Thiophene containing triarylmethanes as antitubercular agents

Article abstract of DOI:10.1016/j.bmcl.2007.10.083

A new series of thiophene containing triarylmethane derivatives were synthesized from the Friedel-Crafts alkylation of diarylcarbinols followed by incorporation of amino alkyl chains. These were evaluated against Mycobacterium tuberculosis H₃₇R_v and showed the activity in the range of 3.12-12.5 μg/mL in vitro.

Full text of DOI:10.1016/j.bmcl.2007.10.083

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 289–292
Thiophene containing triarylmethanes as antitubercular agentsq
Maloy Kumar Parai,a Gautam Panda,a,* Vinita Chaturvedi,b
Y. K. Manjub and Sudhir Sinhab
aMedicinal & Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, UP, India
bDrug Target Discovery and Development Division, Central Drug Research Institute, Lucknow 226001, UP, India
Received 4 July 2007; revised 3 October 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—A new series of thiophene containing triarylmethane derivatives were synthesized from the Friedel–Crafts alkylation of
diarylcarbinols followed by incorporation of amino alkyl chains. These were evaluated against Mycobacterium tuberculosis H37Rv
and showed the activity in the range of 3.12–12.5 lg/mL in vitro.
Ó 2007 Elsevier Ltd. All rights reserved.
Tuberculosis is the leading infectious disease caused by
OMe
Mycobacterium tuberculosis.1,2 The situation is becom-
ing alarming with the recent emergence of multi-drug-
resistant (MDR) strains and its synergy with global
human immunodeficiency virus (HIV).3 The search for
more effective agents against M. tuberculosis (MT) is
ongoing in an attempt to enhance survival and reduce
morbidity, as proven by the high number of patents of
new antitubercular agents in the past decade.4
OMe
Ar
Ar
NR2
O
O
NR2
OH
2
1
Ar = 9-phenanthrenyl, (1-Benzenesulfonyl-1H-indol-3-yl),
pyridine-3-yl, 9-anthracenyl
Figure 1. Structures of antitubercular triarylmethanes with basic
amino alkyl or amino hydroxy alkyl side chains.
Because of this, there is an urgent need for anti-TB
drugs with improved properties such as enhanced activ-
ity against MDR strains, reduced toxicity, shortened
duration of therapy, rapid mycobactericidal mechanism
of action and the ability to penetrate host cells and
exert anti-mycobacterial effects in the intracellular
environment.
TRAMs, we planned to systematically substitute the
aryl group with rings having aromatic properties.
Thiophene containing compounds are well known to
exhibit various biological activities such as BACE1
inhibitors,5 anti-inflammatory agents,6 anti-HIV PR
inhibitors7 and anti-breast cancer.8 Thus, we decided
to replace one of the aryl rings with thiophene in
the triarylmethane nucleus. We also intended to incor-
porate chlorine and thiomethoxy substituted phenyl
ring since it is generally observed that the presence
of chlorine or thiomethoxy in a molecule profoundly
affected its biological properties.9–11 Moreover, several
amino alcohol derivatives such as ethambutol are
well known to have antitubercular activity (Fig. 2).12
Thus in our programme also, we intended to incorpo-
rate 2-hydroxy-amino functionality on thiophene con-
taining pharmacophore for further diversification and
designed to synthesize 3, 4 and 5 as our target mole-
cules (Fig. 2).
We have been involved in the design, synthesis and bio-
evaluation of new antitubercular agents and several tri-
arylmethane (TRAM) derivatives 1 and 2 (Fig. 1) with
antitubercular activity were reported.4 The structural
pharmacophore is based on a triarylmethane nucleus
containing phenanthrene, indole and anthracene rings
and exhibited 1.56–25 lg/mL antitubercular activity
in vitro. In order to optimize the anti-TB activity of
Keywords: Thiophene; Antitubercular; Friedel–Crafts alkylation.
q
CDRI communication No. 7167.
Corresponding author. Tel.: +91 522 2612411; fax: +91 522
2623938; e-mail: gautam.panda@gmail.com
*
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.083

