Design, synthesis and antitubercular activity of diarylmethylnaphthol derivatives

Article abstract of DOI:10.1016/j.bmcl.2007.07.089

A new series of diarylmethylnapthyloxy ethylamines were synthesized by aminoalkylation of diarylmethylnaphthols which were obtained by Friedel-Crafts alkylation on 1- and 2-naphthols using diarylcarbinols as the alkylating agents. The title compounds were evaluated for antitubercular activity against Mycobacterium tuberculosis H₃₇R_v in vitro and showed MIC in the range of 3.12-25 μg/ml.

Full text of DOI:10.1016/j.bmcl.2007.07.089

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5586–5589
Design, synthesis and antitubercular activity of
diarylmethylnaphthol derivativesq
Sajal Kumar Das,a Gautam Panda,a,* Vinita Chaturvedi,b Y. S. Manju,b
Anil K. Gaikwadc and Sudhir Sinhac
aMedicinal & Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, UP, India
bMicrobiology Division, Central Drug Research Institute, Lucknow 226001, UP, India
cDrug Target Discovery and Development Division, Central Drug Research Institute, Lucknow 226001, UP, India
Received 24 February 2007; revised 2 July 2007; accepted 30 July 2007
Available online 22 August 2007
Abstract—A new series of diarylmethylnapthyloxy ethylamines were synthesized by aminoalkylation of diarylmethylnaphthols
which were obtained by Friedel–Crafts alkylation on 1- and 2-naphthols using diarylcarbinols as the alkylating agents. The title
compounds were evaluated for antitubercular activity against Mycobacterium tuberculosis H37Rv in vitro and showed MIC in the
range of 3.12–25 lg/ml.
Ó 2007 Elsevier Ltd. All rights reserved.
The prevalence of TB infection has steadily risen in the
past decade and the appearance of multi-drug-resistant
(MDR) strains, with the threat of global human immu-
OMe
OMe
R
OMe
nodeficiency virus (HIV), has led to declare tuberculosis
as ‘a global epidemic’ which is evident from the fact that
100 million people are infected annually, 10 million
develop the disease, with five million of these progress-
ing to the infectious stage and finally three million
dying.1 Resistance has surfaced for all clinically
prescribed antitubercular drugs.2,3 The search for more
effective agents against Mycobacterium tuberculosis
(MT) and M. avium complex (MAC) is ongoing in an at-
tempt to enhance better antitubercular activity and to
shorten the treatment regimen.4
O
O
R
R
O
OH
2
3
1
R= 2º or 3º Amines, NMe2, NEt2,
N
and N
N
,
Figure 1. Structures of diaryloxy methanophenanthrenes and 4-[10-
(methoxybenzyl)-9-anthryl]-phenols with basic amino alkyl or amino
hydroxy alkyl side chains.
Towards an ongoing programme for developing new
antitubercular agents, we have recently reported
antitubercular activity of several diaryloxy methanoph-
enanthrene derivatives 1 and 2 and 4-[10-(methoxyben-
zyl)-9-anthryl]phenol derivatives 3 (Fig. 1) with basic
amino alkyl or amino hydroxyl alkyl side chains.5 These
compounds are phenanthrene and anthracene containing
triarylmethane derivatives and exhibited 1.56–25 lg/mL
antitubercular activity in vitro. Most importantly, in
case of phenanthrene containing triarylmethane deriva-
tives, one compound has demonstrated significant anti-
tubercular activity in a mouse model of tuberculosis
infection.5a In order to understand the structural fea-
tures of triarylmethane derivatives necessary for en-
hanced anti-tubercular activity, we embarked on the
design, synthesis and antitubercular activity of certain
focused libraries of triarylmethane derivatives through
the incorporation of naphthol moiety as one of the aryl
substituents in triarylmethane nucleus. We also intend
to incorporate fluorine- and chlorine-substituted phenyl
ring since it is observed that the presence of chlorine or
Keywords: Diarylmethylnaphthol
Antitubercular.
derivatives;
Fridel-Crafts;
q
CDRI communication No. 7164.
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.2007.07.089

