Substituted 4-methylquinolines as a new class of anti-tuberculosis agents

Article abstract of DOI:10.1016/S0960-894X(03)00074-X

We report synthesis and anti-tuberculosis activities of a series of novel ring-substituted quinolines. The most effective compound of the series 3d (MIC=6.25 μg/mL, Mycobacterium tuberculosis H37Rv strain) was synthesized in one step; thus is an attractive lead molecule for anti-tuberculosis drug development. The results of this study represent the discovery of ring-substituted 4-methylquinolines as new class of potential anti-tuberculosis agents.

Full text of DOI:10.1016/S0960-894X(03)00074-X

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1051–1054
Substituted 4-Methylquinolines as a New Class of
y
Anti-Tuberculosis Agents
Rahul Jain,* Balasubramanian Vaitilingam, Amit Nayyar and Prakash B. Palde
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar,
Punjab 160 062, India
Received 1 November 2002; accepted 16 January 2003
Abstract—We report synthesis and anti-tuberculosis activities of a series of novel ring-substituted quinolines. The most effective
compound of the series 3d (MIC=6.25 mg/mL, Mycobacterium tuberculosis H37Rv strain) was synthesized in one step; thus is an
attractive lead molecule for anti-tuberculosis drug development. The results of this study represent the discovery of ring-substituted
4
#
-methylquinolines as new class of potential anti-tuberculosis agents.
2003 Elsevier Science Ltd. All rights reserved.
Tuberculosis disease has staged a lethal comeback pri-
marily because of resistance development by the causative
organism, Mycobacterium tuberculosis against all major
anti-tuberculosis drugs, and the rising incidence of
immuno-suppressed situations (through cancer chemo-
entities and to optimize the structure to display the
potent efficacy.
In continuing our drug discovery program, this pre-
liminary communication describes the synthesis and
hitherto unknown in vitro anti-Mycobacterium tubercu-
losis activities of novel ring-substituted 4-methylquino-
lines.
1
therapy, AIDS infection and transplantation).
Approximately, 8 million people develop tuberculosis
each year, and 2–3 million people die annually from the
2
,3
disease; 95% of which reside in developing countries.
According to the World Health Organization (WHO)
predictions, tuberculosis if unchecked, will claim more
than 30million lives over the next decade and infect
The mono and disubstituted 4-methylquinolines 2 and 3
represented in Scheme 1 have been synthesized in one
step by reacting commercially available 4-methylquino-
line (1) with various alkylcarboxylic acids in 10% sul-
furic acid in the presence of ammonium persulfate and
4ꢀ6
another 90million.
Furthermore, it is a well known
fact that no tuberculosis specific drug has been dis-
covered in the last 40years. The inadequate armory of
drugs in widespread use for the treatment, develop-
ment of drug-resistant forms of the disease against
most commonly used mainstay drug isoniazid, and
lack of affordable new drugs are the limiting factors in
fight against tuberculosis. Hence, there are unmet
medical needs for novel, efficacious therapies that
minimize resistance problems in M. tuberculosis. This
underscores the continuing urgent need for the dis-
covery of new structural classes of anti-tuberculosis
agents to replace and/or to supplement the current
drug regimens. To pursue this goal, our research
efforts are directed towards discovery of new chemical
ꢁ
catalytic amounts of silver nitrate at 70 C for 10min.
As reported by us earlier,
7ꢀ9
the reaction proceeds via
silver catalyzed free radical oxidative decarboxylation of
alkylcarboxylic acids by ammonium persulfate in 10%
1
0
sulfuric acid as solvent. Overall yields range from 25–
90%, though not surprisingly lower yields and only
formation of the monosubstituted cyclopropyl adduct
1
2
(2f) was observed (Table 1). Presumably, this is a
consequence of competitive degradation of the cyclo-
propyl radical verses oxidative decomposition of the
quinoline ring. On the other hand, the reduced yields
1
3
were first observed for the adamantyl product (2g),
that may be attributed to the lower solubility of 1-ada-
mantanecarboxylic acid in the aqueous reaction med-
ium rather then steric factors. In this case, unlike the
other alkylcarboxylic acids, a substantial quantity of 1-
adamantanecarboxylic acid was found left unreacted in
the reaction vessel at the conclusion of the reaction.