290
M. K. Parai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 289–292
K2CO3 and acetone and furnished 11a–e, 12a–d, 13a–
OCH3
d, 14a–d and 15a–c in good yields (Scheme 1). The cor-
responding salts were obtained after treating the amines
with ethanolic HCl. Initial bioevaluation of the com-
pounds 11a–e and 12a–d, 13a–d, 14a–d and 15a–c gave
interesting antitubercular activity results in vitro. The
compound 10b was reacted with epichlorohydrin in
presence of K2CO3 to furnish the oxirane 16 in good
yield (86%). The oxirane was then reacted with selected
primary and secondary amines to furnish a variety of 2-
hydroxy amino alkyl derivatives (17a–k) (Scheme 1).
R1
Ar
R1
S
S
Ar
S
O
R2
OH
O
R2
O
4
R2
3
5
Figure 2. General structures of designed molecules.
The title compounds were synthesized essentially follow-
ing the steps as depicted below. Nucleophilic addition of
Grignard reagents 6a–c and 7b onto thiophene-2-carbal-
dehyde 7a and p-chloro benzaldehyde 6d, respectively, in
THF furnished the carbinol derivatives 8a–d in excellent
yields. Out of various protic acids used in Friedel–Crafts
alkylation, concd H2SO4 (cat.) in dry benzene gave bet-
ter results. Thus, FC alkylation of 8a–dwith phenol led
to the mixtures of 9a–d as minor and 10a–d as major
products. The compounds 9a–d were characterized from
its deshielded doublet aromatic protons and singlet
methine proton resonances, respectively, than corre-
sponding para isomers 10a–d due to the presence of
ÀI inductive effect of ortho-hydroxy group. The struc-
tural identity of 9a–d and 10a–d was further confirmed
by their 13C NMR and mass spectrum fragmentation
analysis. In this competitive reaction, the generation of
compounds 9a–d and 10a–d could be attributed to the
fact that Friedel–Crafts alkylation occurs via attack of
phenol at both ortho and para positions of the benzene
nucleus with the carbinol 8a–d.
Biology determination of activity in vitro: The activity of
the compounds against M. tuberculosis H37Rv was deter-
mined by agar microdilution technique.13 (details are de-
scribed in experimental section). The activity of the
compounds 11a–e, 12a–d, 13a–d, 14a–d, 15a–c and
17a–k in vitro is shown below (Table 1).
A closer look into the biological results of the above
compounds reveals that in a given diarylmethylphenol
series (10a–d), 10b containing p-OCH3 gave better activ-
ity. On the other hand, 11a–e with ortho substituent did
not exhibit good activity (>12.5 lg/mL). Among the
pair of compounds 12a, 12b; 13a, 13b; 14a, 14b and
15a, 15b, increasing the alkyl chain on nitrogen gave bet-
ter activity. Increase in polarity of the side chain reduces
the activity (12c, 13c, 14c and 15c). Incorporation of 2-
hydroxy-amino functionality on the pharmacophore for
better activity was not encouraging.
In conclusion we have synthesized thiophene containing
several triarylmethane (TRAM) derivatives as new series
of antitubercular compounds with antimycobacterial
activity. The compounds containing increased amount
of alkyl group on nitrogen of the side chain were active
Friedel–Crafts alkylated products 9a–d and 10a–d were
then aminoethylated with different dialkylaminoethyl
chloride hydrochloride chains in the presence of
R1
R1
S
S
R1
R2
R1
S
b
a
+
+ Y
OH
8a-d
S
X
R2
10a-d
R1= m-OCH3, X = Br, 6a
= p-OCH3, X = Br, 6b
= p-SCH3, X = Br, 6c
Y= CHO, 7a
= Br, 7b
9a-d
c
c
R1
R1
R1= m-OCH3, 12a-d
S
S
=
p
-Cl, X = CHO, 6d
= p-OCH3, 13a-d
= p-SCH3, 14a-d
= p-Cl, 15a-c
O
R2
11a-e
O
OCH3
R2
K2CO3
OCH3
OCH3
Amines (R2H)
S
Epichlorohydrin
Reflux, 86%
S
S
Ethanol
Reflux
OH
10b
OH
O
R2
O
16
O
17 a-k
Scheme 1. Reagents and conditions: (a) Mg, THF, 0 °C, rt, 2 h, 8a (69%), 8b (71%), 8c (74%) and 8d (79%); (b) phenol, concd H2SO4 (cat.), dry
benzene, reflux, 2 h, 9a (12%), 9b (9%), 9c (11%) and 9d (12%); (c) alkylaminoethyl hydrochloride (ClCH2CH2R2ÆHCl), anhyd K2CO3, dry acetone,
reflux, 6–7 h, (yields given in Table 1).

