Synthesis and optimization of antitubercular activities in a series of 4-(aryloxy)phenyl cyclopropyl methanols

Article abstract of DOI:10.1016/j.ejmech.2010.09.063

A series of [4-(aryloxy)phenyl]cyclopropyl methanones were synthesized by reaction of different benzyl alcohols with 4-chloro-4′-fluorobutyrophenone in DMF in the presence of NaH/TBAB. The methanones were further reduced to respective methanols. The antitubercular activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv. Compounds 19, 21, 35, 36 and 37 have shown minimum inhibitory concentration (MIC) of 3.12 μg/mL, while compounds 14, 25 and 18 have shown MIC of 1.56 μg/mL and 0.78 μg/mL respectively. One of the compounds, cyclopropyl-4-[4-(2-piperidin-1- yl-ethoxy)benzyloxy]phenyl}methanol (36) showed 98% killing of intracellular bacilli in mouse bone marrow derived macrophages and was active against MDR, XDR and rifampicin clinical isolates resistant strains with MIC 12.5 μg/mL. Compound 36 was orally active in vivo in mice against M. tuberculosis H37Rv with an increase in MST by 6 days with 1 log reduction in the bacillary density in lungs as compared to control on 30th day after infection.

Full text of DOI:10.1016/j.ejmech.2010.09.063

European Journal of Medicinal Chemistry 45 (2010) 5965e5978
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and optimization of antitubercular activities in a series of 4-(aryloxy)
phenyl cyclopropyl methanols
Surendra S. Bisht a, Namrata Dwivedi a, Vinita Chaturvedi b, Namrata Anand a, Mridul Misra a,
Rahul Sharma a, Brijesh Kumar c, Richa Dwivedi b, Shyam Singh b, Sudhir Kumar Sinha b, Versha Gupta d,
,
P.R. Mishra d, Anil K. Dwivedi d, Rama P. Tripathi a
*
a Medicinal and Process Chemistry Division, CSIR, Lucknow-226001, India
b Drug Target Discovery and Development Division, CSIR, Lucknow-226001, India
c Sophisticated Advanced Instrumentation Facility Division, CSIR, Lucknow-226001, India
d Pharmaceutics Division, Central Drug Research Institute, CSIR, Lucknow-226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of [4-(aryloxy)phenyl]cyclopropyl methanones were synthesized by reaction of different benzyl
alcohols with 4-chloro-40-fluorobutyrophenone in DMF in the presence of NaH/TBAB. The methanones
were further reduced to respective methanols. The antitubercular activity of these compounds was
evaluated in vitro against Mycobacterium tuberculosis H37Rv. Compounds 19, 21, 35, 36 and 37 have
Received 28 July 2010
Received in revised form
7 September 2010
Accepted 28 September 2010
Available online 20 October 2010
shown minimum inhibitory concentration (MIC) of 3.12
mg/mL, while compounds 14, 25 and 18 have
shown MIC of 1.56 g/mL and 0.78 g/mL respectively. One of the compounds, cyclopropyl-4-
m
m
[4-(2-piperidin-1-yl-ethoxy)benzyloxy]phenyl}methanol (36) showed 98% killing of intracellular bacilli
in mouse bone marrow derived macrophages and was active against MDR, XDR and rifampicin clinical
isolates resistant strains with MIC 12.5 mg/mL. Compound 36 was orally active in vivo in mice against
M. tuberculosis H37Rv with an increase in MST by 6 days with 1 log reduction in the bacillary density in
lungs as compared to control on 30th day after infection.
Keywords:
Mycobacterium tuberculosis
Antitubercular agents
(Aryloxy)phenyl cyclopropyl methanone
(Aryloxy)phenyl cyclopropyl methanol
Cytotoxicty
Ó 2010 Elsevier Masson SAS. All rights reserved.
Sodium hydride
1. Introduction
better tools and strategies to control TB [8]. Although several
molecules are known to be potent antitubercular agents [9e11]
Among chronic infectious diseases, tuberculosis (TB) a highly
contagious, air-borne disease caused by Mycobacterium tubercu-
losis is a leading killer in the world and currently it represents the
most threatening health problem globally. The emergence of
multidrug-resistant tuberculosis (MDR-TB) and extensively drug
resistant (XDR-TB), coupled with HIV has aggravated the problem
[1e3]. As per WHO estimate there are about 13.7 million chronic
active cases, 9.4 million new cases, and 1.8 million deaths, mostly
in developing countries [4]. More than 2 million people die of
pulmonary TB every year [5e7]. The existing diagnostics, drugs
and vaccines will be insufficient to achieve the objectives, set by
STOP TB programme, to bring down the mortality of TB by 2015
and halve the incidence by 2050. A substantial effort in basic
science, chemotherapy and epidemiology is necessary to develop
and at least 10 of them are in different stages of clinical trial [12]
yet none of them are expected to be in the market before 2012.
In the light of these, development of new chemical entities with
novel mode of action is need of the hour to strengthen the armory
of the anti-TB drugs.
Since past several years we have been involved in the discovery
and development of new chemical entities as antitubercular agents
that can improve the current therapeutic regimen and be effective
in treatment of MDR-TB [13e21]. Simple acetophenones [22],
benzylideneacetophenones [23] and p-nitro-
a-acetylamino-
b-hydroxypropiophenones [24] different chalcones and flavanoids
[23] possess antimycobacterial activities. In this endeavor we have
recently disclosed potent antimycobacterial activity in cyclo-
propylphenyl methanones (1) and methanols (2) as new chemical
entities active in vitro against both the drug sensitive and MDR
strains of M. tuberculosis (Fig. 1) [16]. However, the in vivo efficacies
of these compounds were not very encouraging. From our
preliminary studies, the key structural feature of this series was
found to be a cyclopropylphenyl methanol unit (A) and variation in
* Corresponding author. Tel.: þ91 0522 2612411; fax: þ91 522 2623405/
2623938/2629504.
E-mail address: rpt.cdri@gmail.com (R.P. Tripathi).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.09.063

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S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
The benzyl alcohol derivatives (27e30) on treatment with
4-chloro-40-fluorobutyrophenone (11) separately in DMF in pres-
ence of NaH and tetrabutylammonium bromide as described above
led to the formation of respective 4{[4-(aminoalkoxy)benzyloxy]
phenyl}cyclopropyl methanones (31e34) respectively in 75e80%
yields (Scheme 2).
Reduction of above methanones (31e34) with NaBH4 afforded
the respective 4{[4-(aminoalkoxy)benzyloxy]phenyl}cyclopropyl
methanols (35e38) in 73e84% yields (Scheme 2).
In order to understand the positional importance of
the hydrophilic chain (aminoalkoxy) in the terminal phenyl ring
on activity, a positional isomer of most active compound 36
was prepared starting from 3-hydroxybenzaldehyde (39). The
3-aminoalkylated benzyl alcohol derivative (40) on reaction with
4-chloro-40-fluorobutyrophenone (11) gave cyclopropyl-4-[3-(2-
piperidin-1-yl-ethoxy)benzyloxy]phenyl} methanone (41) in 80%
yield. The latter on reduction with NaBH4 gave cyclopropyl-4-[3-
(2-piperidin-1-yl-ethoxy)benzyloxy]phenyl}methanol (42) in
78% yield (Scheme 3).
To see the effect of an additional substituent other than 4-ami-
noalkoxy group in the terminal phenyl ring methoxy substituent
was introduced by selecting 3-methoxy-4-hydroxybenzaldehyde
(43). The latter on reaction with different aminoalkyl halides
hydrochlorides as described above gave respective 3-methoxy-4-
ethoxyamino benzyl alcohols (44e46) in 71e79% yields, which on
further reaction with 4-chloro-40-fluorobutyrophenone (11) gave
the respective cyclopropyl-4[3-(methoxy)-4-(aminoalkoxy)benzy-
loxy]phenyl methanones (47e49, Scheme 4). The cyclopropyl-4[3-
(methoxy)-4-(aminoalkoxy)benzyloxy]phenyl methanols (50e52)
were similarly prepared by sodium borohydride reduction of the
respective methanones (47e49) in 75e79% yields (Scheme 4).
In order to see the importance of whole 4-benzyloxy moiety
on antitubercular activity profiles we have synthesized {4-[2-
(N,N-dibutylamino)ethoxy]phenyl}cyclopropyl methanone (54) by
direct coupling of N,N-dibutylaminoethanol (53) with 4-chloro-40-
fluorobutyrophenone (11) in 75% yield. Compound 54 on sodium
borohydride reduction afforded {4-[2-(N,N-dibutylamino)ethoxy]
phenyl}cyclopropyl methanol (55) in 77% yield (Scheme 5).
Fig. 1. Antitubercular cyclopropylphenyl methanones and methanols.
the activities was due to the substituents in the phenyl ring of
4-benzyloxy moiety (B). The most active compound of the series
with marginal in vivo protection was found to be compound 3
(Fig. 1). Therefore, we were interested to optimize this potent
antitubercular compound by keeping the cylopropylphenyl meth-
anone and cyclopropylphenyl methanol unit constant and varying
the 4-benzyloxy substituent.
Herein, we have reported the synthesis and antitubercular
evaluation of [(aryloxy)phenyl]cyclopropyl methanones and meth-
anols leading to identification of new scaffolds with improved
activity against M. tuberculosis H37Rv. Amongst the screened
compounds, cyclopropyl-4-[4-(2-piperidin-1-yl-ethoxy)benzyloxy]
phenyl}methanol (36) was found to be orally active.
2. Results and discussion
2.1. Chemistry
The starting benzyl alcohol derivatives (4e10) were prepared by
sodium borohydride reduction of respective substituted benzal-
dehydes [16]. The [(benzyloxy)phenyl]cyclopropyl methanones
(12e18) were prepared by reaction of the above benzyl alcohol
derivatives (4e10) with 4-chloro-40-fluorobutyrophenone (11) in
presence of NaH and tetrabutylammonium bromide (TBAB) as
phase transfer catalyst as per our earlier reported protocol [16] in
67e82% yields. Reduction of the cyclopropylphenyl methanones
(12e18) with sodium borohydride at ambient temperature led to
the formation of respective cyclopropylphenyl methanols (19e25)
in 67e90% yields (Scheme 1).
2.2. Biological activity
2.2.1. In vitro antimycobacterial activity
All the synthesized compounds were tested for their ability to
inhibit the growth of M. tuberculosis by Agar-based proportion
Scheme 1. Reagents and conditions: (i) NaBH4, MeOH, 0 ꢀC-rt, 1e1.5 h; (ii) NaH, DMF, TBAB, 0 ꢀC- reflux, 4e5 h; (iii) NaBH4, MeOH, 0 ꢀC-rt, 3e4 h.

S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
5967
Scheme 2. Reagents and conditions: (i) R1R2NCH2CH2Cl.HCl, anhydrous THF, K2CO3, TBAB; (ii) NaBH4, MeOH, 0 ꢀC-rt, 1e1.5 h; (iii) NaH, DMF, TBAB, 0 ꢀC- reflux, 4e5 h; (iv) NaBH4,
MeOH, 0 ꢀC-rt, 3e4 h.
Scheme 3. Reagents and conditions: (i) 2-Chloroethylpiperidine hydrochloride, anhydrous THF, K2CO3, TBAB; (ii) NaBH4, MeOH, 0 ꢀC-rt, 1e1.5 h; (iii) NaH, DMF, TBAB, 0 ꢀC- reflux,
4e5 h; (iv) NaBH4, MeOH, 0 ꢀC-rt, 3e4 h.
Assay using H37Rv strains [25]. Subsequently cytotoxicity evalua-
against M. tuberculosis H37Rv were evaluated for their effect to kill
intracellular bacterium in ex vivo models of mouse bone marrow
derived macrophages [28]. Most potent compound was then also
tested for its in vitro efficacy (by proportion assay) against one
multidrug resistant (MDR), one extensively drug resistant (XDR),
tions of compounds showing antitubercular potential (MIC ꢁ
3.12 mg/mL) against a mammalian cell line (VERO) and mouse bone
marrow derived macrophages were carried out [26,27]. The
compounds which were non-toxic and potentially active in vitro
Scheme 4. Reagents and conditions: (i) R1R2NCH2CH2Cl.HCl, anhydrous THF, K2CO3, TBAB; (ii) NaBH4, MeOH, 0 ꢀC-rt, 1e1.5 h; (iii) NaH, DMF, TBAB, 0 ꢀC- reflux, 4e5 h; (iv) NaBH4,
MeOH, 0 ꢀC-rt, 3e4 h.