*Corresponding author. Tel.:+91-172-214-682; fax:+91-172-214-692;
e-mail: rahuljain@niper.ac.in (R. Jain).
y
NIPER communication no. 97
0
960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00074-X

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R. Jain et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1051–1054
exhibited inhibitory activity (67 and 74%, respectively)
that is far less efficacious compared to the disubstituted
derivatives. Along the same lines, all other mono-
substituted 4-methylquinoline analogues were found to
be less effective (Table 1). Amongst the remaining dis-
ubstituted analogues, the diisopropyl derivative (3a) has
shown inhibitory activity (71%) at >6.25 mg/mL;
whereas, the dicyclohexyl derivative (3e) was found to
be even less potent and has demonstrated only 63%
inhibition at a concentration of >6.25 mg/mL. Interest-
ingly, 4-methylquinoline (1), the starting material, utilized
to prepare all analogues was completely devoid of any
activity. These results indicates that placement of more
than one cycloalkyl group containing maximum of five
carbon atoms resulted in compounds with superior and
enhanced biological activity. On the other hand, place-
ment of a branched chain alkyl group at the quinoline
ring led to derivatives with reduced anti-tuberculosis
activity when compared to cycloalkyl derivatives.
Finally, the placement of straight alkyl chain on the
quinoline ring results in a further loss of anti-tubercu-
losis properties (Table 1).
Scheme 1.
Table 1. Yields and antimycobacterial in vitro activity, expressed as
a
MIC (mg/mL) , against M. tuberculosis H37Rv of ring-substituted 4-
methylquinolines 2–3
Compd
R
(%)
Yield
(%)
Inhibition
MIC
(mg/mL)
b
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
1
a
b
c
CH(CH
C(CH )
3 3
3
)
2
65
75
65
7074
65
25
6076
45
41
35
32
22
21
25
24
23
57
NDc
67
>6.25
ND
1
1
c-C
c-C
4
H
H
7
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
ND
d
5
9
1
1
e
f
c-C
c-C
6
H
11
16
29
3
H
5
g
h
i
1-adamantyl
(CH
(CH
(CH
(CH
2
)
2
)
2
)
2
)
2
3
4
5
CH
CH
CH
CH
3
3
3
3
30
28
24
20
j
k
a
b
c
d
e
h
i
CH(CH
C(CH
3
)
2
71
3
)
3
ND
100
100
53
36
33
29
23
0
The most effective compound (3d) of the series was also
evaluated against M. avium complex (ATCC 25291, a
strain susceptible to clarithromycin) and was found to
be inactive at the initial tested concentration of 6.25 mg/
mL. The same compound (3d) was further evaluated in
vitro for cytotoxicity (IC ) in VERO cells, along with
c-C
c-C
4
H
H
7
12.5
6.25
5
9
c-C
6
H
11
>6.25
>6.25
6.25
>6.25
>6.25
>6.25
(CH
(CH
(CH
(CH
2
)
2
)
2
)
2
)
2
3
4
5
CH
CH
CH
CH
3
3
3
3
14
12
14
11
j
k
5
0
safety index (SI) calculated as the ratio of IC /
5
0
H
—
MICH37Rv, and results are reported in Table 2. Con-
currently with testing of 2,8-dicyclopentyl-4-methylquino-
line (3d) in M. avium, evaluation of activity against single-
drug-resistant (SDR) M. tuberculosis was performed.
The compound has shown good activity with MIC
value of 12.5 mg/mL against rifampin (RMP-R),
ethambutol (EMB-R), ciprofloxacin (CIP-R), and iso-
niazid (INH-R) resistant M. tuberculosis strains;
whereas, it has exhibited moderate activity against
kanamycin (KM-R) resistant strains with MIC value of
aMIC is defined as the lowest concentration inhibiting 90% of the
inoculum relative to controls.
b
Based on initial 4-methylquinoline.