S. K. Das et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5586–5589
5587
X
and 10b along with ortho-hydroxy substituted products
in very minor amount and the minor ortho isomers
were not separable from the unreacted 1-naphthol by
chromatography method. Thus, major isomers 8b, 9b
and 10b were separated and characterized. Depending
on the nature of benzhydrols, the above Fridel-Crafts
reaction sequence thus provides an easy access to the
synthesis of symmetric as well as unsymmetric diarylm-
ethylnaphthols. The reaction of 8a, 9a and 10a with dif-
ferent dialkylaminoethyl chloride hydrochloride chains
in the presence of anhydrous K2CO3 in dry acetone un-
der reflux condition led to the formation of diarylmeth-
ylnapthyloxy ethylamines 11a–e, 13a–e and 15a–e in
good yields. Similarly, compounds 8b, 9b and 10b on
reaction with different dialkylaminoethyl chloride
hydrochlorides gave diarylmethylnapthyloxy ethylam-
ines 12a–e, 14a–e and 16a–e in good yields.
X
O
R
O
R
4
5
X= H, Cl and F
N
,
R= NMe , NEt ,
and N
N
2
2
Figure 2. General structures of designed molecules.
fluorine in a molecule can profoundly affect its biologi-
cal properties. Thus, we designed to synthesize 4 and 5
as our target molecules (Figure 2).
The title compounds were synthesized essentially fol-
lowing the steps as depicted in Scheme 1. Reduction
of commercially available benzophenones 6a–c with so-
dium borohydride in methanol furnished the corre-
sponding benzhydrol derivatives 7a–c in excellent
yields. Next, carbinols 7a–c were used as alkylating
agents in the Friedel–Crafts alkylation of 1- and 2-
naphthols. In every case, the reaction was performed
by refluxing a mixture of 1- or 2-naphthol and carbinols
7a or 7b or 7c in dry benzene in the presence of a cat-
alytic amount of conc. H2SO4. It is well known that Fri-
edel–Crafts alkylation reaction of 2-naphthol occurs at
its 1-position whereas the same reaction occurs at
2- and 4 positions in case of 1-naphthol.6 Thus, when
2-naphthol was used in the above reaction, only
ortho-hydroxy substituted diarylmethylnaphthols 8a,
9a and 10a were obtained in every case, which is consis-
tent with the reactivity of 2-naphthol in Friedel–Crafts
reactions. Similarly, the use of 1-naphthol furnished
para-hydroxy substituted diarylmethylnaphthols 8b, 9b
All the synthesized final molecules were evaluated
against M. tuberculosis H37Rv strains following micro
almar blue assay and agar microdilution technique7,8
and their results are shown in Table 1. Out of thirty mol-
ecules tested, 11a–e, 15b and 15d showed MIC of
3.12 lg/mL and 13a–e, 15a and 15c, showed MIC of
6.25 lg/mL in agar microdilution technique. Other com-
pounds of the series showed MIC of 12.5 lg/mL or
above. A closer look into the structure–activity of rela-
tionship of the above compounds reveals that in every
structurally isomeric pair of diarylmethylnapthyloxy
ethylamines (such as 11a and 12a; 13a and 14a; 15a
and 16a, etc.), ortho-substituted diarylmethylnapthyloxy
ethylamines 11a–e, 13a–e and 15a–e are more active
than their para-substituted counterparts 12a–e, 14a–e
and 16a–e. Among all the ortho-substituted diarylmeth-
ylnapthyloxy ethylamines 11a–e, 13a–e and 15a–e,
diphenylmethylnapthyloxy ethylamines 11a–e showed
better activity (except for 15b and 15d) than the rest of
X
X
b
d
HO
O
R
X
X= H, 8a
Cl, 9a
X
X= H, 11a-e
Cl, 13a-e
F, 15a-e
a
F, 10a
O
OH
X
X
X= H, 6a
Cl, 6b
X= H, 7a
Cl, 7b
d
c
F, 6c
F, 7c
OH
O
R
X= H, 8b
Cl, 9b
X= H, 12a-e
Cl, 14a-e
F, 16a-e
F, 10b
Scheme 1. Reagents and conditions: (a) NaBH4, methanol, 0 °C rt, 2 h, 7a (95%), 7b (96%) and 7c (95%); (b) 2-naphthol, dry benzene, reflux, 2 h, 8a
(89%), 9a (84%) and 10a (85%); (c) 1-naphthol, dry benzene, reflux, 2 h, 8b (73%), 9b (70%) and 10b (68%); (d) dialkylaminoethyl chloride
hydrochloride (ClCH2CH2R.HCl), anhyd K2CO3, dry acetone, reflux, 8–10 h, (yields given in Table 1).