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S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
Scheme 5. Reagents and conditions: (i) NaH, DMF, TBAB, 0 ꢀC- reflux, 4e5 h; (ii) NaBH4, MeOH, 0 ꢀC-rt, 3e4 h.
two rifampicin resistant and two drug susceptive clinical isolates of
M. tuberculosis (procured from Central Jalma Institute Immunology
and Leprosy at Agra).
The effect of the substituents of the benzyloxy ring on the
antitubercular activity was investigated and shown in Table 1. As
evident from Table 1 compounds 12, 17, 33, 48, 49, 52, 54 and 55
Compounds were considered non-toxic if its IC50 was ꢁ10 times of
its MIC. The SI (selectivity index) of the compounds was deter-
mined as ratio of IC50 against VERO cells or mouse bone marrow
derived macrophage and MIC against M. tuberculosis H37Rv
(SI ¼ IC50/MIC). For in vivo evaluation of any compound the SI
should be ꢂ10 as it is considered to be safe.
displayed MIC of >12.5
38, 41, and 50 displayed MIC of 12.5
22, 23, 31, 42, 47 and 51 displayed MIC of 6.25
19, 21, 35, 36 and 37 showed potent in vitro activity with MIC of
3.12 g/mL against virulent strain M. tuberculosis H37Rv whereas
the compounds 14 and 25 have MIC value of 1.56 g/mL.
The compounds having MICs range between 0.78 and
3.12 g/mL (14, 18, 19, 21, and 35e37) were screened for their
m
g/mL while compounds 13, 20, 24, 32, 34,
g/mL. The compounds, 15, 16,
g/mL. Compounds
As evident from the activity profiles few of the compounds
showed quite good anti-TB activity in vitro as indicated by their low
m
m
MICs, i.e., 0.78
and 25), and 3.12
36 showed (MIC 12.5
m
g/mL (compound 18), 1.56
g/mL (compounds 19, 21 and 35e37). Compound
g/mL) against one multidrug resistant
mg/mL (compounds 14
m
m
m
m
(MDR), one extensively drug resistant (XDR), two rifampicin
resistant and two drug susceptive clinical isolates of M. tuberculosis
(Table 2).
m
cytotoxicities with IC50 values up to 50
mg/mL concentration.
2.2.2. Structure activity relationship
The SAR of the cyclopropyl[4-(4-methoxybenzyloxy)phenyl]
methanols was carried out with respect to the above compound 3
(Fig. 1, MIC 3.12 mg/mL). In order to understand the importance of
the substituents in benzyloxy ring on the activity, we prepared
compounds cyclopropylphenyl methanone derivatives (12e18) and
their methanoles (19e25). In general compounds having substitu-
ents at para position, either retained the activity (compounds 19, 21
Table 1
In vitro antimycobacterial activities of synthesized compounds against M. tubercu-
losis H37Rv.
Entry
Compounds
Clog Pa
IC50
g/mL)
Selectivity
index (SI)
MICb
(mg/ml)
against H37Rv
(
m
1
2
3
4
5
6
7
8
12
13
14
15
16
17
18
19
20
21
22
23
24
25
31
32
33
34
35
36
37
38
41
42
47
48
49
50
51
52
54
55
3.62
4.13
4.70
4.13
3.31
3.12
5.93
3.54
4.05
4.61
4.05
3.22
3.03
5.84
2.94
4.14
3.02
4.69
2.85
4.06
2.93
4.61
4.14
4.06
2.83
4.04
4.59
2.74
3.94
4.5
nd
nd
>50
nd
nd
nd
nd
>10
nd
nd
>12.5
12.5
have shown MIC of 3.12
increased the in vitro activity profile of the compounds (compounds
14, 25 and 18 have shown MIC of 1.56 g/mL and 0.78 g/mL
mg/mL, Table 1) as shown by compound 3 or
1.56c
6.25c
6.25
m
m
nd
nd
>12.5
0.78c
3.12c
12.5
respectively, Table 1). This observation clearly established the
importance of substituents at para position. Therefore, the effect
polar and hydrophilic aminoalkoxy group as the para substitutent
in the above series was sought in. Therefore, we prepared and
evaluated the 4{[4-(aminoalkoxy)benzyloxy]phenyl}cyclopropyl
methanones (31e34) and 4{[4-(aminoalkoxy)benzyloxy]phenyl}
cyclopropyl methanols (35e38) against M. tuberculosis. As evident
from the activity results compounds 35, 36 and 37 with 2-(mor-
pholinyl)-, 2-(piperidin-1-yl)-ethoxy and 2-(N,N-di-methyl)-ethoxy
as para substitutent in the benzyloxy ring were equipotent (each
>50
>50
nd
>50
nd
nd
nd
nd
nd
nd
nd
nd
>50
>50
>50
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
>10
>10
nd
>10
nd
nd
nd
nd
nd
nd
nd
nd
>10
>10
>10
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
9
10
11
12
13
14
16
17
18
19
24
25
26
27
20
28
21
22
23
29
30
31
38
39
3.12c
6.25
6.25
12.5
1.56
6.25
12.5
>12.5
12.5
MIC ¼ 3.12
m
g/mL) to the compound 3 (Table 1).
g/mL) having [2-(piperidin-1-yl)-
3.12c
3.12c
3.12c
12.5
Compound 42 (MIC ¼ 6.25
m
ethoxy] as the meta substitutent in the benzyloxy moiety (a posi-
tional isomer of compound 36) was slightly less active (MIC
12.5
6.25
6.25
>12.5
>12.5
12.5
6.25 mg/mL) as compared to compound 36. Thus compounds with
para substitutents are more active than the meta substituents.
To understand the influence of methoxy group along with
aminoalkoxy substituents of benzyloxy ring on the activity, we
prepared cyclopropyl{4[3-(methoxy)-4-(aminoalkoxy)benzyloxy]
phenyl} methanones (47e49) and their methanoles (50e52)
6.25
>12.5
>12.5
12.5
4.9
4.81
Table 2
a
In vitro activity of compound 36 against clinical isolates of M. tuberculosis.
Clog P value calculated by using http://www.organic-chemistry.org/prog/peo/.
MIC ¼ Minimum inhibitory concentration, the lowest concentration of the
b
Isolates
Drug susceptible
MDR
XDR
RMF resistant
compound which inhibits the growth of mycobacterium >90%; MIC of the drugs
used as control, INH 0.02, rifampicin 0.20, ethambutol 2.00
mg/mL against
1
2
1
2
M. tuberculosis H37R.
MIC (
m
g/mL)
>12.5
>12.5
12.5
12.5
12.5
12.5
c
Non-toxic (at a dose of 10ꢃ MIC) against VERO and BMDMV
.

S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
5969
Table 3
Table 5
Intracellular (ex-vivo activity) of non-toxic compounds against M. tuberculosis CFU in
mouse bone marrow derived macrophages at a concentration of 5ꢃ MIC.
Detailed in vivo efficacy of compound 36 and isoniazid against M. tuberculosis H37Rv
in mice.
S. no.
Compounds
% Reduction in intracellular
Compound
On day 30
On day 40
Bacilli in lungs
CFU of M. tuberculosis
per g (on day 30)
% survivors MST
% survivors MST
1
2
3
4
5
6
7
8
14
18
19
21
22
35
36
37
0
24
67
54
88
89
98
80
Control
36 (100 mg/kg)
INH (25 mg/kg) 100
25
50
23.37
27.50
30.00 100
12
25
25.12 3.6 ꢃ 108
31.62 9.0 ꢃ 107
40
e
(Scheme 4). This change does not improve the activity as none of
g/mL. This is clear that
the compounds exhibited MIC ꢁ 3.12
m
additional hydrophilic groups of benzyloxy ring did not improve
the activity profile.
Finally to see the importance of benzyloxy ring on activity, we
prepared and evaluated 4-{[2-(N,N-dibutylamino)ethoxy]phenyl}
cyclopropyl methanone (54) and its alcohol derivative (55). The
activity in these compounds (54 and 55) was significantly dropped
as both of them showed MIC ꢂ 12.5
mg/mL only. This observation
Fig. 2. HPLC chromatogram showing main peak (A) of compound 36 at 8.82 min.
again showed the significance of benzyloxy ring in antitubercular
activity. On the basis of above structure activity relationship
following generalization can be made (i) the maximum influence of
substituents at para position on activity; (ii) activity decrease with
increase hydrophilicity of benzyloxy ring; (iii) 4-benzyloxy ring
play an important role for antitubercular action.
acceptable MST. The other two compounds 22 and 37 could not
protect the animals as compared to standard drug INH.
Based on the above results compound 36 was studied in detail
for count of bacilli up to 40 days in mice [29,30]. The antitubercular
activity was analyzed based on percentage of survivors, mean
survival time and load of bacilli in lungs and the results are shown
in Table 5. As evident from results the MST of the group of mice
treated with the compound 36 was 27.50 (calculated on day 30) and
31.62 (calculated on day 40) as compared to untreated infected
control group where the MST were respectively, 23.37 and 25.12.
The percentages of mice survived on these days were 50 and 25 in
the treated group as compared to control group in which 25 and 12
percent mice survived. In the group treated with INH, the MST was
30 on day 30 and 40 on day 40 as there was no mortality (100%
survival) in this group.
2.2.3. Ex-vivo efficacy of compounds against intracellular
M. tuberculosis in bone marrow derived mouse macrophages
Among the non-toxic compounds showing potent in vitro
activities two of the cyclopropyl methanones compounds 14 and 18
and six of the cylopropyl methanols 19, 20, 22, 35, 36 and 37 were
evaluated further for their intracellular (ex-vivo) effect on CFU in
mouse bone marrow derived macrophages at a concentration 5
times of their MIC values as per earlier reported method [28]. The
results are presented in Table 3. It is evident that cyclopropyl
methanones are not active as they reduce <50% of CFU count, while
all the above aryloxyphenyl cyclopropyl methanols screened dis-
played >50% reduction in the CFU count. Compound 36 was the
most active compound as it led to inhibition of 98% growth of
intracellular bacilli.
2.2.5. The stability study of compound 36 at gastric pH (0.1N HCl)
Since the compound did not show expected in vivo activity, the
stability of the compound 36 was studied at gastric pH and the
results are depicted in Figs. 2e4. As shown in HPLC data (Fig. 2)
2.2.4. In vivo oral efficacy of compounds 22, 36 and 37 against
M. tuberculosis H37Rv [29,30]
Based on the above intracellular killing of the bacterium only
aryloxyphenyl cyclopropyl methanols 22, 36 and 37 were further
evaluated for their in vivo oral efficacy against M. tuberculosis H37Rv
in mice and the results were shown in Table 4. Among these
compounds, compound 36 was the most potent compound with
Table 4
In vivo activity of aryloxyphenyl cyclopropyl methanols 22, 36 and 37 and isoniazid
against M. tuberculosis H37Rv in mice.
Compounds
MSTb on day
30 (compound)
MSTb on day
30 (Control)
a
22 (100 mg/kg)
23.37
27.50
12.85
30.0
26.40
23.37
12.00
e
a
36 (100 mg/kg)
a
37 (100 mg/kg)
INH (25 mg/kg)
a
Non-toxic against mammalian cell line, VERO and mouse bone marrow derived
macrophages.
b
MST, mean survival time.
Fig. 3. Effect of 0.1N HCl on stability of compound 36 at ambient temperature.

5970
S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
performed using Quattro II (Micromass) and HRMS were per-
formed using JEOL MSRoute. The purity (>95%) of the compounds
was determined either by HPLC or by combustion analyses.
Elemental analyses were performed on a PerkinElmer 2400 II
elemental analyzer.
4.1.1. General procedure for the synthesis of compounds (12e18)
To a stirring suspension of NaH (60% dispersion in mineral oil, 4
eq.) in DMF at 0 ꢀC, was added benzyl alcohol (1 eq.), followed by
the addition of 4-chloro-40-fluorobutyrophenone 11 (1 eq.) drop-
wise. Tetrabutylammonium bromide (20 mol%) was added as
catalyst to the stirring reaction mixture at ambient temperature for
30 min then transferred it to reflux and stirring continued till the
consumption of the starting material (TLC) for given time. After the
completion of reaction, the reaction mixture was filtered on celite
pad. The filtrate was extracted with ethylacetate (3 ꢃ 25 mL) and
then the organic layer was separated, washed with brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude mass was purified by simple column chromatography (using
60e120 mesh silica gel) to obtain the desired product.
Fig. 4. HPLC chromatogram of compound 36 after incubation in 0.1N HCl for 3 h
showing two degradation peaks (B and C) with retention time of 3.85 min and
14.87 min respectively. The peak of main compound (A) with retention time 8.82 min.
compound 36 is being degraded. After a time interval of 3 h <70% of
the compound is left a major compound with retention time of
3 min.
In view of the instability of this compound under acidic pH, an
enteric coating of the compound has been prepared and is being
evaluated in detail.
4.1.1.1. Cyclopropyl{4-[4-(pyridin-2-ylmethoxy)benzyloxy]phenyl}
methanone (12). To a stirring suspension of NaH (60% dispersion in
mineral oil, 0.39 g, and 16.39 mmol) in DMF (12 mL) at 0 ꢀC, was
added benzyl alcohol derivative 4 (0.88 g, 4.09 mmol) dropwise.
After 0.5 h, 4-chloro-40-fluorobutyrophenone 11 (1.0 mL,
4.09 mmol) was added slowly through dropping funnel. Tetrabu-
tylammonium bromide (0.26 g, 0.082 mmol) was added as catalyst
to the stirring reaction mixture at ambient temperature for 30 min
then transferred it to reflux and stirring continued till the
consumption of the starting material (TLC) for given time. After
completion of reaction, the reaction mixture was filtered on celite
pad and the filtrate was extracted with ethylacetate (3 ꢃ 25 mL)/
water (400 mL); the organic layer was separated, washed with
brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure to give a residual mass. The latter was purified by
simple column chromatography (60e120 mesh silica gel) using
ethyl acetate/hexane (4:6) as eluent to afford product 12 as a white
solid yield 1.74 g (80%); mp 120e123 ꢀC; 1H NMR (200 MHz, CDCl3)
3. Conclusion
In conclusion we have synthesized a library of [4-(aryloxy)
phenyl] cyclopropyl methanones and methanols using simple and
flexible synthetic chemistry in good yields. The compounds were
evaluated against M. tuberculosis H37Rv in vitro with impressive MIC
values. Compounds with potent in vitro activities were screened for
their cytotoxicities against VERO cell line and mouse derived
macrophages. The non-toxic compounds were further screened
intracellulary against M. tuberculosis H37Rv in bone marrow derived
muse macrophages. Several compounds showed good activity
intracellulary too. The intracellulary active compounds 22, 36 and
37 were screened for their in vivo protective efficacy in mouse
model. The compound 36 possesses overall satisfactory drug-like
properties. The mice treated with the compound 36 survived longer
4 days (calculated on day 30) and 6 days (calculated on day 40)
as compared to untreated infected controls. The SAR from the
series provided interesting consideration i.e., hydrophilic groups
ethoxyamines, both aromatic rings were found to be suitable
substituents in order to obtain good anti-TB activity. Further studies
are in progress with this promising anti-TB compound with its
formulation.
d
¼ 8.55 (d, J ¼ 3.156 Hz, 1H, PyH), 7.93 (d, J ¼ 8.8 Hz, 2H, ArH), 7.68
(m, 1H, PyH), 7.50 (d, J ¼ 7.81 Hz, 2H, ArH), 7.28 (d, J ¼ 8.5 Hz, 2H,
ArH), 7.15 (m, 1H, PyH), 7.17 (d, J ¼ 6.6 Hz, 2H, ArH), 6.95 (d,
J ¼ 8.7 Hz, 2H, ArH), 5.19 (s, 2H, OCH2), 5.02 (s, 2H, OCH2), 2.61
(m, 1H, cyclopropyl CH), 1.22 (m, 2H, cyclopropyl CH2), 0.95 (m,
2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 198.3 (CO),
162.7, 158.7, 157.6 (ArC), 149.4, 136.9 (PyCH.), 131.5, 129.1 (ArC),
130.5, 129.5 (ArCH), 122.8, 121.4 (PyCH), 115.3, 114.7 (ArCH), 70.8,
70.1 (OCH2Ar), 16.8 (cyclopropyl CH), 11.3 (cyclopropyl CH2 s);
0
4. Experimental section
IR nmax cmꢄ1 1651 (C]O); MS FAB m/z ¼ 360.1 [M þ H]þ; Anal.
Calcd for C23H21NO3: C, 76.86; H, 5.89; N, 3.90; found C, 76.80; H,
5.85; N, 3.86.
4.1. Chemistry
Commercially available reagent grade chemicals were used as
received. All reaction was followed by TLC on E. Merck Kieselgel 60
F254, with detection by UV light, spraying a 20% KMnO4 aq. solution.
Column chromatography was performed on silica gel (60e120
mesh and 100e200 mesh, E. Merck). IR spectra were recorded as
thin films or on KBr pellets with a PerkinElmer Spectrum RX-1
(4000e450 cmꢄ1) spectrophotometer. 1H and 13C NMR spectra
were recorded on a Brucker DRX-300 in CDCl3 or CDCl3þCCl4
chemical shift values are reported in ppm relative to TMS (tetra-
methylsilane) as internal reference, unless otherwise stated; s
(singlet), d (doublet), dd (double doublet), t (triplet), m (multiplet);
coupling constant (J) in hertz. FAB mass spectra were performed
using a mass spectrometer Jeol SX-102, ES mass spectra were
4.1.1.2. [4-(3-Bromobenzyloxy)phenyl](cyclopropyl)methanone
(13). It was obtained by the reaction of benzyl alcohol derivative 5
(0.75 g, 4.09 mmol), NaH (60% dispersion in mineral oil, 0.39 g, and
16.39 mmol), 4-chloro-40-fluorobutyrophenone (11) (1.0 mL,
4.09 mmol) and tetrabutylammonium bromide (0.26 g,
0.082 mmol) by using the procedure as described for compound 12,
to give compound 13 as white solid, mp 85e86 ꢀC; yield, 1.65 g
(82%); Rf ¼ 0.5 (ethylacetate/hexane, 4:6); 1H NMR (200 MHz,
CDCl3)
d
¼ 7.96 (d, J ¼ 8.5 Hz, 2H, ArH), 7.56 (s, 1H, ArH), 7.44 (d,
J ¼ 7.52 Hz, 1H, ArH), 7.30 (m, 2H, ArH), 6.96 (d, J ¼ 8.6 Hz, 2H, ArH),
5.06 (s, 2H, OCH2), 2.65e2.59 (m, 1H, cyclopropyl CH), 1.27 (m, 2H,
cyclopropyl CH2), 0.99 (m, 2H, cyclopropyl CH2); 13C NMR (50 MHz,
CDCl3)
d
¼ 198.6 (CO), 162.3, 138.9, 131.9, 123.2 (ArC), 131.6, 130.6,

