Synthesis and antitubercular activity of 2-hydroxy-aminoalkyl derivatives of diaryloxy methano phenanthrenes

Article abstract of DOI:10.1016/j.bmcl.2005.08.045

A series of 2-hydroxy-aminoalkyl derivatives of diaryloxy methano phenanthrenes were synthesized from nucleophilic opening of oxirane with different amines. These compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosi

Full text of DOI:10.1016/j.bmcl.2005.08.045

Bioorganic & Medicinal Chemistry Letters 15 (2005) 5222–5225
Synthesis and antitubercular activity of 2-hydroxy-aminoalkyl
derivatives of diaryloxy methano phenanthrenesq
Gautam Panda,a,* Shagufta,a Anil K. Srivastavab and Sudhir Sinhac
aMedicinal and 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 6 December 2004; revised 30 July 2005; accepted 18 August 2005
Available online 19 September 2005
Abstract—A series of 2-hydroxy-aminoalkyl derivatives of diaryloxy methano phenanthrenes were synthesized from nucleophilic
opening of oxirane with different amines. These compounds were evaluated for their antitubercular activity against Mycobacterium
tuberculosis H37Rv in vitro and showed MIC in the range of 3.12–25 lg/ml.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
diversification. However, several amino alcohol deriva-
tives 2, 3, 4, 5, and 6 along with ethambutol 1 are well
known to have antitubercular activity (Fig. 1).12 Consid-
ering antitubercular activity of amino alcohol deriva-
tives, we incorporated this moiety on diaryloxy
methanophenanthrene pharmacophore and thus de-
signed to synthesize 7 as our target molecule.
Despite having modern and sophisticated methods of
prevention, early detection, diagnosis, and thereafter
treatment for TB patients, the appearance of multi-
drug-resistant (MDR) strains, with the threat of global
human immunodeficiency virus (HIV), has led to declare
tuberculosis as Ôglobal emergencyÕ by WHO (World
Health Organization).1–4 Resistance has been surfaced
for all old drugs and for newly appearing drugs.5,6 The
funds for developing antituberculosis agents are increas-
ing enormously from academic and pharmaceutical
institutions. Thus, there is an urgent need for anti-TB
agents having new mechanism of action, which will be
able to minimize the chances of MDR strains.
OH
R
O
R= 20 and 30 amines
OH
R
R'= CH3,
OR'
Phenanthrene and their substituted analogs are well
known to exhibit various biological activities such as
antimicrobial,7 cytotoxic,8 antifungal,9 and antimalari-
al.10 Recently, we have reported that diaryloxy methan-
ophenanthrenes and anthracene derivatives having
enough hydrophobicity through a number of aryl rings
served as a lead for developing antitubercular agents.11
This result prompted us to take diaryloxy methanophe-
nanthrenes as an active pharmacophore for further
7
2. Chemistry
In our program toward synthesizing 2-hydroxy-amino
alkyl derivatives, the compound 811a was reacted with
epichlorohydrin in the presence of K2CO3 to furnish
the oxirane 9 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
(10a–m), Scheme 1 (see Table 1).
q
CDRI Communication No. 6648.
Corresponding author. Tel.: +915222364635; fax: +915222223938;
e-mail addresses: gautam_panda@lycos.com; bapi.rm@yahoo.com
*
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.045

