Synthesis and antimycobacterial evaluation of novel 5,6-dimethoxy-1-oxo-2,5-dihydro-1H-2-indenyl-5,4-substituted phenyl methanone analogues

Article abstract of DOI:10.1016/j.bmcl.2009.10.034

In present investigation, a series of substituted phenyl-5,6-dimethoxy-1-oxo-2,5-dihydro-1H-2-indenylmethanone analogues were synthesized and were evaluated for antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv and INH resistant M. tuberculosis. All the newly synthesized compounds were showing moderate to high inhibitory activities. The compound 5,6-dimethoxy-1-oxo-2,5-dihydro-1H-2-indenyl-4-fluorophenylmethanone (5g) was found to be the most promising compounds active against M. tuberculosis H₃₇Rv and isoniazid (INH) resistant M. tuberculosis with Minimum inhibitory concentration 0.10 and 0.10 μM.

Full text of DOI:10.1016/j.bmcl.2009.10.034

Bioorganic & Medicinal Chemistry Letters 19 (2009) 7000–7002
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antimycobacterial evaluation of novel 5,6-dimethoxy-1-oxo-
2,5-dihydro-1H-2-indenyl-5,4-substituted phenyl methanone analogues
a
a
a
Mohamed Ashraf Ali a, , Jeyabalan Govinda Samy , Elumalai Manogaran , Velmurugan Sellappan ,
*
Mohamed Zaheen Hasan a, Mohamed Jawed Ahsan a, Suresh Pandian a, Mohammad ShaharYar b
a New Drug Discovery Research, Department of Medicinal Chemistry, Alwar Pharmacy College, Alwar, Rajasthan 301 030, India
b Faculty of Pharmacy, Jamia Hamdard University, Department of Pharmaceutical Chemistry, Hamdard Nagar, New Delhi 110 062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In present investigation, a series of substituted phenyl-5,6-dimethoxy-1-oxo-2,5-dihydro-1H-2-indenyl-
methanone analogues were synthesized and were evaluated for antimycobacterial activity against Myco-
bacterium tuberculosis H37Rv and INH resistant M. tuberculosis. All the newly synthesized compounds
were showing moderate to high inhibitory activities. The compound 5,6-dimethoxy-1-oxo-2,5-dihy-
dro-1H-2-indenyl-4-fluorophenylmethanone (5g) was found to be the most promising compounds active
against M. tuberculosis H37Rv and isoniazid (INH) resistant M. tuberculosis with Minimum inhibitory con-
Received 27 July 2009
Revised 2 October 2009
Accepted 5 October 2009
Available online 13 October 2009
Keywords:
Diketone
Antitubercular agents
centration 0.10 and 0.10 lM.
Ó 2009 Elsevier Ltd. All rights reserved.
Tuberculosis or TB is a dreadful life threatening disease caused
by the bacteria Mycobacterium tuberculosis. This infectious disease
affects many parts of the body; the lungs are the most commonly
infected organ. The disease is highly contagious, transmitted by the
droplets from the throat and lungs of the infected people. Globally
there are 9.2 million cases of TB every year. The TB epidemic is get-
ting worsened and kills more than 2 million people around the
world annually.1 There were an estimated 1.57 million new cases
of tuberculosis among HIV-infected people and 456,000 deaths in
2007 as per the WHO survey. TB is shown to be the top cause of
death in HIV-positive people. According to the 2009 global TB con-
trol report one out of four TB deaths is related to HIV infection.2
The current treatment for TB is not satisfactory as the therapy
involves risk of treatment failures, relapses, severe side effects
and some times leads to drug resistant TB. The treatment failure
and relapses occur in patients who fail to strictly follow the treat-
ment regimen. Also the treatment is not patient compliant. The
drugs used for curing TB shows potential side effects including
thrombocytopenia, neuropathy, rashes, fever, drug induced hepati-
tis. The most common drugs used for TB are rifampicin, isoniazid,
ethambutol, pyrazinamide which are the first line drugs. The sec-
ond line drugs include ethionamide, kanamycin, amikacin, capreo-
mycin, ciprofloxacin, etc.3,4
drug resistant tuberculosis (XDR-TB). The MDR-TB is defined as
TB that is resistant to isoniazid and rifampicin. In 2007, an esti-
mated 500,000 people had multidrug-resistant TB (MDR-TB), has
a mortality rate of up to 80%. The XDR-TB is resistant to quinolones
and also to any one of kanamycin, capreomycin, or amikacin. The
drug resistant TB also can be spread from one person to another
person which is a dangerous situation. Hence it is considered to
be a global threat for public health.
The global mortality rate for TB is very high and the develop-
ment of new kinds of TB like MDR and XDR-TB alarming for the
discovery of new drugs to reduce the potential hazards caused
by the fatal disease. Objective of the present work is to develop
new chemical entities that show good effect against the drug resis-
tant strains of TB. The current work describes the synthesis of no-
vel diketone moiety with encouraging antimycobacterial activity
against INH resistant M. tuberculosis. We have recently reported
the synthesis and AChE inhibitory activity of novel diketones.5
The physiological values of diketones have resulted in a tremen-
dous activities and their function is quite stable which has inspired
chemists to utilize this stable fragment in bioactive moieties to
synthesize novel compounds possessing different biological activ-
ities. This prompted us to synthesize various substituted diketone
derivatives using acidic (or) basic media. Therefore in the current
work we have focused on the synthesis of some novel diketones
and their biological evaluation against strains of M. tuberculosis.
The analogues of 5,6-dimethoxy-1-oxo-2,5-dihydro-1H-2-inde-
nyl-5,4-substiutedphenylmethanone 5a–n described in this study
are shown in Table 1 and a reaction sequence for the preparation
is outlined in Scheme 1. In the initial step, the 5,6-dimethoxy-2-
A recent threat to TB is the development of drug resistant
strains. The drug resistant TB is classified in to two categories such
as multi drug resistant tuberculosis (MDR-TB) and extensively
* Corresponding author. Tel.: +91 9911128001; fax: +91 11 26059666.
E-mail address: asraf80med@rediffmail.com (M.A. Ali).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.034