S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
5971
130.5, 126.1, 114.7 (ArCH), 69.4 (OCH2), 16.9 (cyclopropyl CH), 11.6
0.082 mmol) by using the procedure as described for compound 12,
to give compound 17 as white solid, mp 90e92 ꢀC; yield 1.56 g
(75%); Rf ¼ 0.5 (ethylacetate/hexane, 4:6); 1H NMR (200 MHz,
(cyclopropyl CH2 s); IR nmax cmꢄ1 1656 (C]O); MS FAB m/z ¼ 331
0
[M þ H]þ Anal. Calcd for C17H15BrO2: C, 61.65; H, 4.56; found C,
61.63; H, 4.52.
CDCl3)
d
¼ 8.02 (d, J ¼ 8.8 Hz, 2H, ArH), 7.05 (d, J ¼ 8.8 Hz, 2H, ArH),
6.66 (s, 2H, ArH), 5.05 (s, 2H, OCH2), 3.87 (s, 9H, 3ꢃ OCH3), 2.66
4.1.1.3. [4-(4-(Benzyloxy)benzyloxy)phenyl](cyclopropyl)methanone
(14). It was obtained by the reaction of benzyl alcohol derivative 6
(0.87 g, 4.09 mmol), NaH (60% dispersion in mineral oil, 0.39 g,
and 16.39 mmol), 4-chloro-40-fluorobutyrophenone (11) (1.0 mL,
4.09 mmol) and tetrabutylammonium bromide (0.26 g, 0.082 mmol)
by using the procedure as described for compound 12, to give
compound 14 as liquid; yield 1.46 g (67%); Rf ¼ 0.5 (ethylacetate/
(m, 1H, cyclopropyl CH), 1.23 (m, 2H, cyclopropyl CH2), 1.03 (m, 2H,
cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
153.4, 137.8, 131.7, 131.2 (ArC), 130.2, 114,4, 104.5 (ArCH), 70.3
d
¼ 198.7 (CO) 162.2,
(OCH2), 60.7(OCH3), 56.0 (2ꢃ OCH3), 16.5 (cyclopropyl CH), 11.2
0
(cyclopropyl CH2 s); Anal. Calcd for C20H22O5 (345): C, 70.16; H,
6.48; found C, 70.10; H, 6.45; IR nmax cmꢄ1 1651 (C]O); MS FAB
m/z ¼ 343 [M þ H]þ; HRMS (JEOL MSRoute) m/z calcd for C20H22O5
(Mþ) 342.1467, found 342.1467.
hexane, 3:7); 1H NMR (200 MHz, CDCl3)
ArH), 7.32 (m, 7H ArH), 7.20 (d, J ¼ 8.4 Hz, 2H ArH), 6.94 (m, 2H ArH),
5.07 (s, 4H, 2ꢃ OCH2), 2.66 (m, 1H, cyclopropyl CH), 1.24 (m, 2H,
cyclopropyl CH2), 1.03 (m, 2H, cyclopropyl CH2); 13C NMR (50 MHz,
d
¼ 7.99 (d, J ¼ 8.7. Hz, 2H,
4.1.1.7. Cyclopropyl{4-[3-(3,4-dichlorobenzyloxy)benzyloxy]phenyl}
methanone (18). It was obtained by the reaction of compound 10
(1.15 g, 4.09 mmol), NaH (60% dispersion in mineral oil, 0.39 g, and
16.39 mmol), 4-chloro-40-fluorobutyrophenone (11) (1.0 mL,
4.09 mmol) and tetrabutylammonium bromide (0.26 g,
0.082 mmol) by using the procedure as described for compound 12,
to give compound 18 as white solid, mp 80e82 ꢀC; yield 1.95 g
(75%); Rf ¼ 0.5 (ethylacetate/hexane, 4:6); 1H NMR (200 MHz,
CDCl3)
d
¼ 199.4 (CO), 162.9, 159.2, 156.9, 137.2, 132.4 (ArC), 130.6,
129.7,129.4,129.0,128.9,128.7,128.4,128.2,127.8,127.8,115,4,114.9,
112.2 (ArCH’s), 70.4, 70.3 (2ꢃ OCH2), 17.0 (cyclopropyl CH), 11.6
(cyclopropyl CH2’s); IR nmax cmꢄ1, 1659.6 (C]O); MS FAB m/z ¼ 359
[M þ H]þ Anal. Calcd for C24H22O3: C, 80.42; H, 6.19; found C,
80.54; H, 6.31.
CDCl3)
d
¼ 8.10 (d, J ¼ 8.8 Hz, 2H, ArH), 7.65 (s, 1H, ArH), 7.56
4.1.1.4. [4-(4-Bromobenzyloxy)phenyl](cyclopropyl)methanone
(15). It was obtained by the reaction of benzyl alcohol derivative 7
(0.76 g, 4.09 mmol), NaH (60% dispersion in mineral oil, 0.39 g,
and 16.39 mmol), 4-chloro-40-fluorobutyrophenone (11) (1.0 mL,
4.09 mmol) and tetrabutylammonium bromide (0.26 g, 0.082 mmol)
by using the procedure as described for compound 12, to give
compound 15 as white solid, mp 130e131 ꢀC; yield 1.5 g (75%);
Rf ¼ 0.5 (ethylacetate/hexane, 4:6); 1H NMR (200 MHz, CDCl3)
(d, J ¼ 8.2 Hz, 1H, ArH), 7.43 (m, 1H, ArH), 7.05 (m, 6H, ArH), 5.23
(s, 2H, OCH2), 5.13 (s, 2H, OCH2), 2.63 (m, 1H, cyclopropyl CH), 1.25
(m, 2H, cyclopropyl CH2), 0.92 (m, 2H, cyclopropyl CH2); 13C NMR
(50 MHz, CDCl3)
d
¼ 199.3 (CO), 159.5, 157.6, 139.5, 136.9, 134.6,
133.8, 132.1 (ArC), 130.9, 130.6, 130.3, 129.6, 126.9, 120.6, 115.3,
114.9, 114.8, 114.7 (ArCH), 70.2, 68.9 (OCH2Ar), 17.0 (cyclopropyl
CH), 11.7 (cyclopropyl CH2’s); IR nmax cmꢄ1 1696 (C]O); HRMS
(JEOL MSRoute) m/z calcd for C24H20Cl2O3 (Mþ) 426.0781, found
426.0790, MS FAB m/z ¼ 449 [M þ Na]þ Anal. Calcd for C24H20Cl2O3:
C, 67.46; H, 4.72; found C, 67.45; H, 4.65.
d
¼ 7.99 (d, J ¼ 9.71 Hz, 2H, ArH), 7.51 (d, J ¼ 8.34 Hz, 2H, ArH), 7.29 (d,
J ¼ 8.46 Hz, 2H, ArH), 6.90 (d, J ¼ 9.68 Hz, 2H, ArH), 5.06 (s, 2H, OCH2),
2.62 (m, 1H, cyclopropyl CH), 1.23 (m, 2H, cyclopropyl CH2), 1.00 (m,
2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 198.8 (CO) 162.4
4.1.2. General procedure for synthesis of compounds 19e25
To a stirred solution of the above 4-(benzyloxy)phenyl cyclo-
propyl methanones (12e18)(1 eq.) in MeOH (5 mL), NaBH4 (0.10 g,
2.78 mmol) was slowly added at 0 ꢀC. The reaction mixture was
brought at ambient temperature and stirring continued until the
disappearance of the starting material (TLC). The reaction mixture
was quenched by adding saturated aqueous ammonium chloride in
order to remove the unused NaBH4 and the reaction mixture was
evaporated under reduced pressure to give a crude mass. The latter
was extracted with chloroform several times. The organic layer was
separated, dried over anhydrous Na2SO4 and evaporated under
reduced pressure to give a crude material which was chromato-
graphed over silica (silica gel 60e120 mesh) to afford desired
products (19e25).
(ArC), 153.4, 135.6 (ArC), 132.2, 131.2, 131.8, 130.6, 129.4, 122.5,
(ArCH’s), 114.8 (ArC), 70.1 (OCH2) 69.6 (OCH2’s), 16.9 (cyclopropyl
CH), 11.6 (cyclopropyl CH2’s); IR nmax cmꢄ1 2943 (CeH stretching),
1651 (C]O); HRMS (JEOL MSRoute) m/z calcd for C17H15BrO2 (Mþ)
330.0255, found 330.0249; MS FAB m/z ¼ 331 [M þ H]þ; Anal. Calcd
for C17H15BrO2: C, 69.75; H, 7.02; found C, 69.70; H, 7.18.
4.1.1.5. Cyclopropyl[4-(3-nitrobenzyloxy)phenyl]methanone (16). It
was obtained by the reaction of benzyl alcohol derivative 8 (0.63 g,
4.09 mmol), NaH (60% dispersion in mineral oil, 0.39 g, and
16.39 mmol), 4-chloro-40-fluorobutyrophenone (11) (1.0 mL,
4.09 mmol) and tetrabutylammonium bromide (0.26 g, 0.082 mmol)
by using the procedure as described for compound 12, to give
compound 16 as liquid; yield 1.48 g (82%); Rf ¼ 0.5 (ethylacetate/
hexane,1:1); 1H NMR (200 MHz, CDCl3)
d
¼ 8.33 (s,1H, ArH), 8.23 (d,
4.1.2.1. Procedure for the synthesis of cyclopropyl{4-[4-(pyridin-2-
ylmethoxy)benzyloxy]phenyl}methanol (19). To a stirred solution of
cyclopropyl{4-[4-(pyridin-2-ylmethoxy)benzyloxy]phenyl}- meth-
anone 12 (1.0 g, 2.78 mmol) in MeOH (5 mL), NaBH4 (0.10 g,
2.78 mmol) was slowly added at 0 ꢀC. The reaction mixture was
brought at ambient temperature and stirring continued tills the
disappearance of the starting material (TLC). The reaction mixture
was quenched by adding saturated aqueous ammonium chloride in
order to remove the unused NaBH4 and the reaction mixture was
evaporated under reduced pressure to give a crude mass. The latter
was extracted with chloroform several times. The organic layer was
separated, dried over anhydrous Na2SO4 and evaporated under
reduced pressure to give a crude material which was chromato-
graphed (SiO2, 60e12-mesh) over to afford desired product 19 as
white solid, mp 120e123 ꢀC; yield 0.80 g (80%); Rf ¼ 0.5 (methanol/
J ¼ 7.9 Hz, 1H, ArH), 8.05 (m, 2H, ArH), 7.80 (d, J ¼ 7.5 Hz, 1H, ArH),
7.63 (t, 1H, J ¼ 7.9 Hz, ArH), 7.06 (d, J ¼ 8.6 Hz, 2H, ArH), 5.23 (s, 2H,
OCH2), 2.67 (m, 1H, cyclopropyl CH), 1.26 (m, 2H, cyclopropyl CH2)
1.04 (m, 2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 199.43
(CO) 162.09, 148.90, 138.89, 132.18 (ArC), 133.51, 130.76, 130.12,
123.55, 122.58, 114.87 (ArCH), 69.10 (OCH2), 17.14 (cyclopropyl CH),
11.75 (cyclopropyl CH2’s); IR nmax cmꢄ1 1653 (C]O), 1599; Anal.
Calcd for C17H15NO4: C, 68.68; H, 5.09; N, 4.71; found, C, 68.64; H,
5.02; N, 4.68; MS FAB m/z ¼ 298 [M þ H]þ.
4.1.1.6. Cyclopropyl[4-(3,4,5-trimethoxybenzyloxy)phenyl]meth-
anone (17). It was obtained by the reaction of benzyl alcohol
derivative 9 (0.81 g, 4.09 mmol), NaH (60% dispersion in mineral oil,
0.39 g, and 16.39 mmol), 4-chloro-40-fluorobutyrophenone (11)
(1.0 mL, 4.09 mmol) and tetrabutylammonium bromide (0.26 g,
chloroform, 2:98); 1H NMR (200 MHz, CDCl3)
d
¼
8.55