Not done.
c
However, the yield was improved to 60% through
modification of the reaction conditions by first dissolving
the 1-adamantanecarboxylic acid in acetonitrile, which
1
3
was then added to the reaction mixture.
25 mg/mL (Table 2).
All of the synthesized compounds 2 and 3 were evaluated
for tuberculosis inhibition against M. tuberculosis H37Rv
strain (ATCC 27294, susceptible both to rifampin and
isoniazid) using the Microplate Alamar Blue Assay
The minimum bactericidal concentration (MBC) for
2,8-dicyclopentyl-4-methylquinoline (3d) was then
determined against M. tuberculosis H37Rv strain and
against drug-resistant strain of isoniszid (INH-R) and
rifampin (RMP-R) by subculturing onto drug-free solid
media and enumerating colony forming units following
exposure in supplemented Middlebrook 7H9 media to
various concentrations of test compound. The observed
minimum bactericidal concentrations (Table 3), which
1
4
(
then tested in the BACTEC 460radiometric system
MABA). Compounds exhibiting fluorescence were
1
5
and results are summarized in Table 1. Compounds
demonstrating at least 90% inhibition are re-tested at
lower concentrations in the MABA and/or in BACTEC
4
60radiometric assay to determine the actual Minimum
Inhibitory Concentration (MIC), a value defined as the
lowest concentration inhibiting 90% of the inoculum
relative to controls.
Table 2. Cytotoxicity and SDR anti-tuberculosis activities of 2,8-
dicyclopentyl-4-methylquinoline (3d)
Amongst the tested compounds, 4-methylquinoline
analogue (3d) with two cyclopentyl groups placed at C-2
and C-8 position of the ring exhibited highest inhibitory
activity (100%) at a concentration of 6.25 mg/mL (MIC).
At the same time, 2,8-dicyclobutyl-4-methylquinoline (3c)
also exhibited potent activity (100% inhibition) at a
concentration of 12.5 mg/mL (MIC). Whereas, the
monosubstituted counterparts of compounds 3c and 3d
No.
IC50
mg/mL)
SI
Assay
Strain
MIC
(mg/mL)
(
3
d
>50
>8
Alamar
Alamar
Alamar
Alamar
Alamar
Alamar
Erdman
EMB-R
RMP-R
CIP-R
KM-R
INH-R
50
12.5
12.5
12.5
25
12.5

R. Jain et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1051–1054
1053
Table 3. Minimum bactericidal concentration (MBC) assay data of
,8-dicyclopentyl-4-methylquinoline (3d)
8.03 (d, 1H, Ar–H, J=8.5 Hz); analysis for C H N
15 17
2
(211.1), calcd, C, 85.26; N, 8.11; N, 6.63; found, C,
5.22; H, 8.02; N, 6.57; CIMS (NH ) m/z 212 (M+1).
8
3
No.
Assay
MIC (H37Rv)
Strain
MBC
(mg/mL)
MBC/MIC
(mg/mL)
(mg/mL)
Spectral data for 2,8-dicyclopentyl-4-methylquinoline
1
3d
Alamar
25
H37Rv
RMP-R
INH-R
502
200
100
(
3d). Yield: 24%; oil, H NMR (CDCl ) d 2.04 (m,
3
8
4
1
3
6H, 8ꢂCH ), 2.64 (s, 3H, CH ), 3.19 (m, 1H, CH),
2
3
.31 (m, 1H, CH), 7.10(s, 1H, Ar–H), 7.40(m, 1H, Ar–
H), 7.86 (m, 2H, Ar–H); analysis for C H N (279.2),
2
0
25
calcd, C, 85.97; H, 9.02; N, 5.01; found, C, 85.99; H,
9.12; N, 5.05; CIMS (NH ) m/z 280(M+1).
are higher, compared to MIC value does indicates that
compound 3d is bacteriostatic in nature.