M. K. Parai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 289–292
291
Table 1.
Entry
Compound
R1
R2
Yielda (%)
MIC (lg/mL) agar microdilution method13
>12.5
3.12
1
2
3
4
5
6
10a
10b
10c
10d
11a
11b
m-OCH3
p-OCH3
p-SCH3
p-Cl
OH
OH
61
59
63
58
71
76
OH
OH
>12.5
>12.5
>12.5
>12.5
p-OCH3
p-OCH3
N(CH3)2
N(CH2CH3)2
7
11c
p-OCH3
78
>12.5
N
N
N
8
11d
p-OCH3
73
>12.5
9
11e
p-OCH3
68
>12.5
12.5
10
11
12a
12b
m-OCH3
m-OCH3
N(CH3)2
N(CH2CH3)2
71
78
3.12
12
12c
m-OCH3
82
12.5
N
N
O
13
12d
m-OCH3
79
3.12
14
15
13a
13b
p-OCH3
p-OCH3
N(CH3)2
N(CH2CH3)2
79
72
12.5
6.25
16
13c
p-OCH3
76
>12.5
N
N
O
17
13d
p-OCH3
72
12.5
18
19
14a
14b
p-SCH3
p-SCH3
N(CH3)2
N(CH2CH3)2
70
71
>12.5
3.12
20
14c
p-SCH3
76
>12.5
N
N
O
21
14d
p-SCH3
78
3.12
22
23
15a
15b
p-Cl
p-Cl
N(CH3)2
N(CH2CH3)2
71
76
6.25
3.12
24
25
26
27
28
29
30
15c
17a
17b
17c
17d
17e
17f
p-Cl
69
80
77
83
70
86
81
12.5
N
N
O
N
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-OCH3
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
N
HN
N
N
O
N
S
OCH3
OCH3
HN
N
N
N CH3
N
31
32
33
34
17g
17h
17i
17j
p-OCH3
p-OCH3
p-OCH3
p-OCH3
77
76
79
85
>12.5
12.5
HN
HN
N
12.5
>12.5
N
HN
N
35
17k
p-OCH3
81
>12.5
0.1
N
36
37
Rifampin
Isoniazid (INH)
—
—
—
—
—
—
0.05
a Isolated yield after silica gel column chromatography.