5972
S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
(d, J ¼ 4.156 Hz, 1H, PyH), 7.65 (m, 2H, PyH), 7.31 (m, 5H, PyH, ArH),
6.91 (m, 4H, ArH), 5.18 (s, 2H, OCH2), 4.95 (s, 2H, OCH2), 3.96
(d, J ¼ 7.9 Hz, 1H, CHOH), 1.50 (bs, 1H, OH), 1.18 (m, 1H, cyclopropyl
CH), 0.55 (m, 2H, cyclopropyl CH2), 0.33 (m, 2H, cyclopropyl CH2);
(200 MHz, CDCl3)
d
¼ 8.32 (s, 1H, ArH), 8.20 (d, J ¼ 7.7 Hz, 1H, ArH),
7.79 (d, J ¼ 7.4 Hz, 1H, ArH), 7.60 (t, 1H, J ¼ 7.9 Hz, ArH), 7.40
(d, J ¼ 8.5 Hz, 2H, ArH), 6.98 (d, J ¼ 8.6 Hz, 2H, ArH), 5.16 (s, 2H,
OCH2), 3.99 (d, 1H, CHOH), 1.25 (m, 1H, cyclopropyl CH), 0.62 (m,
2H, cyclopropyl CH2), 0.35 (m, 2H, cyclopropyl CH2); 13C NMR
13C NMR (50 MHz, CDCl3)
d
¼ 158.6, 157.5 (ArC), 149.5, 137.3 (ArCH),
136.9, 130.0 (ArC),129.6, 127.6,123.0, 121.7, 115.3,115.0 (ArCH), 70.9,
70.1 (OCH2Ar), 31.3 (CHOH), 19.4 (cyclopropyl CH), 3.9, 3.1 (cyclo-
propyl CH2’s); IR nmax cmꢄ1 3413 (OeH stretching), 2903 (CeH
stretching); MS FAB m/z ¼ 361 [M þ H]þ; Anal. Calcd for C23H23NO3
(361): C, 76.43; H, 6.41; N, 3.88; found C, 76.63; H, 6.31; N, 3.78.
(50 MHz, CDCl3)
d
¼ 158.00, 148.88, 139.73, 137.46, (ArC), 133.51,
129.97, 127.84, 123.28, 122.52, 115.09 (ArCH), 69.13 (OCH2), 19.53
(cyclopropyl CH), 3.94, 3.17 (cyclopropyl CH2’s); IR nmax cmꢄ1
1527, 1350, 1236; MS FAB m/z ¼ 282 [M ꢄ 18]þ; Anal. Calcd for
C17H17NO4: C, 68.21; H, 5.72; N, 4.68; found, C, 68.18; H, 5.70;
N, 4.65.
4.1.2.2. [4-(3-Bromobenzyloxy)phenyl](cyclopropyl)methanol (20).
It was obtained by the reaction of compound 13 (1.0 g, 3.03 mmol),
NaBH4 (0.12 g, 3.03 mmol), by using the procedure as described for
compound 19, to give compound 20 as white solid, mp 70e72 ꢀC;
yield 0.90 g (90%); Rf ¼ 0.5 (methanol/chloroform, 2:98); 1H NMR
4.1.2.6. Cyclopropyl[4-(3,4,5-trimethoxybenzyloxy)phenyl]methanol
(24). It was obtained by the reaction of compound 17 (1.0 g,
2.92 mmol), NaBH4 (0.11 g, 2.92 mmol), by using the procedure as
described for compound 19, to give compound 24 as liquid; yield
0.85 g (85%); Rf ¼ 0.5 (methanol/chloroform, 3:97); 1H NMR
(200 MHz, CDCl3)
d
¼ 7.59 (s, 1H, ArH), 7.46 (d, J ¼ 7.7 Hz, 1H, ArH),
7.32 (m, 4H, ArH), 6.93 (d, J ¼ 8.6 Hz, 2H, ArH), 5.06 (s, 2H, OCH2),
3.94 (d, 1H, CHOH), 2.03 (brs exchangeable with D2O), 1.21 (m, 1H,
cyclopropyl CH), 0.55 (m, 2H, cyclopropyl CH2), 0.33 (m, 2H,
(200 MHz, CDCl3)
d
¼ 7.35 (d, J ¼ 8.5 Hz, 2H, ArH), 6.95 (d, J ¼ 8.5 Hz,
2H, ArH), 6.66 (s, 2H, ArH), 4.95 (s, 2H, OCH2), 3.95 (m, 10H, OCH3,
CHOH), 2.01 (brs exchangeable with D2O, 1H, OH), 1.24 (m, 1H,
cyclopropyl CH), 0.55 (m, 2H, cyclopropyl CH2), 0.36 (m, 2H,
cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 158.3, 139.8,
137.0, 123.1 (ArC), 131.4, 130.7, 130.5, 126.2, 115.0 (ArCH), 78.5
(CHOH), 69.5 (OCH2), 19.5 (cyclopropyl CH), 4.0, 3.2 (cyclopropyl
CH2’s); IR nmax cmꢄ1 3380 (OH stretching); HRMS (JEOL MSRoute)
m/z calcd for C17H17BrO2 (Mþ) 332.0412, found 332.0421, MS FAB
m/z ¼ 333 [M þ H]þ; Anal. Calcd for C17H17BrO2: C, 61.28; H, 5.14;
found C, 61.25; H, 5.10.
cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 158.4, 153.8, 1385,
137.1, 132.7(ArC), 127.5, 114.8, 105.0 (ArCH’s), 77.5 (CHOH), 70.4
(OCH2), 60.7, 56.3 (OCH3), 19.5 (cyclopropyl CH), 3.7, 3.1 (cyclo-
propyl CH2’s); IR nmax cmꢄ1 3492 (OeH stretching), 2937 (CeH
stretching), 1597 (C]C stretching); HRMS (JEOL MSRoute) m/z
calcd for C20H24O5 (Mþ) 344.1624, found 344.1612, MS FAB m/
z ¼ 345 [M þ H]þ; Anal. Calcd for C20H24O5: C, 69.75; H, 7.02; found
C, 69.83; H, 7.21.
4.1.2.3. 4-{4-[Benzyloxy)benzyloxy]phenyl}(cyclopropyl)methanol
(21). It was obtained by the reaction of compound 14 (1.0 g,
3.87 mmol), NaBH4 (0.15 g, 3.87 mmol), by using the procedure as
described for compound 19, to give compound 21, as liquid; yield
0.67 g (67%); Rf ¼ 0.5 (methanol/chloroform, 2:98); 1H NMR
4.1.2.7. Cyclopropyl{4-[3-(3,4-dichlorobenzyloxy)benzyloxy]phenyl}
methanol (25). It was obtained by the reaction of compound 18
(1.0 g, 2.23 mmol), NaBH4 (0.08 g, 2.23 mmol), by using the
procedure as described for compound 19, to give compound 25 as
liquid; yield 0.85 g (85%); Rf ¼ 0.5 (methanol/chloroform, 2:98); 1H
(200 MHz, CDCl3)
d
¼ 7.40 (m, 4H, ArH), 7.23 (m, 5H, ArH), 7.99 (m,
4H ArH), 5.05 (s, 4H, 2ꢃ OCH2), 4.59 (m, 1H, cyclopropyl CHOH),
2.14 (m, 1H, cyclopropyl CH), 1.30 (m, 2H, cyclopropyl CH2), 1.19
NMR (200 MHz, CDCl3)
d
¼ 7.51e7.21 (m, 6H, ArH), 6.99e6.97
(m, 2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 158.78,
(m, 2H, ArH), 6.90e6.85 (m, 3H ArH), 5.01 (s, 2H, OCH2), 4.99
(s, 2H, OCH2), 3.97 (d, 1H, J ¼ 7.96 Hz, cyclopropyl CHOH), 1.18 (m,
1H, cyclopropyl CH), 0.58 (m, 2H, cyclopropyl CH2), 0.31 (m, 2H,
137.36, 131.08 (ArC), 130.18, 130.03, 129.63, 129.02, 128.41, 127.87,
127.56 (ArCH’s), 70.48, 70.24 (2ꢃOCH2), 17.0 (cyclopropyl CH), 11.6
(cyclopropyl CH2’s); IR nmax cmꢄ1, 3387, 1610, 1586; MS FAB
m/z ¼ 343 [M ꢄ OH]þ; Anal. Calcd for C24H24O3: C, 79.97; H, 6.71;
found C, 79.95; H, 6.67.
cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 158.95, 158.51,
130.94, 130.13, 129.61, 127.66, 126.82 (ArC), 139.34, 137.60, 136.87,
133.23, 132.40, 120.57, 115.07, 114.66, 113.99 (ArCH’s), 70.10, 68.86
(2ꢃ OCH2), 19.54 (cyclopropyl CH), 3.96, 3.19 (cyclopropyl CH2’s); IR
nmax cmꢄ1, 3445 (OeH stretching), 1595 (C]C stretching); MS FAB
m/z ¼ 451 [M þ H]þ; Anal. Calcd for C24H22Cl2O3: C, 67.14; H, 5.16;
Cl, 16.52; found C, 67.10; H, 5.13; Cl, 16.44.
4.1.2.4. [4-(4-Bromobenzyloxy)phenyl](cyclopropyl)methanol (22).
It was obtained by the reaction of compound 15 (1.0 g, 3.03 mmol),
NaBH4 (0.12 g, 3.03 mmol), by using the procedure as described for
compound 19, to give compound 22 as white semisolid; yield 0.90 g
(90%); Rf ¼ 0.5 (methanol/chloroform, 2:98); 1H NMR (200 MHz,
4.1.3. Preparation of benzyl alcohols (27e30)
CDCl3)
d
¼ 7.49 (d, J ¼ 8.3 Hz, 2H, ArH), 7.30 (m, 4H, ArH), 7.29
4.1.3.1. Procedure for preparation of 4-(2-morpholinoethoxy)phenyl
methanol (27). A mixture of the 4-hydroxybenzaldehyde 26 (1.0 g,
8.19 mmol), anhydrous K2CO3 (3.3 g, 24.58 mmol), TBAB (0.26 g,
0.819 mmol) and 4-(2-chloroethyl) morpholine hydrochloride
(1.82 g, 9.83 mmol), in anhydrous THF (10 mL) was refluxed with
stirring at till the disappearance of the starting materials (TLC). The
reaction mixture was filtered and the filtrate was evaporated under
reduced pressure to give the crude mass which was used as such in
the subsequent step of reduction with sodium borohydride.
To the stirring solution of the above crude 4-(2-morpholinoe-
thoxy)benzaldehyde in methanol (10 mL), was added NaBH4
(0.31 g, 8.19 mmol) slowly at 0 ꢀC and the stirring was continued at
an ambient temperature till the complete reduction (TLC). The
excess amount of NaBH4 was quenched with aq. NH4Cl at 0 ꢀC and
the reaction mixture was evaporated under reduced pressure to
remove the solvent. The crude product, thus obtained was extrac-
ted with ethyl acetate/water (50 mL/200 mL). The organic layer was
(d, J ¼ 8.6 Hz, 2H ArH), 5.00 (s, 2H, OCH2), 3.93 (d, J ¼ 8.15 Hz,
1H, CHOH), 1.91 (brs exchangeable with D2O, 1H, OH), 1.20 (m,
1H, cyclopropyl CH), 0.55 (m, 2H, cyclopropyl CH2), 0.33 (m,
2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 158.3, 137.0,
136.5, 122.2 (ArC), 132.1, 129.3, 121.7, 115.0 (ArCH), 78.3 (CHOH),
69.2 (OCH2) 19.5 (cyclopropyl CH), 3.9, 3.1 (cyclopropyl CH2’s); IR
nmax cmꢄ1 3405 (OeH stretching); HRMS (JEOL MSRoute) m/z calcd
for C17H17BrO2 (Mþ) 332.0412, found 332.0417, MS FAB m/z ¼ 334
[M þ 2H]þ; Anal. Calcd for C17H17BrO2: C, 61.28; H, 5.14; found C,
61.53; H, 5.21.
4.1.2.5. Cyclopropyl[4-(3-nitrobenzyloxy)phenyl]methanol (23). It
was obtained by the reaction of compound 16 (1 g, 3.36 mmol),
NaBH4 (0.13 g, 3.36 mmol), by using the procedure as described for
compound 19, to give compound 23. It was obtained as liquid; yield
0.83 g (82%); Rf ¼ 0.5 (methanol/chloroform, 2:98); 1H NMR

