolone was obtained
through bioactivity guided isolation from the chloroform extract of
roots of Euclea natalensis (Family: Ebenaceae), exhibiting antituber-
cular activity against Mycobacterium tuberculosis H37Rv strain with
OH OCH3
OH
Hydroxymethoxy tetralone
MIC=6.25 μg/mL
Shinanolone
MIC=100 μg/mL
OAc
Cl
Cl
CHO
OCHO
H3CO
MIC at 100
lg/mL. Hydroxymethoxy tetralone showed better
potency having MIC at 6.25
l
g/mL against the same strain of M.
H3CO
tuberculosis. Hydroxymethoxy tetralone was isolated from the
chloroform extract of Engelhardia roxburghiana Hay (Family:
12
26
23
MIC=60 μg/mL
MIC=30 μg/mL
MIC=30 μg/mL
⇑
Corresponding author. Tel.: +91 522 2717529x327; fax: +91 522 2342666.
E-mail address: arvindcimap@rediffmail.com (A.S. Negi).
Figure 1. Shinanolone, hydroxymethoxy tetralone and some of the active ana-
logues as antitubercular agents.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.016

D. Chanda et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3966–3969
3967
O
reagent to get corresponding 1-chloro-2-formyl tetralene (12–15)
and indene (16–22) derivatives. Substrate 11 was synthesized as
per our previously reported method.14 For Vilsmeier reagent, a mix-
ture of dry dimethylformamide–phosphorus oxychloride (DMF–
POCl3) was used.15 However, 2-tetralone (b-tetralone) unexpectedly
yielded a fully aromatized product, that is, 1-chloro-2, 3-diformyl
naphthalene (30) under the similar reaction conditions. All the com-
pounds were characterized by spectroscopy.16
Cl
DMF-POCl3
0-10ºC
CHO
A.
R2
R2
R1
R1
1: R1=R2=H
2: R1=H, R2=OCH3
3: R1=CH3, R2=H
12: R1=R2=H, Yield=53%
13: R1=H, R2=OCH3, 83% ;
14: R1=CH3, R2=H, 47%
;
Further, in order to establish structure activity relationship of
these compounds, 13 and 2 were further modified to various ana-
logues as shown in Scheme 2. Aldehyde 13 underwent Baeyer–
Villiger oxidation in presence of m-chloroperbenzoic acid to af-
ford a formate ester 23. On sodium borohydride reduction com-
pound 2 yielded a corresponding alcohol 25. Its subsequent
acetylation gave 26 in good yield.17 The oxime derivative (27)
was obtained by treating it with hydroxylamine hydrochloride.18
While, a fully reduced tetralin analogue (28) was obtained by
treating it with sodium borohydride in trifluoroacetic acid in good
yield.19
OAc
OAc
DMF-POCl3
B.
C.
º
0-10 C
H3CO
H3CO
CHO
Cl
O
4
15, 31%
R5
Cl
R5
R2
O
R4
R4
R3
DMF-POCl3
0-10ºC
CHO
R3
R2
R2
R1
Recently, NMR spectroscopy has been used for monitoring the
chemical reactions in real.20 The 1H NMR experiment was run at
2–5 min intervals for substrate 2 after dissolving it in deuterated
chloroform and adding the reagents (POCl3 + DMF). From the pro-
ton spectra it was evident that over the period of time some of
the tetralone 2, resonances at d 2.0, 2.5, 6.7, and 7.8 ppm were
disappeared and appearance of new peaks at d 2.7, 3.2, 3.8, 5.8,
7.6, 8.2, and 10.2 ppm just after one minute of reaction indicated
the spontaneity of the reaction. The complete transformation of
starting tetralone was observed after 15–20 min. Then final prod-
uct 13, was obtained after pouring this reaction mixture in cold
water.
16: R1=R2=R4=R5=H, R3=CH3 , Yield=48%;
17: R1=R2=R4=R5=H, R3=OCH3 , 89% ;
18: R1=R2=R5=H, R3-R4=-O-CH2-O-, 64%;
19: R1=R2=R4=R5=H, R3=Cl, 29% ;
20: R1=R2=R3=R4=H, R5=CH3, 54% ;
21: R1=C6H5-, R2=R3=R4=R5=H, 42% ;
22: R1=3,4,5-trimethoxy phenyl-,
5: R1=R2=R4=R5=H, R3=CH3
;
6: R1=R2=R4=R5=H, R3=OCH3
;
7: R1=R2=R5=H, R3-R4=-O-CH2-O- ;
8: R1=R2=R4=R5=H, R3=Cl ;
9: R1=R2=R3=R4=H, R5=CH3
;
10: R1=C6H5-, R2=R3=R4=R5=H ;
11: R1=3,4,5-trimethoxy phenyl-,
R2=R3=R4=OCH3, R5=H.
R2=R3=R4=OCH3, R5=H, 57%.
Cl
O
CHO
CHO
DMF-POCl3
d.
All these analogues were evaluated21 for antitubercular activ-
ity against M. tuberculosis H37Rv strain radiometrically by BAC-
TEC 460 and their minimum inhibitory concentrations (MICs)
are presented in Table 1. Most of the compounds of this series
exhibited antitubercular activity with MICs ranging from 30 to
º
0 C
β-Tetralone
30, 46%
Scheme 1. Vilsmeier–Haack–Arnold reaction of indanones and tetralones.
The synthesis of these analogues is depicted in Scheme 1. Various
tetralones (1–4) and indanones (5–11) were treated with Vilsmeier
500
l
g/mL. Compounds 16, 21, 24, 27, 29, and 30 possessed
low level of activity showing MIC value of 500–250
lg/mL,
Cl
O
O-C-H
H3CO
iii
23
ii
Cl
Cl
CH2OH
CHO
i
H3CO
H3CO
24
13
OAc
OH
iv
v
O
H3CO
H3CO
26
25
H3CO
viii
NOH
vi
2
OHC
H3CO
27
H3CO
29
vii
H3CO
28
Scheme 2. Reagents and conditions: (i) DMF–POCl3, 0 °C to rt, 1 h, 83%; (ii) DCM, m-CPBA, 0–10 °C for 1 h then rt for overnight, 39%; (iii) NaBH4, MeOH, RT, 89%; (iv) NaBH4,
MeOH, rt, 91%; (v) Ac2O, dry pyridine, rt, overnight, 89%; (vi) NH2OH.HCl, ethanol, reflux, 1 h, 79%; (vii) NaBH4–TFA, 0–10 °C, 83%; (viii) DMF–POCl3, 80 °C, 3 h, 76%.