292
M. K. Parai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 289–292
Siddiqi, I. J. Mol. Model. 2007, 99; (e) Panda, G.; Parai, M.
K.; Das, S. K.; Shagufta; Sinha, M.; Chaturvedi, V.;
Srivastava, A. K.; Manju, Y. S.; Gaikwad, A.; Sinha, S.
Eur. J. Med. Chem. 2007, 42, 410.
with MIC 3.12 lg/mL and might be a lead for further
optimization and development.
5. Giordanetto, F.; Karlsson, O.; Lindberg, J.; Larsson, L.-
O.; Linusson, A.; Evertsson, E.; Morgan, D. G. A.;
Inghardt, T. Bioorg. Med. Chem. Lett. 2007, 17, 5222.
6. Kumar, P. R.; Raju, S.; Goud, P. S.; Sailaja, M.; Sarma,
M. R.; Reddy, G. O.; Kumar, M. P.; Reddy, V. V. R. M.
K.; Suresha, T.; Hegdeb, P. Bioorg. Med. Chem. 2004, 12,
1221.
7. Bonini, C.; Chiummiento, L.; Bonis, M. D.; Funicello, M.;
Lupattelli, P.; Suanno, G.; Berti, F.; Campaner, P.
Tetrahedron 2005, 61, 6580.
Acknowledgements
M.K.P. thanks CSIR for providing fellowship (NET
SRF). The Department of Science and Technology
(DST) and Indian Council of Medical Research
(ICMR), New Delhi, India, partly supported this
project.
´
8. Brault, L.; Migianu, E.; Neguesque, A.; Battaglia, E.;
Supplementary data
Bagrel, D.; Kirsch, G. Eur. J. Med. Chem. 2005, 40, 757.
9. Savini, L.; Chiasserini, L.; Gaeta, A.; Pellerano, C. Bioorg.
Med. Chem. 2002, 10, 2193.
10. Madrid, P. B.; Polgar, W. E.; Tolla, L.; Tangaa, M. J.
Bioorg. Med. Chem. Lett. 2007, 17, 3014.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2007.10.083.
11. Das, S. K.; Panda, G.; Chaturvedi, V.; Manju, Y. K.;
Gaikwad, A. N.; Sinha, S. Bioorg. Med. Chem. Lett. 2007,
17, 5586.
References and notes
12. (a) Wilkinson, R. G.; Cantrall, M. B.; Shepherd, R. G. J.
Med. Chem. 1962, 5, 835; (b) Shepherd, R. G.; Wilkinson,
R. G. J. Med. Chem. 1962, 5, 823.
13. Siddiqi, S.. In Clinical Microbiology Handbook; ASM
Press: Washington, DC, 1992; Vol. 1.
1. (a) Tuberculosis, HIV/Aids and Malaria, The status and
impact of the three diseases. WHO, Geneva, 2005; (b)
Raviglione, M. C. Tuberculosis 2003, 83, 4; (c) Espinal, M.
A. Tuberculosis 2003, 83, 44.
Agar microdilution method: Drug susceptibility and deter-
mination of MIC of the test compounds/drugs against M.
tuberculosis H37Rv were performed by agar microdilution
method where serial twofold dilutions of each test
compound were added into 7H10 agar and M. tuberculosis
H37Rv was used as test organism. MIC is the concentra-
tion of the compound that completely inhibits the growth
and colony forming ability of M. tuberculosis. In a 24-well
plate, 3 mL Middle brook 7H11 agar medium with OADC
supplement is dispensed in each well. The test compound
is added to the middle brook medium agar before in
duplicate so that final concentration of test compound in
each well is 12.5, 6.25, 3.125 and 1.56 lg/mL, respectively.
The known CFU of H37Rv culture was dispensed on top
of agar in each well in negative pressure biosafety hood.
The plates are then incubated at 37 °C/5% CO2 incubator.
The concentration at which complete inhibition of colo-
nies was observed was taken as MIC of test drug..
2. (a) Young, D. B.; Duncan, K. Ann. Rev. Microbiol. 1995,
49, 641; (b) Schaeffer, M. L.; Khoo, K. H.; Besra, G. S.;
Chatterjee, D.; Brennan, P. J.; Belisle, J. T.; Inamine, J. M.
J. Biol. Chem. 1999, 274, 31625; (c) Collins, L.; Franzblau,
S. G. Antimicrob. Agents Chemother. 1997, 41, 1004; (d)
Saito, H.; Tomioka, H.; Sato, K.; Emori, M.; Yamane, T.;
Yamashita, K.; Hosoe, K.; Hidaka, T. Antimicrob. Agents
Chemother. 1991, 35, 542.
3. De Jong, B. C.; Israelski, D. M.; Corbett, E. L.; Small, P.
M. Clinical management of tuberculosis in the context of
HIV infection. Annu. Rev. Med. 2004, 55, 283.
4. (a) Panda, G.; Shagufta; Mishra, J. K.; Chaturvedi, V.;
Srivastava, A. K.; Srivastava, R.; Srivastava, B. S. Bioorg.
Med. Chem. 2004, 12, 5269; (b) Panda, G.; Shagufta;
Srivastava, A. K.; Sinha, S. Bioorg. Med. Chem. Lett. 2005,
15, 5222; (c) Panda, G.; Mishra, J. K.; Sinha, S.; Gaikwad,
A. K.; Srivastava, A. K.; Srivastava, R.; Srivastava, B. S.
Arkivoc 2005, 2, 29; (d) Shagufta; Kumar, A.; Panda, G.;