G. Panda et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5222–5225
5223
C2H5-CH-NH-CH2CH2NH-CHC2H5 1-OH-sec-Bu-NH-CH2CH2NH2
CH2OH
CH2OH
1
2
Ethambutol
1-OH-sec-Bu-NH-CH2CH2N(C2H5)2
1-OH-sec-Bu-NH-CHCHNH-sec-Bu-1-OH
Ph
4
Ph
3
1-OH-sec-Bu-NH-CH2CH2CONH-sec-Bu-1-OH (CH3)3C-NH-CH2CH2NH-CH-C2H5
CH2OH
5
6
Figure 1.
OCH3
K2CO3
OCH3
OCH3
Amines (RH)
Epichlorohydrin
Reflux, 86%
Ethanol
Reflux
OH
OH
O
O
9
O
10 a-g
R
8
Scheme 1.
Table 1. Synthesis of 2-hydroxy-amino alkyl derivatives (10a–m)
3.2. Structure/activity relationship
Compound
Amines (RH)
Yield 10a–m (%)
In our earlier paper,11a it was noted that diaryloxy meth-
ano phenanthrene derivatives showed antitubercular
activity with MIC ranging from 6.25 to 12.5 lg/mL. Inter-
estingly, introducing 2-hydroxy-amino-alkyl moiety on
the diaryloxymethanophenanthrene pharmacophore
gave better antitubercular activity in compounds 10a–m
and 13a–d. Among all the compounds tested, two com-
pounds 10a and 10k showed MIC of 3.12 lg/ml and six
compounds 10b, 10d, 10i, 10m, 13a, and 13c showed
MIC of 6.25 lg/ml. Compound 10c having cyclopropyl
amine gave MIC 25 lg/ml, whereas cyclohexyl and cyclo-
heptyl amine containing compounds 10b and 10a showed
MIC of 6.25 and 3.12 lg/ml, respectively, implying that
increasing the ring size of the amines gave a lower order
of MIC for antitubercular activity. Compounds contain-
ing n-butylamine 10d and diethyl amine 10i showed MIC
of 6.25 lg/ml, whereas compounds containing piperidine
10h and pyrrolidine 10j gave MIC 12.5 lg/ml. Thus,
change of cyclic amines to acyclic amines gave better
antitubercular activity. Compound 10e containing mor-
pholine ring showed MIC of 25 lg/ml. Introduction of
4-(2-amino ethyl) chain onto morpholine in 10m gave bet-
ter activity (MIC 6.25 lg/ml). Further, replacement of
morpholine with imidazole in 10k gave MIC of 3.12 lg/
ml. Thus, incorporation of imidazole ring with a longer
aliphatic chain gave better activity. Introduction of
another 2-hydroxy-aminoalkyl group on diaryloxy meth-
ano phenanthrene in 13a–d does not have much effect on
activity.
10a
10b
10c
10d
10e
10f
10g
10h
10i
Cycloheptylamine
Cyclohexylamine
Cyclopropylamine
n-Butylamine
73
84
74
69
73
70
60
96
72
75
76
67
74
Morpholine
N-Methyl-piperazine
N-Benzyl-piperazine
Piperidine
Diethylamine
Pyrrolidine
10j
10k
10l
1-(3-Aminopropyl)imidazole
1-(2-Aminoethyl)-pyrrolidine
4-(2-Aminoethyl)-morpholine
10m
All the 2-hydroxy-amino alkyl derivatives 10a–m were
active against Mycobacterium tuberculosis (Table 3).
We became interested in synthesizing their bis-2-
hydroxy-amino alkyl derivatives to evaluate their antitu-
bercular activity. Toward this objective, the bis-phenolic
derivative 1111a was reacted with epichlorohydrin in the
presence of K2CO3 to furnish the bis-oxirane 12 (90%).
Nucleophilic addition of different amines gave bis-2-
hydroxy-amino alkyl derivatives (13a–d), Scheme 2
(see Table 2).
3. Biology
3.1. Determination of antitubercular activity in vitro
The activity of the compounds (10a–m and 13a–d)
against M. tuberculosis H37Rv was determined through
agar microdilution technique,13 and standard BACTEC
radiometric growth assay13 and their results are shown
in Table 3.
In conclusion, a series of 2-hydroxy-amino alkyl
derivatives of diaryloxy methano phenanthrenes that
have been synthesized demonstrated significant antitu-
bercular activity. Compounds containing cycloheptyl
amine 10a and imidazole ring with long aliphatic chain