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

D. Chanda et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3966–3969
3969
137.01 (CH aromatic), 188.94 (CH aldehyde), 192.02 (CH aldehyde); ESI mass
(MeOH): 258 [M+K]+.
18. Singh, S.; Kumar, J. K.; Saikia, D.; Shanker, K.; Thakur, J. P.; Negi, A. S.; Banerjee,
S. Eur. J. Med. Chem. 2010, 45, 4379.
Cl
19. Srivastava, V.; Darokar, M. P.; Fatima, A.; Kumar, J. K.; Chowdhury, C.; Dwivedi,
G. R.; Shrivastava, K.; Gupta, V.; Chattopadhyay, S. K.; Luqman, S.; Saxena, H.
O.; Gupta, M. M.; Negi, A. S.; Khanuja, S. P. S. Bioorg. Med. Chem. 2007, 15, 518.
20. J. Bargon, L.T. Kuhn (Eds.), in: In situ NMR-Methods in Catalysis, Topics in
Current Chemistry, 2007, pp 276.
21. Siddiqi, SH; 1996. BACTEC 460 TB SYSTEM, Product and Procedure Manual,
MA-0029 (Revision E, May 1996), Becton Dickinson and Company, USA.
22. Chanda, D.; Shanker, K.; Pal, A.; Luqman, S.; Bawankule, D. U.; Mani, D. N.;
Darokar, M. P. J. Toxicol. Sci. 2008, 34, 99.
H
H
C=O
H
H
C=O
H
H
H
HMBC correlations of compound 30.
HMBC correlations of compound 30.
17. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s text book of
practical organic chemistry, fifth ed.; England: Addition Wesley Longman, 1998.