5588
S. K. Das et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5586–5589
Table 1. Synthesized diarylmethyl naphthol derivatives with in vitro antitubercular activity against M. tuberculosis H37Rv
Serial No.
Compound
X
R
Yielda (%)
MICb (lg/mL)
MABA
MIC (lg/mL)
Agar microdilution method
1
2
11a
11b
H
H
N(CH3)2
N(C2H5)2
70
67
6.25
6.25
3.12
3.12
3
11c
H
80
6.25
3.12
N
N
4
11d
H
81
6.25
3.12
5
11e
H
69
6.25
3.12
N
6
7
12a
12b
H
H
N(CH3)2
N(C2H5)2
78
73
12.5
6.25
6.25
12.5
8
9
12c
12d
H
H
68
63
6.25
12.5
12.5
N
N
>12.5
10
12e
H
63
12.5
12.5
N
11
12
13a
13b
Cl
Cl
N(CH3)2
N(C2H5)2
66
68
3.12
3.12
6.25
6.25
13
14
13c
13d
Cl
Cl
74
70
3.12
3.12
6.25
6.25
N
N
15
13e
Cl
69
3.12
6.25
N
16
17
14a
14b
Cl
Cl
N(CH3)2
N(C2H5)2
79
67
NA
>12.5
12.5
12.5
18
19
14c
14d
Cl
Cl
61
62
NA
NA
12.5
12.5
N
N
20
14e
Cl
69
NA
>12.5
N
21
22
15a
15b
F
F
N(CH3)2
N(C2H5)2
69
75
3.12
6.25
6.25
3.12
23
24
25
15c
15d
15e
F
F
F
79
83
76
3.12
6.25
6.25
6.25
3.12
12.5
N
N
N
26
27
16a
16b
F
F
N(CH3)2
N(C2H5)2
74
73
NA
NA
>12.5
>12.5
28
29
16c
16d
F
F
69
79
6.25
12.5
12.5
12.5
N
N

S. K. Das et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5586–5589
5589
Table 1 (continued)
Serial No.
Compound
X
F
R
Yielda (%)
MICb (lg/mL)
MABA
MIC (lg/mL)
Agar microdilution method
30
16e
65
12.5
>12.5
N
31
32
Rifampin
Isoniazid (INH)
—
—
—
—
69
—
0.2
0.025
0.2
0.025
a Isolated yield after silica gel column chromatography.
b NA means not active at MIC of 12.5.
compounds in this series with a chloro or fluoro substi-
tuent on the para-position of a phenyl ring. This result
indicated that presence of chloro or fluoro substituent
on one phenyl ring has no beneficial effect on the antitu-
bercular activity of diarylmethylnapthyloxy ethylam-
ines. Further, within a particular series antitubercular
activity almost remains unchanged on changing the ba-
sic alkylaminoethyl side chains.
References and notes
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The in vitro cytotoxicity of compounds 11a–e, 15b and
15d (having a MIC of 3.12 lg/mL in agar microdilution
technique) in VERO cell lines was determined using a
dye reduction assay following three days exposure to
test compounds as previously described.5e All these
compounds were found to be toxic and hence not suit-
able for in vivo evaluation.
In conclusion, a series of diarylmethylnapthyloxy
ethylamines were synthesized by aminoalkylation of
diarylnaphthols obtained by Friedel–Crafts alkylation
of 1- and 2-naphthols using diarylcarbinols as the alkyl-
ating agents. Ortho-substituted diarylmethylnapthyloxy
ethylamines 11a–e, 13a–e and 15a–e are more active
than their para-substituted counterparts 12a–e, 14a–e
and 16a–e. Among the ortho-substituted diarylmethyl-
napthyloxy ethylamines, 11a–e, 15b and 15d showed
promising activity in vitro. It is conceivable that these
triarylmethane derivatives containing naphthalene ring
might act as a lead for optimizing antitubercular activ-
ity. It will be interesting to prepare new analogues of
the most active compounds, which may be nontoxic
with significant anti-tubercular activity.
Acknowledgements
6. For Friedel–Crafts alkylation of 1-and, 2-naphthols, see:
(a) MacLeod, P. D.; Li, Z.; Feng, J.; Li, C.-J. Tetrahedron
Lett. 2006, 47, 6791, and references cited therein.; (b) Zhan,
J.-P.; Cui, Y.-Y.; Liu, H.-J. Tetrahedron Lett. 2006, 47,
9143; (c) Liguori, L.; Bjorsvik, H.-R.; Fontana, F.; Bosco,
D.; Galimberti, L.; Minisci, F. J. Org. Chem. 1999, 64,
8812; (d) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.;
Mitchell, W. L.; Kociovsky, P. J. Org. Chem. 1999, 64,
2751; (e) Buu-Hoi, N. P.; Demerseman, P. J. Org. Chem.
1955, 20, 1129.
S.K.D. thanks CSIR for providing fellowship (NET
SRF). The Department of Science and Technology
(DST) and Indian Council of Medical Research
(ICMR), New Delhi, India, supported this project.
Supplementary data
7. Collins, L. A.; Franzblau, S. G. Antimicrob. Agents
Chemother. 1997, 41, 1004.
8. Siddiqi, S.. In Clinical Microbiology Handbook; ASM Press:
Washington, DC, 1992; Vol. 1.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2007.07.089.