S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
5973
dried over anhydrous Na2SO4 and concentrated to give a crude
mass, which was chromatographed over SiO2 column using ethyl
acetate/hexane (3:7) as eluent to afford the compound 27 as col-
J ¼ 8.6 Hz, ArH), 5.04 (s, 2H, OCH2), 4.07 (t, 2H, J ¼ 6.0 Hz, OCH2),
3.17 (m, 4H, OCH2), 2.73 (t, J ¼ 6.0 Hz, 2H, NCH2), 2.58 (m, 5H, 2ꢃ
NCH2 morpholine protons, m cyclopropyl CH), 1.18 (m, 2H, cyclo-
propyl CH2), 0.96 (m, 2H, cyclopropyl CH2); 13C NMR (50 MHz,
ourless liquid; yield 1.5 g (78%); 1H NMR (200 MHz, CDCl3)
d
¼ 7.23
(d, J ¼ 8.5 Hz, 2H, ArH), 6.86 (d, 2H, J ¼ 8.5 Hz, ArH), 4.54 (s, 2H,
OCH2), 4.07 (t, 2H, J ¼ 5.74 Hz, OCH2), 3.72 (m, 4H, OCH2), 2.80
(t, J ¼ 5.72 Hz, 2H, NCH2), 2.57 (m, 4H, 2ꢃ NCH2 morpholine
protons); IR nmax cmꢄ1 3437 (OH stretching), 1603 (C]C stretch-
ing); MS FAB m/z ¼ 237 [M]þ.
CDCl3)
d
¼ 198.9 (C]O), 162.8, 159.2 (ArC), 131.0, 128.8 (ArC), 130.5,
129.4, 115.0, 114.8 (ArCH’s), 70.2 (OCH2), 67.2 (OCH2CH2), 66.1
(2ꢃ CH2’s), 58.3 (NCH2CH2O), 55.4 (2ꢃ CH2), 16.9 (cyclopropyl CH),
11.5 (cyclopropyl CH2’s); IR nmax cmꢄ1 1661(C]O); HRMS (JEOL
MSRoute) m/z calcd for C23H27NO4 (Mþ) 381.1940, found 381.1938,
MS FAB m/z ¼ 382 [M þ H]þ; Anal. Calcd for C23H27NO4: C, 72.42; H,
7.31; N, 3.67; found C, 72.63; H, 7.11; N, 3.78.
4.1.3.2. 4-[2-(Piperidin-1-yl)ethoxy]phenyl methanol (28). It was
obtained by the reaction of 4-hydroxybenzaldehyde 26 (1.0 g,
8.19 mmol), anhydrous K2CO3 (3.39 g, 24.58 mmol), TBAB (0.26 g,
0.819 mmol), 1-(2-chloroethyl)piperidine hydrochloride (1.79 g,
9.83 mmol) and NaBH4 (0.31 g, 8.19 mmol) by using the procedure
as described for compound 27, to give compound 28 as colourless
liquid, yield 1.64 g (85%); Rf ¼ 0.5 (ethylacetate/hexane, 4:6); 1H
4.1.3.6. Cyclopropyl{4-[4-(2-piperidin-1-yl-ethoxy)benzyloxy]
phenyl}methanone (32). It was obtained by the reaction of benzyl
alcohol derivative 28 (0.96 g, 4.09 mmol), NaH (60% dispersion in
mineral oil, 0.39 g, and 16.39 mmol), 4-chloro-40-fluorobutyr-
ophenone (11) (1.0 mL, 4.09 mmol) and tetrabutylammonium
bromide (0.26 g, 0.082 mmol) by using the procedure as described
for compound 12, to give compound 32 as white solid, mp
87e90 ꢀC; yield 1.85 g (80%); Rf ¼ 0.5 (methanol/chloroform, 2:8);
NMR (200 MHz, CDCl3)
d
¼ 7.19 (d, 2H, J ¼ 8.0 Hz, ArH), 6.79 (d,
J ¼ 8.0 Hz, 2H, ArH), 4.54 (s, 2H, OCH2), 4.02 (t, J ¼ 6.1 Hz, 2H, OCH2),
3.03 (bs, 1H, OH), 2.72 (t, J ¼ 6.1 Hz, 2H, NCH2), 2.45 (m, 4H, 2ꢃ
NCH2 piperidine protons),1.54 (m, 4H, CH2 piperidine protons),1.44
(m, 2H, CH2 piperidine protons); 13C NMR (50 MHz, CDCl3)
1H NMR (200 MHz, CDCl3)
d
¼ 7.96 (d, 2H, J ¼ 8.0 Hz, ArH), 7.30
(d, J ¼ 8.0 Hz, 2H, ArH), 6.95 (m, 4H, ArH), 5.01 (s, 2H, OCH2), 4.07
(t, J ¼ 6.0 Hz, 2H, OCH2), 2.73 (t, J ¼ 6.0 Hz, 2H, NCH2), 2.50 (m, 1H,
cyclopropyl CH), 2.45 (m, 4H, 2ꢃ NCH2 piperidine protons), 1.62 (m,
4H, piperidine protons), 1.44 (m, 2H, CH2 piperidine protons), 1.18
(m, 2H, cyclopropyl CH2), 0.96 (m, 2H, cyclopropyl CH2); 13C NMR
d
¼ 158.6, 134.0 (ArC), 128.8, 114.8 (ArCH’s), 66.1, 64.9 (OCH2), 58.3,
55.4 (NCH2), 26.2 (2ꢃ CH2), 24.6 (CH2); IR (KBr), nmax cmꢄ1 3404
(OH stretching), 1611 (C]C stretching); ESMS m/z ¼ 236 [M þ H]þ.
4.1.3.3. 4-[2-(Dimethylamino)ethoxy]phenyl methanol (29). It was
obtained by the reaction of 4-hydroxybenzaldehyde 26 (1.0 g,
8.19 mmol), anhydrous K2CO3 (3.39 g, 24.58 mmol), TBAB (0.26 g,
0.819 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride
(1.40 g, 9.83 mmol) and NaBH4 (0.31 g, 8.19 mmol) by using the
procedure as described for compound 27, to give compound 29, as
yellow liquid, yield 1.08 g (68%); Rf ¼ 0.5 (ethylacetate/hexane, 4:6);
(50 MHz, CDCl3)
d
¼ 198.5 (C]O), 162.8, 159.2 (ArC), 131.0, 128.6
(ArC), 130.5, 129.4, 115.0, 114.8 (ArCH’s), 70.2 (OCH2), 66.3
(OCH2CH2), 58.3 (NCH2CH2O), 55.4 (2ꢃ CH2), 26.2 (2ꢃ CH2), 24.6
(CH2), 16.8 (cyclopropyl CH), 11.4 (cyclopropyl CH2’s); IR (KBr), nmax
cmꢄ1 1656 (C]O); HRMS (JEOL MSRoute) m/z calcd for C24H29NO3
(Mþ) 379.2147, found 379.2172, MS FAB m/z ¼ 380 [M þ H]þ; Anal.
Calcd for C24H29NO3: C, 75.96; H, 7.70; N, 3.69; found, C, 75.90; H,
7.65; N, 3.65.
1H NMR (200 MHz, CDCl3)
d
¼ 7.18 (d, J ¼ 8.3 Hz, 2H, ArH), 6.78 (d,
J ¼ 8.3 Hz, 2H, ArH), 4.38 (s, 2H, OCH2), 4.04 (t, 2H, J ¼ 5.6 Hz, OCH2),
3.22 (bs, 1H OH), 2.72 (t, J ¼ 5.6 Hz, 2H, NCH2); 13C NMR (50 MHz,
4.1.3.7. Cyclopropyl{4-[4-(2-(dimethylamino)ethoxoy]benzyloxy}
phenyl methanone (33). It was obtained by the reaction of benzyl
alcohol derivative 29 (0.8 g, 4.09 mmol), NaH (60% dispersion in
mineral oil, 0.39 g, 16.39 mmol), 4-chloro-40-fluorobutyrophenone
(11) (1.0 mL, 4.09 mmol) and tetrabutylammonium bromide (0.26 g,
0.082 mmol) by using the procedure as described for compound 12,
to give compound 33 as white solid, mp 118e119 ꢀC; yield 1.55 g
(75%); Rf ¼ 0.5 (methanol/chloroform, 2:8); 1H NMR (200 MHz,
CDCl3)
d
¼ 158.6, 129.9 (ArC), 127.8, 114.9 (ArCH), 690, 66.2 (OCH2),
23.9 (CH3); IR nmax cmꢄ1 3416 (OH stretching), 1611 (C]C
stretching); ESMS m/z ¼ 196 [M þ H]þ.
4.1.3.4. 4-[2-(Diisopropylamino)ethoxy]phenyl methanol (30). It was
obtained by the reaction of 4-hydroxybenzaldehyde 26 (1 g,
8.19 mmol), anh. K2CO3 (3.39 g, 24.58 mmol), TBAB (0.26 g,
0.819 mmol), 2-chloro-N,N-diisopropylethanamine hydrochloride
(1.95 g, 9.83 mmol) and NaBH4 (0.31 g, 8.19 mmol) by using the
procedure as described for compound 27, to give compound 30 as
yellow liquid, yield 1.44 g (70%); Rf ¼ 0.5 (ethylacetate/hexane, 4:6);
CDCl3)
d
¼ 7.97 (d, J ¼ 8.3 Hz, 2H, ArH), 7.31 (d, J ¼ 8.3 Hz, 2H, ArH),
7.96 (d, J ¼ 8.4 Hz, 2H, ArH), 6.90 (d, J ¼ 8.4 Hz, 2H, ArH), 5.03
(s, 2H, OCH2), 4.07 (t, 2H, J ¼ 5.62 Hz, OCH2), 2.71 (t, J ¼ 5.62 Hz, 2H,
NCH2), 2.59 (m, cyclopropyl CH), 1.19 (m, 2H, cyclopropyl CH2), 0.97
1H NMR (200 MHz, CDCl3)
d
¼ 7.24 (d, J ¼ 8.0 Hz, 2H, ArH), 6.84
(m, 2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 199.4 (CO),
(d, J ¼ 8.0 Hz, 2H, ArH), 4.55 (s, 2H, OCH2), 3.90 (t, 2H, J ¼ 7.3 Hz,
OCH2), 3.10 (m, 2H, 2ꢃ NCH), 2.84 (t, J ¼ 7.3 Hz, 2H, NCH2), 2.25
(bs,1H, OH),1.06,1.03 (each singlet, 6H, 2ꢃ CH3); 13C NMR (50 MHz,
162.9, 159.3, 129.3, 128.0 (ArC), 115.8, 115.1, 115.0, 114.8, (ArCH),
70.6, 66.4, 58.6 (OCH2Ar), 17.0 (cyclopropyl CH), 11.6, 11.5 (cyclo-
propyl CH2’s); IR nmax cmꢄ1 1657 (C]O stretching); HRMS (JEOL
MSRoute) m/z calcd for C21H25NO3 (Mþ) 339.1834, found 339.1837,
MS FAB ESI MS m/z ¼ 340 [M þ H]þ; Anal. Calcd for C21H25NO3; C,
74.31; H, 7.42; N, 4.13; found, C, 74.28; H, 7.39; N, 4.10.
CDCl3)
d
¼ 158.8, 133.5 (ArC), 128.9, 114.8 (ArCH), 69.4, 65.1 (OCH2),
50.1 (2ꢃ CHN), 44.8 (CH2N), 21.3 (4ꢃ CH3); IR nmax cmꢄ1 3344 (OH
stretching), 1612(C]C stretching); ESI MS m/z ¼ 252 [M þ H]þ.
4.1.3.5. Cyclopropyl{4-[4-(2-morpholin-4-yl-ethoxy)benzyloxy]
phenyl}methanone (31). It was obtained by the reaction of benzyl
alcohol derivative 27 (0.97 g, 4.09 mmol), NaH (60% dispersion in
mineral oil, 0.39 g, and 16.39 mmol), 4-chloro-40-fluorobutyr-
ophenone (11) (1.0 mL, 4.09 mmol) and tetrabutylammonium
bromide (0.26 g, 0.082 mmol) by using the procedure as described
for compound 12, to give compound 31 as white solid; mp
90e91 ꢀC; yield 1.86 g (80%); Rf ¼ 0.5 (methanol/chloroform, 2:8);
4.1.3.8. Cyclopropyl{4-[4-(2-diisopropylamino)ethoxy)benzyloxy]
phenyl}methanone (34). It was obtained by the reaction of benzyl
alcohol 30 derivative (1.01 g, 4.09 mmol), NaH (60% dispersion in
mineral oil, 0.39 g, 16.39 mmol), 4-chloro-40-fluorobutyrophenone
(11) (1.0 mL, 4.09 mmol) and tetrabutylammonium bromide (0.26 g,
0.082 mmol) by using the procedure as described for compound 12,
to give compound 34 as white solid, mp 107e108 ꢀC; yield 1.8 g
(75%); Rf ¼ 0.5 (methanol/chloroform, 2:8); 1H NMR (200 MHz,
1H NMR (200 MHz, CDCl3)
d
¼ 7.97 (d, J ¼ 8.8 Hz, 2H, ArH), 7.30
CDCl3)
d
¼ 7.96 (d, J ¼ 8.8 Hz, 2H, ArH), 7.30 (d, J ¼ 8.6 Hz, 2H, ArH),
(d, 2H, J ¼ 8.6 Hz, AreH), 6.97 (d, J ¼ 9.3 Hz, 2H, ArH), 6.89 (d, 2H,
7.97 (d, J ¼ 8.8 Hz, 2H, ArH), 6.87 (d, J ¼ 8.6 Hz, 2H, ArH), 5.03