3
We have described the synthesis and anti-tuberculosis
activities of ring-substituted 4-methylquinoline analo-
gues. The most significant aspect of this research is the
exhibition of potent anti-tuberculosis activities in the
reported compounds, which are synthesized in single step
from inexpensive commercially available 4-methylquino-
line (lepidine) via a homolytic free radical alkylation in
excellent yield. The above results clearly established the
discovery of ring-substituted 4-methylquinolines as a new
class of anti-tuberculosis agents, and therefore, these mole-
cules are very attractive for further chemical and biological
optimization. Efforts are currently underway towards
further optimization of the lead molecules through the
replacement of methyl group with other synthetically
negotiable groups at the various positions of the quino-
line ring. Although, the most effective compound 3d of
the series is bacteriostatic in nature, it can be concluded
that this class of compounds certainly holds great pro-
spects, and that further exploration in this field may
lead to potent anti-tuberculosis agents.
Acknowledgements
The Tuberculosis Antimicrobial Acquisition and Coor-
dination Facility (TAACF) provided antimycobacterial
data through a research and development contract with the
US National Institute of Allergy and Infectious Diseases.
References and Notes
1. (a) World Health Organization. In Anti-tuberculosis Drug
Resistance in the World. The WHO/IUALTD Global Project on
Anti-Tuberculosis DrugResistance Surveillance . World Health
Organization (Publication # WHO/TB/ 97.229), Geneva,
Switzerland, 1997. (b) Duncan, K. Chem. Ind. 1997, 861. (c)
Shinnick, T. M.; King, C. H.; Quinn, F. D. Am. J. Med. Sci.
995, 309, 92.
. World Health Organization. Global Tuberculosis Control;
WHO Report 2001; World Health Organization, (Publication
# WHO/CDS/TB/2001.287), Geneva, Switzerland, 2001.
3. Snider, D. E., Jr; LaMontagane, J. R. J. Infect. Dis. 1994,
1
2
1
4
5
69, 1189.
. McConnell, J. The Lancet 1998, 351, 852.
. Ken, D. J. Pharm. Pharmacol. 1997, 49, 1.
Typical procedure for the synthesis of ring-substituted
6. David, S. Tuberculosis; Spring-Verlag Ed: New York, 1996.
7. Jain, R.; Cohen, L. A.; El-Kadi, N. A.; King, M. M. Tet-
rahedron 1997, 53, 2365.
4-methylquinolines
A freshly prepared solution of ammonium persulfate (3
mmol) in water (7 mL) was added drop wise to a pre-
8
4
9
. Jain, R.; Cohen, L. A.; King, M. M. Tetrahedron 1997, 53,
539.
. Narayanan, S.; Suryanarayana, V.; Jain, R. Bioorg. Med.
ꢁ
heated (70 C) mixture of 4-methylquinoline (1, 1
mmol), silver nitrate (0.6 mmol) and cyclopentane-
carboxylic acid (2.2 mmol) in 10% H SO (10mL)
Chem. Lett. 2001, 11, 1133.
10. (a) For mechanistic details of the homolytic radical reac-
tion, please see: Minisci, F.; Bernardi, R.; Bertini, F.; Galli,
R.; Perchinummo, M. Tetrahedron 1971, 27, 3575. (b) Minisci,
F.; Visamara, E.; Fontana, F.; Morini, G.; Serravalle, M.;
Giordano, C. J. Org. Chem. 1987, 52, 730. (c) Giordano, C.;
Minisci, F.; Visamara, E.; Levi, S. J. Org. Chem. 1986, 51, 536.
2
4
during 5 min. The heating source was then removed and
reaction proceeded with evolution of carbon dioxide.
After 10min, reaction mixture was poured onto ice, and
resulting mixture was made alkaline with addition of
3
mL), and combined extracts were washed with NaCl
0% NH OH. Extracted with dichloromethane (3ꢂ20
4
(
1
d) Visamara, E.; Serravalle, M.; Minisci, F. Tetrahedron Lett.