M. A. Ali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 7000–7002
7001
Table 1
methanolic potassium hydroxide to get titled compounds. The
yields of titled compounds were ranging from 56% to 92% after
recrystallization with ethanol. The purity of the compounds was
checked by TLC and elemental analyses. Both analytical and spec-
tral data (1H NMR, IR) of all the synthesized compounds were in
full agreement with the proposed structures. In general, infra red
spectra (IR) revealed CH, C@O, and C–F peak at 1640, 1520, and
786 cmÀ1, respectively. In the Nuclear Magnetic resonance spectra
(1H NMR) the signals of the respective protons of the prepared
titled compounds were verified on the basis of their chemical
shifts, multiplicities and coupling constants. The spectra showed
a triplet at d 3.20–3.55 ppm corresponding to CH group; doublet
at d 3.41–3.44 ppm corresponding to CH2 group; singlet at d 3.82,
3.86 ppm corresponding to OCH3 multiplet at d 6.48–7.20 ppm cor-
responding to aromatic protons. The elemental analysis results
were within 0.4% of the theoretical values.
The synthesized compounds 5a–n were tested for their in vitro
antimycobacterial activity against MTB and INHR-MTB by agar
dilution method using double dilution technique similar to that
recommended by the National Committee for Clinical Laboratory
Standards.6 The INHR-MTB clinical isolate was obtained from
Tuberculosis Research Center, Alwar, India. The MIC was defined
as the minimum concentration of compound required to inhibit
90% of bacterial growth and MIC of the compounds were reported
in Table 1 with standard drug INH for comparison.
Physical constants and antimycobacterial activity of the synthesized compounds
O
O
O
O
R
H3C
H3C
5a-5n
Compound
R
Yield
Mp
(°C)
(MIC) lM
MTBa MTBb
(%)
5a
5b
5c
4-Methoxy phenyl-
4-Chloro phenyl-
4-Dimethylamino
phenyl-
74
70
72
164
142
114
>6.25 >6.25
1.52
5.94
8.20
8.78
5d
5e
5f
Phenyl-
80
82
85
151
118
155
6.62
11.56
3,4-Dimethoxy phenyl-
3,4,5-Trimethoxy
phenyl-
4-Fluoro phenyl-
2-Chloro phenyl-
2,6-Dichloro phenyl-
3-Nitro Phenyl-
Furyl-
>6.25 >6.25
>6.25 >6.25
5g
5h
5i
5j
5k
5l
5m
5n
INH
92
85
77
82
90
56
81
76
—
146
125
154
104
98
198
184
202
—
0.10
1.82
2.48
3.46
6.59
6.25
4.94
0.10
3.72
4.96
8.72
6.58
6.25
11.74
Thiophenyl
4-Bromo phenyl-
4-Cyano phenyl-
—
>6.25 >6.25
0.75 11.57
Among the fourteen compounds synthesized ten compounds
were found to be most active compounds with minimum inhibi-
tory concentration of less than 1 lV and were more active than
INH against MTB. Compounds with electron withdrawing group
substituted phenyl group were showing more activity. Among
the fourteen newly synthesized compounds, the compound 5,6-
dimethoxy-1-oxo-2,5-dihydro-1H-2-indenyl-4-fluoroyphenylmetha-
none (5g) was found to be most active against M. tuberculosis H37Rv
(MTB) and INH resistant M. tuberculosis (INHR-MTB) with mini-
[(E)-1-phenylmethylidene]-1-indanone derivatives were synthe-
sized by condensing 5,6-dimethoxy-1-indanone with appropriate
aromatic aldehydes in dilute methanolic sodium hydroxide solu-
tion at room temperature. Then the resulting products 5,6-dime-
thoxy-2-[(E)-1-phenylmethylidene]-1-indanone were brominated
in minimum quantity of chloroform followed by hydrolysis with
O
O
O
O
H3C
H3C
CH3OH-NaOH
H3C
H3C
R-CHO
+
R
O
O
2a-n
3a-n
1
CHCl3-Br2.HCl
O
Br
O
O
H3C
H3C
R
4a-n
CH3OH-KOH
O
O
O
H3C
H3C
R
O
5a-n
Scheme 1. Protocol for synthesis.