5974
S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
(s, 2H, OCH2), 3.87 (t, 2H, J ¼ 7.3 Hz, OCH2), 3.03 (m, 2H, 2ꢃ NCH),
2.80 (t, J ¼ 7.3 Hz, 2H, NCH2), 2.50 (m, 1H, cyclopropyl CH), 1.19
(m, 2H, cyclopropyl CH2), 1.05 (s, 6H, 2ꢃ CH3), 1.02 (s, 6H, 2ꢃ CH3),
stretching); HRMS (JEOL MSRoute) m/z calcd for C21H27NO3 (Mþ)
341.1991, found 341.1928, ESI MS m/z ¼ 342 [M þ H]þ; Anal.
Calcd for C21H27NO3: C, 73.87; H, 7.97; N, 4.10; found C, 73.82; H,
7.91; N, 4.06.
0.97 (m, 2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 199.5
(CO), 162.8, 159.4, 131.5, 128.3 (ArC), 131.5, 130.5, 115.0, 114.8,
(ArCH), 70.3, 69.6, (OCH2Ar), 50.0 (2ꢃ CHN), 44.7 (CH2N), 21.3 (4ꢃ
CH3), 16.9 (cyclopropyl CH), 11.5 (cyclopropyl CH2’s); IR nmax cmꢄ1
1658 (C]O stretching); HRMS (JEOL MSRoute) m/z calcd for
C25H33NO3 (Mþ) 395.2450, found 395.2461, ESI MS m/z ¼ 396
[M þ H]þ; Anal. Calcd for C25H33NO3; C, 75.91; H, 8.41; N, 3.54;
found, C, 75.86; H, 8.38; N, 3.50.
4.1.3.12. Cyclopropyl{4-[4-(2-diisopropylamino)ethoxy)benzyloxy]
phenyl}methanol (38). It was obtained by the reaction of compound
34 (1.0 g, 2.94 mmol), NaBH4 (0.11 g, 2.94 mmol), by using the
procedure as described for compound 19, to give compound 38 as
white solid, mp 84e85 ꢀC; yield 0.73 g (73%); Rf ¼ 0.5 (methanol/
chloroform, 3:7); 1H NMR (200 MHz, CDCl3)
d
¼ 7.20 (m, 4H, ArH),
6.81 (m, 4H, ArH), 5.20 (s, 2H, OCH2), 3.87 (d, J ¼ 8.1 Hz, 1H, CHOH),
3.79 (t, 2H, J ¼ 7.4 Hz, OCH2), 2.96 (m, 2H, 2ꢃ NCH), 2.73
(t, J ¼ 7.4 Hz, 2H, CH2), 1.81 (s, 1H, OH), 1.08 (m, cyclopropyl CH),
0.98 (s, 6H, 2ꢃ CH3), 0.95 (s, 6H, 2ꢃ CH3), 0.51 (m, 2H, cyclopropyl
CH2), 0.25 (m, 2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
4.1.3.9. Cyclopropyl{4-[4-(2-morpholin-4-yl-ethoxy)benzyloxy]
phenyl}methanol (35). It was obtained by the reaction of compound
31 (1.0 g, 2.62 mmol), NaBH4 (0.09 g, 2.62 mmol), by using the
procedure as described for compound 19, to give compound 35 as
white solid, mp 114e115 ꢀC; yield 0.84 g (84%); Rf ¼ 0.5 (methanol/
d
¼ 159.2, 158.7, 136.8, 129.2 (ArC), 129.4, 127.5, 115.0, 114.9 (ArC),
chloroform, 4:6); 1H NMR (200 MHz, CDCl3)
d
¼ 7.29 (d, J ¼ 8.2 Hz,
78.4 (CHOH), 70.2 (OCH2), 69.6 (OCH2), 50.0 (2ꢃ CHN), 44.7 (NCH2),
21 (4ꢃ CH3), 19.4, (cyclopropyl CH), 3.9, 3.1 (cyclopropyl CH2’s); IR
nmax cmꢄ1 3413 (OH stretching); HRMS (JEOL MSRoute) m/z calcd
for C25H35NO3 (M þ Hþ) 398.2695, found 398.2692, ESI MS
m/z ¼ 398 [M þ H]þ; Anal Calcd for C25H35NO3: C, 75.53; H, 8.87; N,
3.52; found C, 75.50; H, 8.82; N, 3.48.
4H, ArH), 6.89 (d, J ¼ 7.9 Hz, 4H, ArH), 4.97 (s, 2H, OCH2), 3.97
(t, J ¼ 5.6 Hz, 2H, OCH2CH2), 3.93 (d, J ¼ 8.0 Hz, 2H, CHOH), 3.68 (m,
4H, OCH2’s morpholine protons), 2.78 (t, J ¼ 5.6 Hz, 2H, OCH2CH2),
2.54 (m, 4H, NCH2’s morpholine protons), 1.59 (bs, 1H, OH), 1.17
(m, 1H, cyclopropyl CH), 0.55 (m, 2H, cyclopropyl CH2), 0.34 (m, 2H,
cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 158.9, 158.6, 136.9,
129.7 (ArC), 129.7, 127.6, 115.0 (ArCH’s), 78.2, (CHOH), 70.1 (OCH2)
67.1 (OCH2’s), 66.1 (OCH2CH2), 57.9 (NCH2CH2O) 54.4 (CH2’s), 19.4
(cyclopropyl CH), 4.0, 3.0 (cyclopropyl CH2’s); IR nmax cmꢄ1 3196
(OH stretching), 2927 (CeH stretching), 1608 (CeO); HRMS (JEOL
MSRoute) m/z calcd for C23H29NO4 (Mþ) 383.2097, found 383.2081,
MS FAB m/z ¼ 383 [M þ H]þ; Anal. Calcd for C23H29NO4: C, 72.04; H,
7.62; N, 3.65; found C, 72.03; H, 7.31; N, 3.78.
4.1.3.13. 3-[2-(Piperidin-1-yl)ethoxy]phenyl methanol (40). It was
obtained by the reaction of 3-hydroxybenzaldehyde 39 (1.0 g,
8.19 mmol), anhydrous K2CO3 (3.39 g, 24.58 mmol), TBAB
(0.26 g, 0.819 mmol), 1-(2-chloroethyl)piperidine hydrochloride
(1.79 g, 9.83 mmol) and NaBH4 (0.31 g, 8.19 mmol) by using the
procedure as described for compound 27, to give compound 40, as
yellow liquid, yield 1.54 g (80%); Rf ¼ 0.5 (methanol/chloroform,
3:7); 1H NMR (200 MHz, CDCl3)
d
¼ 7.19 (m, 2H, ArH), 6.91 (m, 2H,
4.1.3.10. Cyclopropyl-4-[4-(2-piperidin-1-yl-ethoxy)benzyloxy]
phenyl}methanol (36). It was obtained by the reaction of compound
32 (1.0 g, 2.63 mmol), NaBH4 (0.10 g, 2.63 mmol), by using the
procedure as described for compound 19, to give compound 36 as
a white solid mp 125e126 ꢀC, yield 0.78 g (78%); Rf ¼ 0.5 (methanol/
ArH), 6.86 (m, 1H, ArH), 5.76 (bs, 1H, OH), 4.58 (s, 2H, OCH2), 4.17
(t, J ¼ 5.3 Hz, 2H, OCH2), 2.94 (t, J ¼ 5.3 Hz, 2H, NCH2), 2.84 (m, 4H,
2ꢃ NCH2 piperidine protons), 1.69 (m, 4H, CH2 piperidine protons),
1.46 (m, 2H, CH2 piperidine protons); IR nmax cmꢄ1 3404 (OH
stretching), 1611 (C]C stretching); ESMS m/z ¼ 236 [M þ H]þ.
chloroform, 4:6); 1H NMR (200 MHz, CDCl3)
d
¼ 7.32 (d, J ¼ 8.2 Hz,
4H, ArH), 6.91 (d, J ¼ 8.7 Hz, 4H, ArH), 4.96 (s, 2H, OCH2), 4.96 (t, 2H,
J ¼ 5.9 Hz, OCH2), 3.95 (d, J ¼ 8.2 Hz, 1H, CHOH), 2.74 (t, J ¼ 5.9 Hz,
2H, NCH2CH2O), 2.49 (m, 4H, 2ꢃ NCH2 piperidine protons), 2.37
(s, 1H, OH), 1.59 (s, 4H, piperidine protons), 1.44 (m, 2H, CH2
piperidine protons), 1.18 (m, 1H, cyclopropyl CH), 0.44 (m, 2H,
cyclopropyl CH2), 0.34 (m, 2H, cyclopropyl CH2); 13C NMR (50 MHz,
4.1.3.14. Cyclopropyl{4-[3-(2-piperidin-1-yl-ethoxy)benzyloxy]phenyl}
methanone (41). It was obtained by the reaction of benzyl alcohol 40
(1.05 g, 4.09 mmol), NaH (60% dispersion in mineral oil, 0.39 g,
16.39 mmol), 4-chloro-40-fluorobutyrophenone (11) (1.0 mL,
4.09 mmol) and tetrabutylammonium bromide (0.26 g, 0.082 mmol)
by using the procedure as described for compound 12, to give
compound 41 as white solid, mp 79e80 ꢀC; yield 1.84 g (80%);
Rf ¼ 0.5 (methanol/chloroform, 4:6); 1H NMR (200 MHz, CDCl3)
CDCl3)
d
¼ 159.0, 158.6, 136.0 (ArC), 129.5, 127.6, 115.0 (ArCH’s), 78.4
(CHOH), 70.2 (OCH2), 66.2 (OCH2CH2), 58.2 (NCH2CH2O), 55.4 (2ꢃ
CH2), 26.2 (2ꢃ CH2), 24.5 (CH2), 19.4 (cyclopropyl CH), 4.0, 3.1
(cyclopropyl CH2’s); IR nmax cmꢄ1 3422 (OeH stretching); HRMS
(JEOL MSRoute) m/z calcd for C24H31NO3 (Mþ) 381.2304, found
381.2302, MS FAB m/z ¼ 382 [M þ H]þ; Anal. Calcd for C24H31NO3:
C, 75.56; H, 8.19; N, 3.67; found C, 75.50; H, 8.13; N, 3.64.
d
¼ 7.98 (d, 2H, J ¼ 8.8 Hz, ArH), 7.23 (m, 1H, ArH), 6.96 (m, 4H, ArH),
6.86 (m, 1H, ArH), 5.08 (s, 2H, OCH2), 4.09 (t, J ¼ 6.0 Hz, 2H, OCH2),
2.75 (t, J ¼ 6.0 Hz, 2H, NCH2), 2.60 (m, 1H, cyclopropyl CH), 2.50
(m, 4H, 2ꢃ CH2 piperidine protons),1.62 (m, 4H, piperidine protons),
1.46 (m, 2H, CH2 piperidine protons), 1.18 (m, 2H, cyclopropyl CH2),
0.96 (m, 2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 198.4
4.1.3.11. Cyclopropyl{4-[4-(2-(dimethylamino)ethoxy]benzyloxy}
phenyl)methanol (37). It was obtained by the reaction of compound
33 (1.0 g, 2.53 mmol), NaBH4 (0.1 g, 2.53 mmol), by using the
procedure as described for compound 19, to give compound 37 as
white solid, mp 118e119 ꢀC; yield 0.77 g (77%); Rf ¼ 0.5 (methanol/
(C]O), 162.3, 159.1, 137.8, 131.2 (ArC), 130.1, 129.6, 114.4, 114.2, 113.5
(ArCH’s), 69.9, (OCH2), 65.8 (OCH2CH2), 57.8 (NCH2CH2O), 55.0
(2ꢃ CH2), 29.6 (2ꢃ CH2), 24.1 (CH2), 16.5 (cyclopropyl CH), 11.0
(cyclopropyl CH2’s); IR nmax cmꢄ1 1659(C]O); HRMS (JEOL
MSRoute) m/z calcd for C24H29NO3 (Mþ) 380.2225, found 380.2215,
MS FAB m/z ¼ 380 [M þ H]þ; Anal. Calcd for C24H29NO3: C, 75.96; H,
7.70; N, 3.69; found, C, 75.89; H, 7.67; N, 3.63.
chloroform, 3:7); 1H NMR (200 MHz, CDCl3)
d
¼ 7.23 (m, 4H, ArH),
6.85 (m, 4H, ArH), 4.89 (s, 2H, OCH2), 3.96 (t, 2H, J ¼ 5.4 Hz, OCH2),
3.86 (d, J ¼ 8.1 Hz, 1H, CHOH), 2.63 (t, J ¼ 5.4 Hz, 2H, NCH2), 2.63
(t, J ¼ 5.4 Hz, 2H, 2ꢃ CH3), 1.13 (m, cyclopropyl CH), 0.52
(m, 2H, cyclopropyl CH2), 0.22 (m, 2H, cyclopropyl CH2); 13C NMR
4.1.3.15. Cyclopropyl{4-[3-(2-piperidin-1-yl-ethoxy)benzyloxy]
phenyl}methanol (42). It was obtained by the reaction of compound
41 (1.0 g, 2.63 mmol), NaBH4 (0.1 g, 2.63 mmol), by using the
procedure as described for compound 19, to give compound 42 as
liquid; yield 0.78 g (78%); Rf ¼ 0.5 (methanol/chloroform, 4:6); 1H
(50 MHz, CDCl3)
d
¼ 159.0, 158.6, 136.8, 129.3, 128.0 (ArC), 127.6,
115.0, 78.4, 70.2, 66.3, 58.5, 46.2, 19.4 (cyclopropyl CH), 3.9, 3.0
(cyclopropyl CH2’s); IR nmax cmꢄ1 1601 (C]O stretching), 3429 (OH