986, 27, 3187. (e) Anderson, J. M.; Kochi, J. K. J. Am. Chem.
solution (2ꢂ5 mL). Dried over Na SO and solvent
2
4
Soc. 1970, 92, 1651. (f) Minisci, F. Synthesis 1973, 1. (g) Minisci,
F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489.
11. Minisci, F.; Fontana, F.; Pianese, G.; Yan, Y. M. J. Org.
Chem. 1993, 58, 4207.
removed in vacuo to afford a mixture of mono and dis-
ubstituted products, which were readily separated by
flash column chromatography [EtOAc–hexanes, 10:90]
over silica gel (230–400 mesh) to provide 2d and 3d
12. Spectral data for 2-cyclopropyl-4-methylquinoline (2f):
ꢁ
1
Yield: 25%; mp: 57–58 C; H NMR (CDCl
ꢂCH ), 2.19 (m, 1H, CH), 2.65 (s, 3H, CH
H), 7.44 (m, 1H, Ar–H), 7.63 (m, 1H, Ar–H), 7.93 (m, 2H, Ar–
H); analysis for C13 13N (183.1), calcd, C, 85.21; H, 7.15; N,
.64, found, C, 85.52; N, 7.02; N, 7.48; CIMS (NH ) m/z 184
M+1).
3
) d 1.10(m, 4H,
(Table 1).
2
2
3
), 7.0(s, 1H, Ar–
H
7
(
3
Spectral data for 2-cyclopentyl-4-methylquinoline (2d).
ꢁ
1
Yield: 70%, mp: 80–82 C; H NMR (CDCl ) d 1.84
3
13. In this particular case, 1-adamantanecarboxylic acid (2
ꢁ
(
m, 6H, 3ꢂCH ), 2.15 (m, 2H, CH ), 2.68 (s, 3H, CH ),
2
2
3
mmol) was dissolved in CH CN (2.5 mL) at 70 C followed by
3
3.30(m, 1H, CH), 7.17 (s, 1H, Ar–H), 7.49 (m, 1H, Ar–
H), 7.66 (m, 1H, Ar–H), 7.93 (d, 1H, Ar–H, J=8.5 Hz),
the addition of 4-methylquinoline (1, 1 mmol), silver nitrate
(0.6 mmol) and 10% H SO (10mL). A freshly prepared
2
4

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R. Jain et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1051–1054
solution of ammonium persulfate (3 mmol) in water (7 mL)
ꢁ
23
8.06 (d, 1H, 8-Ar–H, J=7.7 Hz); analysis for C20H N
(277.2), calcd, C, 86.59; H, 8.36; N, 5.05, found, C, 86.55; N,
+
8.33; N, 5.01; EIMS m/z 277 (M ).
14. Franzblau, S. G.; Witzig, R. S.; McLaughlin, J. C.;
Torres, P.; Madico, G.; Herandez, A.; Degnan, M. T.; Cook,
M. B.; Quenzer, V. K.; Ferguson, R. M.; Gilman, R. H. J.
Clin. Microb 1998, 36, 362.
15. Collins, L.; Franzblau, S. G. Antimicrob. Agents Che-
mother. 1997, 41, 1004.
was added drop wise to the pre-heated (70 C) reaction mix-
ture during 5 min, and reaction mixture was allowed to stir for
another 10min. The reaction was worked up as for the pro-
tocol of other carboxylic acids described earlier. Spectral data
for 2-adamantan-1-yl-4-methylquinoline (2g): Yield: 60%; mp:
ꢁ
1
1
3
14–115 C; H NMR (CDCl
3
) d 1.64 (m, 15H, 6ꢂCH
2
and
ꢂCH), 2.69 (s, 3H, CH ), 7.32 (s, 1H, 3-Ar–H), 7.48 (m, 1H,
3
Ar-H), 7.64 (m, 1H, Ar–H), 7.93 (d, 1H, 5-Ar–H, J=8.2 Hz),