5224
G. Panda et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5222–5225
OH
O
R
OH
K2CO3
O
O
R
Amines (RH)
Epichlorohydrin
Reflux, 90%
Ethanol
OH
11
OH
O
O
O
12
13a-d
Scheme 2.
Table 2. Synthesis of bis-2-hydroxy-amino alkyl derivatives (13a–d)
for 7 h. The ethanol was removed and the residue was
column chromatographed over silica gel and elution
with 5% methanol in chloroform furnished the com-
pounds 10a–10m.
Compound
Amines (RH)
Yield (%)
13a
13b
13c
13d
Piperidine
Pyrrolidine
94
64
66
72
Cyclohexylamine
N-Methyl-piperazine
4.1.1. 1-Cycloheptylamino-3-{4-[(4-Methoxy-phenyl)-phe-
nanthren-9-yl-methyl]-phenoxy}-propan-2-ol 10a. Pale
yellow solid, 275 mg (74%), mp 72 °C. IR (KBr): 3370,
1
2923, 1603, 1507, 1246, 1177, 1033, 801, 746 cmÀ1. H
NMR (CDCl3, 200 MHz): d 8.70–8.60 (m, 2H), 8.01 (d,
1H, J = 7.8 Hz), 7.63–7.45 (m, 5H), 7.13–7.01 (m, 5H),
6.82–6.77 (m, 4H), 6.11 (s, 1H), 4.15–4.01 (m, 1H),
3.92–3.90 (m, 2H), 3.74 (s, 3H), 3.00 (br s, 1H), 2.90–
2.64 (m, 3H), 1.84–1.80 (m, 2H), 1.64–1.38 (m, 10H).
MS: 560 (M+1). Anal. C38H41NO3; Calcd: C, 81.54; H,
7.38; N, 2.50%. Found: C, 81.59; H, 7.42; N, 2.55%.
Table 3. In vitro antituberculosis activity of 10a–m and 13a–d against
M. tuberculosis H37Rv
Compound
MIC (lg/mL)
Agar micro dilution method BACTEC method
9
10a
25
3.12
ND
3.12
6.25
25
10b
10c
12.5
25
4.1.2.
1-Cyclopropylamino-3-{4-[(4-Methoxy-phenyl)-
10d
10e
6.25
6.25
ND
12.5
ND
12.5
6.25
12.5
3.12
25
phenanthren-9-yl-methyl]-phenoxy}-propan-2-ol 10c. Pale
yellow solid, (275 mg, 94%), mp 60 °C. IR (KBr): 3344,
25
10f
10g
12.5
25
3015, 2936, 1607, 1508, 1243, 1178, 1037, 832, 743 cmÀ1
.
1H NMR (CDCl3, 200 MHz): d 8.73–8.62 (m, 2H), 8.03
(d, 1H, J = 8.1 Hz), 7.69–7.44 (m, 5H), 7.14 (s, 1H), 7.03
(d, 4H, J = 8.4 Hz), 6.82 (m, 4H, J = 8.4 Hz), 6.14 (s,
1H), 4.07–4.03 (m, 1H), 3.95–3.88 (m, 2H), 3.78 (s,
1H), 2.94–2.82 (m, 2H), 2.38 (br s, 2H), 2.20–2.14 (m,
1H), 0.47–0.36 (m, 4H). MS: 504 (M+1). Anal.
C34H33NO3; Calcd: C, 81.08; H, 6.60; N, 2.78%. Found:
C, 81.12; H, 6.65; N, 2.83%.
10h
10i
12.5
6.25
12.5
3.12
25
6.25
6.25
12.5
6.25
12.5
10j
10k
10l
10m
6.25
12.5
12.5
12.5
12.5
0.2
13a
13b
13c
13d
4.1.3. 1-{4-[(4-Methoxy-phenyl)-phenanthren-9-yl-meth-
yl]-phenoxy}-3- morpholin-4-yl-propan-2-ol 10e. Pale yel-
low solid, 260 mg (73%), mp 72 °C. IR (KBr): 3417,
Rifampin
Isoniazid (INH)
0.1
0.05
0.025
ND means not done in that particular test system.
1
2928, 1609, 1504, 1243, 1174, 1113, 1032, 747 cmÀ1. H
NMR (CDCl3, 200 MHz): d 8.73–8.63 (m, 2H), 8.03 (d,
1H, J = 8.1 Hz), 7.69–7.44 (m, 5H), 7.14 (s, 1H), 7.05
(d, 4H, J = 8.3 Hz), 6.86–6.80 (m, 4H), 6.14 (s, 1H),
4.13–4.06 (m, 1H), 3.97–3.95 (m, 2H), 3.78 (s, 3H),
3.74–3.70 (m, 4H), 2.68–2.63 (m, 2H), 2.56–2.42 (m,
4H). MS: 534 (M+1). Anal. C35H35NO4; Calcd: C,
78.77; H, 6.11; N, 2.62%. Found: C, 78.81; H, 6.17; N,
2.67%.
10k seem to have an encouraging effect on activity. This
suggests that incorporation of amino alcohol moiety
through opening of oxirane with various nitrogen con-
taining nucleophiles might be a suitable pharmacophore
for optimizing antitubercular activity of diaryloxy meth-
ano phenanthrenes.
4. Experimental
Acknowledgments
4.1. Typical procedure for 10a–10m
This research project was supported by Department of
Science and Technology (SR/FTP/CSA-05/2002), New
Delhi, India. Shagufta thanks CSIR for providing
fellowship.
The compound 9 (300 mg, 0.67 mmol) and amine
(1.05 mmol) were taken in ethanol (20 mL) and refluxed

G. Panda et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5222–5225
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