S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
5975
NMR (200 MHz, CDCl3)
d
¼ 7.30 (m, 3H, ArH), 6.95 (m, 4H, ArH),
6.92 (m, 5H, ArH), 5.28 (s, 2H, OCH2), 4.14 (t, J ¼ 6.0 Hz, 2H, OCH2),
3.86 (s, 3H, OCH3), 3.72 (t, J ¼ 4.8 Hz, 4H, eCH2OCH2e), 2.83
(t, J ¼ 5.9 Hz, 2H, NCH2), 2.55e2.65 (m, 5H, 2ꢃ NCH2 morpholine
protons and cyclopropyl CH), 1.20 (m, 2H, cyclopropyl CH2), 0.99
6.85 (m, 1H, ArH), 5.03 (s, 2H, OCH2), 4.11 (t, 2H, J ¼ 6.0 Hz, OCH2),
3.98 (d, J ¼ 8.0 Hz, 1H, CHOH), 2.76 (t, J ¼ 6.0 Hz, 2H, NCH2CH2O),
2.54 (m, 4H, 2ꢃ NCH2 piperidine protons), 2.37 (s, 1H, OH), 1.62
(s, 4H, piperidine protons), 1.48 (m, 2H, CH2 piperidine protons),
1.19 (m, 1H, cyclopropyl CH), 0.65 (m, 2H, cyclopropyl CH2), 0.33 (m,
2H, cyclopropyl CH2); IR nmax cmꢄ1 3350 (OH stretching); HRMS
(JEOL MSRoute) m/z calcd for C24H31NO3 (M þ Hþ) 382.2382, found
382.2371, MS FAB m/z ¼ 382 [M þ H]þ; Anal. Calcd for C24H31NO3:
C, 75.56; H, 8.19; N, 3.67; found C, 75.52; H, 8.15; N, 3.65.
(m, 2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 199.0 (C]
O), 162.7, 148.7, 131.6, 129.6 (ArC), 130.6, 120.6, 114.2, 113.9, 111.8
(ArCH’s), 70.5 (OCH2), 67.2 (OCH2CH2), 57.9 NCH2CH2O), 56.3 (2ꢃ
CH2), 54.6 (OCH3), 53.7 (CH2), 16.9 (cyclopropyl CH), 11.5 (cyclo-
propyl CH2’s); IR nmax cmꢄ11658 (C]O); HRMS (JEOL MSRoute) m/z
calcd for C24H29NO5 (Mþ) 411.2046, found 411.2041, ESI MS
m/z ¼ 412 [M þ H]þ; Anal. Calcd for C24H29NO5: C, 70.05; H, 7.10; N,
3.40; found, C, 70.00; H, 7.06; N, 3.33.
4.1.3.16. 3-Methoxy[4-(2-morpholinoethoxy)phenyl]methanol
(44). It was obtained by the reaction of 4-hydroxy-3-methox-
ybenzaldehyde 43 (1.0 g, 6.57 mmol), anhydrous K2CO3 (2.72 g,
19.73 mmol), TBAB (0.21 g, 0.657 mmol), 4-(2-chloroethyl)mor-
pholine hydrochloride (1.46 g, 7.89 mmol) and NaBH4 (0.25 g,
6.57 mmol) by using the procedure as described for compound 27,
to give compound 44, as colourless liquid, yield 1.37 g (79%);
Rf ¼ 0.5 (methanol/chloroform, 3:7); 1H NMR (200 MHz, CDCl3)
4.1.3.20. Cyclopropyl{4-[3-methoxy-4-(2-piperidin-1-yl)ethoxy)ben-
zyloxy]phenyl} methanone (48). It was obtained by the reaction of
benzyl alcohol derivative 45 (1.09 g, 4.09 mmol), NaH (60%
dispersion in mineral oil, 0.39 g, 16.39 mmol), 4-chloro-40-fluo-
robutyrophenone 11 (1.0 mL, 4.09 mmol) and tetrabutylammonium
bromide (0.26 g, 0.082 mmol) by using the procedure as described
for compound 12, to give compound 48 as white solid, mp
70e71 ꢀC; yield 2.12 g (85%); Rf ¼ 0.4 (methanol/chloroform, 4:6);
d
¼ 6.86 (s, 1H, ArH), 6.78 (m, 2H, ArH), 4.54 (s, 2H, OCH2), 4.09
(t, J ¼ 5.8 Hz, 2H, OCH2), 3.80 (s, 3H, OCH3), 3.70 (t, J ¼ 5.9 Hz, 2H,
NCH2), 2.80 (m, 4H, 2ꢃ OCH2 morpholine protons), 2.56 (m, 4H, 2ꢃ
1H NMR (200 MHz, CDCl3)
d
¼ 7.98 (d, 2H, J ¼ 8.7 Hz, ArH), 6.98
NCH2 morpholine protons); 13C NMR (50 MHz, CDCl3)
d
¼ 148.7,
(d, J ¼ 8.7 Hz, 2H, ArH), 6.90 (m, 3H, ArH), 5.02 (s, 2H, OCH2), 4.10
(t, J ¼ 6.3 Hz, 2H, OCH2), 2.80 (s, 3H, OCH3), 2.77 (t, J ¼ 6.3 Hz, 2H,
NCH2), 2.49e2.60 (m, 5H, 2ꢃ NCH2 piperidine protons and cyclo-
propyl CH), 1.61 (m, 4H, piperidine protons), 1.44 (m, 2H, CH2
piperidine protons), 1.21 (m, 2H, cyclopropyl CH2), 0.98 (m,
129.6 (ArC), 119.5, 113.8, 111.3 (ArCH’s), 66.9, 65.1 (OCH2), 57.9, 54.3
NCH2CH2O), 56.0 (OCH3); IR nmax cmꢄ1 3421 (OH stretching), 1600
(C]C stretching); ESI MS m/z ¼ 268 [M þ H]þ.
4.1.3.17. 3-Methoxy-4-[2-(piperidin-1-yl)ethoxy]phenyl
methanol
2H, cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d (C]O),
(45). It was obtained by the reaction of 4-hydroxy-3-methox-
ybenzaldehyde 43 (1.0 g, 6.57 mmol), anhydrous K2CO3 (2.72 g,
19.73 mmol), TBAB (0.21 g, 0.657 mmol), 4-(2-chloroethyl)piperi-
dine hydrochloride (1.44 g, 7.89 mmol) and NaBH4 (0.25 g,
6.57 mmol) by using the procedure as described for compound 27,
to give compound 45, as yellow liquid, yield 1.34 g (77%); Rf ¼ 0.5
162.2149.5, 148.2, 131.0, 128.8 (ArC), 130.5, 120.1, 114.2, 113.4, 113.0,
111.3 (ArCH’s), 69.9 (OCH2), 66.7 (OCH2CH2), 58.3 (NCH2CH2O), 57.5
(2ꢃ CH2), 55.6 (OCH3), 54.8(CH2), 25.7 (2ꢃ CH2), 24.0 (CH2),
16.3 (cyclopropyl CH), 10.9 (cyclopropyl CH2’s); IR nmax cmꢄ1 1658
(C]O); HRMS (JEOL MSRoute) m/z calcd for C25H31NO4 (Mþ)
409.2253, found 409.2245, ESI MS m/z ¼ 410 [M þ H]þ; Anal. Calcd
for C25H31NO4: C, 73.32; H, 7.63; N, 3.42; found, C, 73.27; H, 7.60;
N, 3.38.
(methanol/chloroform, 4:6); 1H NMR (200 MHz, CDCl3)
d
¼ 6.91
(s, 1H, ArH), 6.78 (m, 2H, ArH), 5.50 (bs, 1H, OH), 4.56 (s, 2H, OCH2),
4.22 (t, 5.46 Hz, 2H, OCH2), 3.80 (s, 3H, OCH3), 3.06
J
¼
(t, J ¼ 5.4 Hz, 2H, NCH2), 2.83 (m, 4H, 2ꢃ NCH2 piperidine protons),
1.77 (m, 4H, CH2 piperidine protons), 1.54 (m, 2H, CH2 piperidine
protons); IR nmax cmꢄ1 3425 (OH stretching), 1632 (C]C stretch-
ing); ESI MS m/z ¼ 266 [M þ H]þ.
4.1.3.21. Cyclopropyl{4-[4-(2-diisopropylamino)ethoxy)-3-methox-
ybenzyloxy]-phenyl}methanone (49). It was obtained by the reac-
tion of benzyl alcohol derivative 46 (1.15 g, 4.09 mmol), NaH (60%
dispersion in mineral oil, 0.39 g, 16.39 mmol), 4-chloro-40-fluo-
robutyrophenone 11 (1.0 mL, 4.09 mmol) and tetrabutylammonium
bromide (0.26 g, 0.082 mmol) by using the procedure as described
for compound 12, to give compound 49 as white solid, mp
64e65 ꢀC; yield 1.97 g (76%); Rf ¼ 0.4 (methanol/chloroform, 4:6);
4.1.3.18. 3-Methoxy-4-[2-(diisopropylamino)ethoxy]phenyl methanol
(46). It was obtained by the reaction of 4-hydroxy-3-methox-
ybenzaldehyde (1.0 g, 6.57 mmol), anhydrous K2CO3 (2.72 g,
19.73 mmol), TBAB (0.21 g, 0.657 mmol), 2-chloro-N,N-dimethy-
lethanamine hydrochloride (1.12 g, 7.89 mmol) and NaBH4 (0.25 g,
6.57 mmol) by using the procedure as described for compound 27,
to give compound 46, as yellow liquid; yield, 1.31 g (71%); Rf ¼ 0.4
1H NMR (200 MHz, CDCl3)
d
¼ 7.98 (d, J ¼ 8.8 Hz, 2H, ArH), 7.00 (d,
J ¼ 8.8 Hz, 2H, ArH), 6.90 (m, 3H, ArH), 5.02 (s, 2H, OCH2), 3.91 (m,
5H, OCH2 and OCH3), 3.03 (m, 2H, 2ꢃ NCH), 2.87 (t, J ¼ 7.5 Hz, 2H,
NCH2), 2.70 (m, 1H, cyclopropyl CH), 1.19 (m, 2H, cyclopropyl CH2),
1.05 (s, 6H, 2ꢃ CH3), 1.02 (s, 6H, 2ꢃ CH3), 0.96 (m, 2H, cyclopropyl
(methanol/chloroform, 3:7); 1H NMR (200 MHz, CDCl3)
d
¼ 6.83
(s, 1H, ArH), 6.76 (s, 2H, ArH), 4.51 (s, 2H, OCH2), 3.88 (t, J ¼ 7.7 Hz,
2H, OCH2), 3.79 (s, 3H, OCH3), 3.05 (m, 2H, CHN ꢃ2), 2.86
(t, J ¼ 7.7 Hz, 2H, NCH2),1.03,1.00 (each singlet, 6H, 2ꢃ CH3); IR nmax
cmꢄ1 3420 (OH stretching), 1635 (C]C stretching); ESI MS
m/z ¼ 282 [M þ H]þ.
CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 198.7 (CO), 162.8, 149.8, 149.0,
131.5, 128.8 (ArC), 130.5, 120.6, 114.8, 112.9, 111.6 (ArCH), 70.5, 70.3
(OCH2Ar), 56.2 (OCH3), 50.0 (2ꢃ CHN), 44.6 (CH2N), 21.3 (4ꢃ CH3),
16.9 (cyclopropyl CH), 11.5 (cyclopropyl CH2’s); IR nmax cmꢄ1 1611
(C]O stretching); HRMS (JEOL MSRoute) m/z calcd for C26H35NO4
(M þ Hþ) 426.2644, found 426.2651, ESI MS m/z ¼ 426 [M þ H]þ.
Anal. Calcd for C26H35NO4 C, 73.38; H, 8.29; N, 3.29; found C, 73.34;
H, 8.25; N, 3.26.
4.1.3.19. Cyclopropyl{4-[3-methoxy-4-(2-morpholino)ethoxy)benzy-
loxy]phenyl} methanone (47). It was obtained by the reaction
of benzyl alcohol derivative 44 (1.09 g, 4.09 mmol), NaH
(60% dispersion in mineral oil, 0.39 g, 16.39 mmol), 4-chloro-40-
fluorobutyrophenone 11 (1.0 mL, 4.09 mmol) and tetrabuty-
lammonium bromide (0.26 g, 0.082 mmol) by using the procedure
as described for compound 12, to give compound 47 as white solid,
mp 69e70 ꢀC; yield 2.05 g (82%), Rf ¼ 0.4 (methanol/chloroform,
4.1.3.22. Cyclopropyl{4-[3-methoxy-4-(2-morpholino)ethoxy)benzy-
loxy]phenyl} methanol (50). It was obtained by the reaction of
compound 47 (1.0 g, 2.43 mmol), NaBH4 (0.09 g, and 2.43 mmol), by
using the procedure as described for compound 19, to give
compound 50 as white solid, mp 72e73 ꢀC; yield 0.79 g (79%);
Rf ¼ 0.4 (methanol/chloroform, 4:6); 1H NMR (200 MHz, CDCl3)
3:7); 1H NMR (200 MHz, CDCl3)
d
¼ 7.99 (d, 2H, J ¼ 8.8 Hz, ArH),