7002
M. A. Ali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 7000–7002
mum inhibitory concentration of <0.10
lV. When compared to
modified to exhibit better potency than the standard drugs. Fur-
INH, the compound (5g) was found to be 9.12-fold and 115.7-fold
more active against MTB and INHR-MTB. Following compounds 2-
chlorophenyl (5h), 4-chlorophenyl (5b), and 2,6-dichlorophenyl
(5i) substituents were found to be more active against MTBa and
ther studies will be performed to acquire more information about
Quantitative Structure–Activity Relationships (QSAR) and MDR
which are in progress in our laboratory. The diketone derivatives
discovered in this study may provide valuable therapeutic inter-
vention for the treatment of anti-tubercular diseases.
MTBb with MIC of 1.82
2.48 V, 4.96
lV, 3.72
lV, and 1.52 lV, 8.20 lV,
l
lV, respectively. The 4-fluoro group substituted
(5g) derivative displayed relatively higher inhibitory activity in
general. However the electron withdrawing group such as 4-cholr-
ophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, thiophenyl, furyl,
and 4-nitrophenyl substituted analogues showed moderate to
good inhibitory activity against M. tuberculosis (H37Rv) and INH
resistant M. tuberculosis (INHR-MTB). On the other hand the elec-
tron donating group containing analogues like (OCH3) group
substituted 4-methoxy phenyl (5a), 3,4 dimethoxy phenyl (5e),
and 3, 4, 5 trimethoxy phenyl (5f) functional groups showed low
antitubercular activity. These reports clearly show that the substi-
tution of electron withdrawing group like 4-fluoro substitution
causes remarkable improvement in antimycobacterial activity.
All the compounds were tested for cytotoxicity (IC50) in VERO
Acknowledgments
The authors wish to express their thanks to Dr. V. K Agarwal, S.
P. Garg, and Dr. Manju Agarwal, Alwar Pharmacy College, Alwar,
Rajasthan for providing research facilities.
Reference and notes
1. WHO report 2008, Global Tuberculosis Control Surveillance, Financing, and
Planning.
2. WHO News Release 24 March 2009, Rio De Janeiro.
3. Steel, M. A.; Burk, R. F.; DesPrez, R. M. Chest 1991, 99, 465.
4. Daphne, Y.; Chantal, V.; Marthe Pelletier, I.; Parisien, I.; Rocher; Dick, M. Am. J.
Respir. Crit. Care Med. 2005, 167, 1472.
5. Ali, M. A.; Shahar Yar, M.; Hasan, M. Z.; Ahsan, M. J.; Pandian, S. Bioorg. Med.
Chem. Lett. 2009, 19, 5075–5077.
cells at concentrations of 62.5 lg/mL or 10 times. After 72 h expo-
6. Heifets, L. B.; Flory, M. A.; Lindholm-Levy, P. J. Antimicrob. Agents. Chemother
1989, 33, 1252.
sure, viability was assessed on the basis of cellular conversion of
MTT into a formazan product using the Promega Cell Titer 96
Non-radioactive Cell proliferation method. Most of the active com-
7. Gundersen, L. L.; Nissen-Meyer, J.; Spilsberg, B. J Med.Chem, 2002, 45, 1383.
Compound (5g): 5,6-dimethoxy-1-indanone with 4-fluorobenzaldehyde in dilute
methanolic sodium hydroxide solution at room temperature to get 2-[(E)-1-
(4-fluorophenyl)methylidene]-5,6-dimethoxy-1-indanone then brominated in
minimum quantity of chloroform to get 2-[(Z)-1-bromo-1-(4-fluorophenyl)
methylidene]-5,6-dimethoxy-1-indanone followed by hydrolysis with
methanolic potassium hydroxide to get (5g) 5,6-dimethoxy-1-oxo-2,5-dihydro-
1H-2-indenyl-4-fluorophenylmethanone. IR: (KBr) cmÀ1: 3042 (CH), 1642 (C@O),
786 (C–F). 1H NMR (DMSO-d6) ppm: 3.20–3.35(1H, t, CH), 3.41–3.44 (2H, d, CH2),
3.86 (6H, s, OCH3), 6.68–7.20 (6H, m, aromatic); mass (m/z) 315 (M+1); Calcd/Anal.
[C (68.78) 68.79, H (4.81) 4.82, O (20.36) 20.37].
pounds were found to be non-toxic till 62.5 l
g/mL.7 The screening
of diketone derivatives identified novel compounds that were en-
dowed with antimycobacterial activity, exhibiting MIC values less
than 1 lM. It is conceivable that derivatives showing more po-
tency, selectivity and low toxicity make them excellent leads for
synthesizing novel derivatives for antimycobacterial activity
against MTB and INHR-MTB. Also these derivatives can be further