5976
S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
d
¼ 7.33 (d, J ¼ 8.6 Hz, 2H, ArH), 6.91 (m, 5H, ArH), 4.97 (s, 2H,
(t, 2H, J ¼ 6.3 Hz, OCH2), 2.83 (t, J ¼ 6.3 Hz, 2H, NCH2), 2.60 (m, 1H,
cyclopropyl CH), 2.51 (m, 4H, 2ꢃ NCH2), 145e1.18 (m, 10H, n-butyl
2ꢃ CH2CH2 and cyclopropyl CH2), 1.00e0.88 (m, 8H, 2ꢃ CH3 and
OCH2), 4.13 (t, 2H, J ¼ 5.9 Hz, OCH2), 3.95 (d, J ¼ 8.2 Hz, 1H, CHOH),
3.86 (s, 3H, OCH3), 3.71 (t, J ¼ 4.4 Hz, 4H, eCH2OCH2e), 2.82
(t, J ¼ 5.9 Hz, 2H, NCH2CH2O), 2.59e2.55 (m, 4H, 2ꢃ NCH2 mor-
pholine protons), 2.16 (s, 1H, OH protons), 1.21 (m, 1H, cyclopropyl
CH), 0.56 (m, 2H, cyclopropyl CH2), 0.43 (m, 2H, cyclopropyl CH2);
cyclopropyl CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 198.9 (CO), 163.0,
131.3 (ArC),130.5,130.5,114.5 (ArCH), 67.3 (OCH2Ar), 55.1, 53.1, 29.8,
21.0, 14.4 (4ꢃ CH3), 16.9 (cyclopropyl CH), 11.9, 11.4 (cyclopropyl
CH2’s); IR nmax cmꢄ1 1671 (C¼O stretching); HRMS (JEOL MSRoute)
m/z calcd for C20H31NO2 (M þ Hþ) 318.2433 found 318.2435, ESI MS
m/z ¼ 318 [M þ H]þ; Anal. Calcd for C20H31NO2: C, 75.67; H, 9.84; N,
4.41; found C, 75.60; H, 9.80; N, 4.39.
13C NMR (50 MHz, CDCl3)
d
¼ 158.6, 150.1, 148.4, 136.8, 130.5 (ArC),
127.6, 120.5, 115.0, 113.9, 111.8, 109.9 (ArCH’s), 78.3 (CHOH), 70.4
(OCH2), 67.2 (OCH2CH2), 57.9 (NCH2CH2O), 56.2 (OCH3), 54.4 (2ꢃ
CH2), 19.5 (cyclopropyl CH), 3.9, 3.1 (cyclopropyl CH2’s); IR nmax
cmꢄ1 3449 (OH stretching); HRMS (JEOL MSRoute) m/z calcd for
C24H31NO5 (Mþ) 413.2202, found 413.2192, ESI MS m/z ¼ 414
[M þ H]þ; Anal. Calcd C24H31NO5 found C, 69.71; H, 7.56; N, 3.39;
found C, 69.68; H, 7.50; N, 3.33.
4.1.3.26. {4-[2-(N,N-Dibutylamino)ethoxy]phenyl}cyclopropyl meth-
anol (55). It was obtained by the reaction of cyclopropyl{4-
[2-(dibutylamino)ethoxy]phenyl}methanone 54 (0.5 g, 1.57 mmol),
NaBH4 (0.06 g, 1.57 mmol), by using the procedure as described for
compound 12, to give compound 55 as yellow liquid; yield 0.39 g,
(77%); Rf ¼ 0.5 (methanol/chloroform, 2:8); 1H NMR (200 MHz,
4.1.3.23. Cyclopropyl{4-[3-methoxy-4-(2-(piperidin-1-yl)ethoxy)
benzyloxy]phenyl} methanol (51). It was obtained by the reaction
of compound 48 (1.0 g, 2.44 mmol), NaBH4 (0.09 g, and 2.44 mmol),
by using the procedure as described for compound 19, to give
compound 51 as white solid, mp 119e121 ꢀC; yield 0.78 g (78%);
Rf ¼ 0.5 (methanol/chloroform, 4:6); 1H NMR (200 MHz, CDCl3)
CDCl3)
d
¼ 7.31 (dd, J1 ¼ 1.9 Hz, J2 ¼ 6.7 Hz, 2H, ArH), 6.87 (dd,
J1 ¼1.9 Hz, J2 ¼ 6.7 Hz, 2H, ArH), 4.02 (t, 2H, J ¼ 6.4 Hz, OCH2), 3.92
(d, J ¼ 7.3 Hz, 1H, CHOH), 2.83 (t, J ¼ 6.4 Hz, 2H, NCH2), 2.53 (m, 4H,
2ꢃ NCH2), 2.12 (bs, 1H, OH), 145e1.18 (m, 9H, n-butyl 2ꢃ CH2CH2
and cyclopropyl CH), 1.00e0.88 (m, 8H, 2ꢃ CH3 and cyclopropyl
d
¼ 7.30 (d, J ¼ 8.4 Hz, 2H, ArH), 6.89 (m, 5H, ArH), 4.94 (s, 2H, OCH2),
4.10 (t, 2H, J ¼ 6.4 Hz, OCH2), 3.93 (d, J ¼ 8.0 Hz,1H, CHOH), 3.8 (s, 3H,
OCH3), 2.90 (s, 1H, OH), 2.77 (t, J ¼ 6.3 Hz, 2H, NCH2), 2.49e2.60 (m,
5H, 2ꢃ NCH2 piperidine protons and cyclopropyl CH), 1.61 (m, 4H,
piperidine protons), 1.44 (m, 2H, CH2 piperidine protons), 1.21 (m,
2H, cyclopropyl CH2), 0.98 (m, 2H, cyclopropyl CH2); 13C NMR
CH2); 13C NMR (50 MHz, CDCl3)
d
¼ 158.7, 136.5 (ArC), 127.5, 114.6
(ArCH), 78.2 (CHOH), 67.0, (OCH2Ar), 55.1, 53.1, 30.1, 29.7, 21.0 (CH2),
19.4 (cyclopropyl CH), 14.5 (CH3), 3.9, 3.0 (cyclopropyl CH2’s); IR
nmax cmꢄ1 3428 (OH stretching); HRMS (JEOL MSRoute) m/z calcd
for C20H33NO2 (M þ Hþ) 320.2589 found 320.2592, ESI MS
m/z ¼ 320 [M þ H]þ. Anal. Calcd for C20H33NO2: C, 75.19; H, 10.41;
N, C, 75.15; H, 10.37; N, 75.10.
(50 MHz, CDCl3)
d
¼ 198.1 (C]O), 162.2149.5, 148.2, 131.0, 128.8
(ArC), 130.5, 120.1, 114.2, 113.4, 113.0, 111.3 (ArCH’s), 69.9 (OCH2),
66.7 (OCH2CH2), 58.3 NCH2CH2O), 57.5 (2ꢃ CH2), 55.6 (OCH3), 54.8
(CH2), 25.7 (2ꢃ CH2), 24.0 (CH2), 16.3 (cyclopropyl CH), 10.9 (cyclo-
propyl CH2’s); IR nmax cmꢄ1 3566 (OH stretching); HRMS (JEOL
MSRoute) m/z calcd for C25H33NO4 (Mþ) 411.2410, found 411.2398,
ESI MS m/z ¼ 412 [M þ H]þ; Anal. Calcd for C25H33NO4: C, 72.96; H,
8.08; N, 3.40; found C, 72.96; H, 8.08; N, 3.40.
4.2. Bio-evaluation methods
4.2.1. Determination of antitubercular activity against M.
tuberculosis H37Rv strain (agar microdilution method) [25]
Drug susceptibility and determination of MIC of the test
compounds/drugs against M. tuberculosis H37Rv was done by agar
microdilution method. The MIC of the test compounds was deter-
mined by incorporating two-fold dilution of this suspension were
added to (in tubes) 7H10 middle brook’s medium (containing 1.7 mL
medium and 0.2 mL OADC supplement) at different concentration of
the test compounds keeping the volume constant i.e. 0.1 mL.
Mediumwas allowed tocool keepingthe tubes in slantingposition. A
culture of M. tuberculosis H37Rv growing on LeJ medium was har-
vested in 0.85% saline with 0.05% Tween-80. A suspension of
4.1.3.24. Cyclopropyl{4-[4-(2-diisopropylamino)ethoxy)-3-methox-
ybenzyloxy] phenyl}methanol (52). It was obtained by the reaction
of compound 49 (1.0 g, 2.35 mmol), NaBH4 (0.08 g, 2.35 mmol), by
using the procedure as described for compound 19, to give
compound 52 as white solid, mp 84e85 ꢀC; yield 0.75 g (75%);
Rf ¼ 0.5 (methanol/chloroform, 4:6); 1H NMR (200 MHz, CDCl3)
d
¼ 7.23 (m, 2H, ArH), 6.88 (m, 5H, ArH), 4.94 (s, 2H, OCH2), 3.90 (m,
5H, OCH2 and OCH3), 3.57 (d, J ¼ 8.1 Hz, 1H, CHOH), 3.00 (m, 2H, 2ꢃ
NCH), 2.87 (t, 2H, J ¼ 7.8 Hz, NCH2), 1.81 (s, 1H, OH), 1.18
(m, cyclopropyl CH), 1.05 (s, 6H, 2ꢃ CH3), 1.02 (s, 6H, 2ꢃ CH3), 0.57
(m, 2H, cyclopropyl CH2), 0.30 (m, 2H, cyclopropyl CH2); 13C NMR
1 m
g mLꢄ1 concentration of extracts/compounds was prepared in
dimethyl sulphoxide (DMSO). These tubes were then incubated at
37 ꢀC for 24 h followed by streaking of M. tuberculosis H37Rv (5 ꢃ105
bacilli per tube). The tubes were then incubated at 37 ꢀC. Growth of
bacilli was seen after 30 days of incubation. Tubes having the
compounds were compared with control tubes where medium
alone was incubated with H37Rv. The lowest concentration of the
compound at which complete inhibition of colonies occurred was
taken as minimum inhibitoryconcentration (MIC) of test compound.
(50 MHz, CDCl3)
d
¼ 159.9, 158.6, 149.7, 148.7, 141.0, 129.7 (ArC),
127.8, 127.6, 120.6, 115.6, 115.2, 115.0, 112.9, 111.6 (ArCH), 78.2
(CHOH), 70.4, 70.1 (OCH2), 56.2 (OCH3), 50.0 (2ꢃ CHN), 44.7 (NCH2),
21.2 (4ꢃ CH3), 19.4, (cyclopropyl CH), 3.9, 3.1 (cyclopropyl CH2’s); IR
nmax cmꢄ1 3430 (OH stretching); HRMS (JEOL MSRoute) m/z calcd
for C26H37NO4 (Mþ) 428.2800 found 428.2788, ESI MS m/z ¼ 428
[M þ H]þ; Anal. Calcd, for C26H37NO4: C, 73.03; H, 8.72; N, 3.28;
found C, 73.00; H, 8.70; N, 3.25.
4.2.2. Cytotoxicity evaluation [26,27]
4.2.2.1. In VERO cell line. Cell line was procured from laboratory
animal division of CDRI. The cell suspension was plated in 96-well
tissue culture plates at a density of 10,000 cells per well (in 200 mL)
in Dulbecco’s minimal essential medium (DMEM) with
antibiotics þ 10% fetal bovine serum (FBS). The monolayers were
then incubated overnight at 37 ꢀC and 5% CO2 for allowing adher-
ence of cells. Compounds of different concentrations (minimum
10ꢃ MIC) were added in DMEM þ 10% FBS. As a positive control,
a known toxic compound was used. DMSO was used as negative
4.1.3.25. {4-[2-(N,N-Dibutylamino)ethoxy]phenyl}cyclopropyl meth-
anone (54). It was obtained by the reaction of 2-(N,N-dibutylamino)
ethanol 53 (0.82 g, 4.09 mmol), NaH (60% dispersion in mineral oil,
0.39 g, 16.39 mmol), 4-chloro-40-fluorobutyrophenone (11) (1.0 mL,
4.09 mmol) and tetrabutylammonium bromide (0.26 g, 0.082 mmol)
by using the procedure as described for compound 12, to give
compound 54 as liquid; yield 1.45 g (75%); Rf ¼ 0.4 (methanol/
chloroform, 3:7); 1H NMR (200 MHz, CDCl3)
d
¼ 7.99 (dd, J1 ¼1.9 Hz,
J2 ¼ 6.9 Hz, 2H, ArH), 6.90 (dd, J1 ¼1.9 Hz, J2 ¼ 6.9 Hz, 2H, ArH), 4.07
control. After 24 h incubation, 20 mL of MTS solution (tetrazolium

S.S. Bisht et al. / European Journal of Medicinal Chemistry 45 (2010) 5965e5978
5977
compound, Owen’s reagent) was added to each well and incubated
for 2 h at 37 ꢀC, 5% CO2. Reading was taken at 490 nm using a plate
reader. Absorbance shown by DMSO containing wells was taken as
100% survivors. A compound is considered toxic if it causes 50%
inhibition at concentration 10-fold higher than its MIC.
orthophosphate (analytical reagent grade) was purchased from SD
fine chemicals Limited (Mumbai, India).
4.2.4.2. HPLC conditions. The HPLC system (Shimadzu, Kyoto,
Japan) was equipped with a pump (LC-10 ATvp), a PDA detector (LC-
10MAvp), a Rheodyne (Cotati, CA, USA) model 7125 in Jector with
4.2.2.2. In mouse bone marrow derived macrophages. Prior
permission of the institute’s ethics committee (CPCSEA registration
no. 34/1999 dated 11.3.99, extended up to 2012) had been taken for
performing in vivo experiments.
a 20 m
L loop. HPLC separation was achieved on a LichrosphereÒ
LichrocartÒ CN column (250 mm, 4 mm, 5
mm; Merck Ltd., Mumbai,
India) at 25 ꢅ 3 ꢀC.
The mobile phase was consisted of mixture of potassium dihy-
drogen phosphate buffer (0.01 M) and acetonitrile (30:70 v/v) at
a flow rate of 1 mL/min. Column effluent was monitored at 240 nm.
Data was acquired and processed using CLASS-VP software (version
6.14).
Mouse was euthanized by exposure to CO2 and the femur bones
were dissected out. The bones were trimmed at each end, and the
marrow was flushed out (using 26-gauge needle) with 5 mL of
Dulbecco’s minimal essential medium (DMEM) supplemented with
10% FBS, 15% L-929 fibroblast conditioned supernatant (prepared as
described below), and non-essential amino acids. Cells werewashed
twice and plated in 96-well tissue culture plates at a concentration
Acknowledgment
of 105 cells per well (100
mL) in supplemented DMEM. The mono-
This is a CDRI communication no. 7973. Surendra and Mridul
thank CSIR New Delhi for SRF, Namrata to UGC New Delhi for SRF
and Rahul to DRDO New Delhi for PA. We sincerely acknowledge
the financial assistance from DRDO and DBT New Delhi. SAIF CDRI is
also acknowledged for providing the spectral and microanalytical
data of the compounds.
layers were then incubated at 37 ꢀC in 5% CO2 with the medium
change every 3rd day. Macrophages were used 5 days later. Different
concentrations of compounds were added in antibiotic free, FBS
supplemented, DMEM and incubated at 37 ꢀC in 5% CO2. After 48 h,
20 mL of MTS solutionwas added to each well and incubated for 2 h at
37 ꢀC in 5% CO2. Reading was taken at 490 nm using a plate reader.
Absorbance shown by DMSO containing wells is taken as 100%
survivors. A compound is considered toxic if it causes 50% inhibition
at concentration 10-fold higher than its MIC.
Appendix. Supporting Information
All experimental details, biological assays, HPLC result, 1H NMR
and 13C NMR, HRMS spectral data of prototype compounds are
available free of charge via the internet at doi:10.1016/j.ejmech.
2010.09.063.
4.2.3. Ex vivo (macrophage) model of TB
4.2.3.1. Ex vivo assay for intracellular killing of M. tuberculosis H37Rv
[28]. Mouse macrophages were used after 5 days in culture as
described above. They were infected with 1ml suspension con-
taining 5 ꢃ 106 M. tuberculosis (H37Rv) in antibiotic-free DMEM
(with 10% FBS) and incubated for 3 h. After incubation, the wells
were thoroughly washed to remove the extracellular bacteria and
were later replenished with 1 mL antibiotic-free DMEM (with 10%
FBS) containing 5ꢃ MIC of compounds being tested. In order to
determine the number of bacilli that were phagocytosed during the
3-h incubation period, 1 well was lysed with 0.1% saponin (20 min),
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