Synthesis and antitubercular activity of substituted phenylmethyl- and pyridylmethyl amines

Article abstract of DOI:10.1016/j.bmc.2006.09.020

A total of 42 benzyl- and pyridylmethyl amines were synthesized either by reductive amination of aromatic/heteroaromatic aldehydes with amines or by conjugate addition of amines to the cinnamates followed by reduction of the ester group with lithium aluminium hydride to the respective propanolamines. All the synthesized compounds were evaluated against both avirulent and virulent strains of Mycobacterium tuberculosis. Many of the compounds exhibited MIC as low as 1.56 μg/mL. Few of potent compounds were also evaluated against clinical isolates of MDR TB and found to be active at one or other concentrations with MIC as low as 3.12 μg/mL.

Full text of DOI:10.1016/j.bmc.2006.09.020

Bioorganic & Medicinal Chemistry 14 (2006) 8186–8196
Synthesis and antitubercular activity of substituted
phenylmethyl- and pyridylmethyl amines
R. P. Tripathi,a,* Nisha Saxena,a V. K. Tiwari,a S. S. Verma,a Vinita Chaturvedi,b
Y. K. Manju,b A. K. Srivastva,b A. Gaikwadc and S. Sinhac
aMedicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
bMicrobiology, Central Drug Research Institute, Lucknow 226001, India
cDrug Target Discovery and Development Division, Central Drug Research Institute, Lucknow 226001, India
Received 23 August 2006; revised 9 September 2006; accepted 12 September 2006
Available online 28 September 2006
Abstract—A total of 42 benzyl- and pyridylmethyl amines were synthesized either by reductive amination of aromatic/heteroaromat-
ic aldehydes with amines or by conjugate addition of amines to the cinnamates followed by reduction of the ester group with lithium
aluminium hydride to the respective propanolamines. All the synthesized compounds were evaluated against both avirulent and
virulent strains of Mycobacterium tuberculosis. Many of the compounds exhibited MIC as low as 1.56 lg/mL. Few of potent
compounds were also evaluated against clinical isolates of MDR TB and found to be active at one or other concentrations with
MIC as low as 3.12 lg/mL.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
drops to as low as 2 months, against the 6 months stipu-
lated. The answer to these problems lies in the discovery
of new drugs with novel mode of action and shorter
duration of treatment along with better compliance
and reduced incidence of adverse reactions to drugs.4
Tuberculosis (TB) an infectious disease caused by differ-
ent species of mycobacteria represents a major public
health and socioeconomic problem in most of the devel-
oping countries.1 One-third of the World’s population (2
billion people) is infected with this disease, of which 16
million are active cases with an additional 8 million add-
ed every year. Mortality figures have reached 3 million
per year, with one-third of all AIDS patients eventually
dying of TB. Of the new cases, 22% are from India,
21% from Sub-Saharan Africa and another 21% from
other Asian Countries.2 The coincidence of tuberculosis
with the AIDS epidemic is an additional problem.3 isoni-
azid, rifampicin, ethambutol, pyrazinamide and many
other first and second line agents are known today to
treat tuberculosis. Even though in a qualitative manner,
the Directly Observed Short Course (DOTS) has been
successful, the fact is that only half the patients are diag-
nosed for treatment in the first place. Second half of the
rest do not complete the full course of treatment, leading
to emergence of Multi Drug Resistant (MDR) TB. In
weak monitoring cases the compliance with treatment
The new drugs should also be effective against latent
infections of TB, defined as TB that has not manifested
as a disease. Although number of new prototype leads
are known today and the effort to get the best com-
pound for the treatment of this devastating disease is
still on globally, yet no new chemical entity has yet
entered into clinics since 1966.5
Since the beginning of medical history chemotherapeutic
principles of various amine derivatives have been known
either as therapeutic agents or as biological tools.6 It is
the lone pair of electrons on nitrogen imparting it the
unique feature to act as a proton acceptor, which makes
it one of the largest acid scavengers used in the synthesis
of pharmaceuticals. Bacteriostatic activity in tertiary
amines and quaternary ammonium salts, p-toluidine
moiety have been reported long back.7 A number of aro-
matic and heteroaromatic amines were synthesized and
evaluated for their antitubercular efficacy and some of
them possess very good antitubercular activities.8 Struc-
ture–activity relationship has been discussed in this class
of compounds previously. N-Alkyl benzylamines (A)
Keywords: Tuberculosis; MDR TB; Phenylmethyl amines; Antituber-
cular agents; Reductive amination CDRI Communication No. 7035.
*
Corresponding author. Tel.: +91 522 2612412x4462/4382; fax: +91
522 26123405; e-mail: rpt_56@yahoo.com
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.09.020

R. P. Tripathi et al. / Bioorg. Med. Chem. 14 (2006) 8186–8196
8187
have been reported to be specific antitubercular com-
pounds as they are inactive against a number of
Gram-positive, Gram-negative bacteria and fungi.9
Detailed structure activities in this class of compounds
have been reported, some of the compounds of this
series viz. bromohexine and ambroxol isolated from
Indian shrub Adhatoda vasicca widely used as mucolyt-
ics have shown pH-dependent growth inhibitory effect
on Mycobacterium tuberculosis.10
agents we were interested to synthesize some benzyl
amine derivatives, observe the effect of various substitu-
ents in the benzene ring and alkyl chain and evaluate
them for their antitubercular efficacy.
2. Results and discussion
2.1. Chemistry
We have recently discovered new prototype amine
hybridized molecules as potent antitubercular both from
sugars and nonsugars.11 It has been reported that these
compounds are concentrated in macrophages where the
mycobacterium resides; they might exert a clinically sub-
stantial effect on intracellular tubercle bacilli. Further, it
has also been established that such compounds have cer-
tain indirect effect on enhancing the antitubercular activ-
ities. Such compounds elevate the lysozyme levels in
bronchial secretion12 and levels of rifampicin in lung tis-
sue and sputum and thereby help in clearance of bacilli
laden mucus from cavities and bronchi.13 Thus these
compounds may be useful as potential adjunctive in
the treatment of tuberculosis (Fig. 1).
The first series of compounds without any substituents
at the methylene carbon of the phenyl (pyridyl)
methyl amine and in the side-chain alkyl moiety at
the nitrogen atom were prepared by reductive amina-
tion process involving different methods reported so
far. Out of all the methods used for this, the reaction
of aromatic (heteroaromatic) aldehydes with amines in
˚
presence of dehydrating agents (4 A mol Sieves) fol-
lowed by reduction of the intermediate imines with
sodium borohydride proved to be the best one with
respect to economy and yields. Thus reaction of
appropriate aromatic aldehydes and selected amines
˚
in dichloromethane in presence of 4 A mol Sieves
resulted in the intermediate Schiff’s bases, which were
reduced in situ either with NaBH4 to give the phenyl
(pyridyl) methyl amine derivatives (1–19) in very
good yields (Scheme 1). All of these compounds were
Keeping the above facts in mind and in continuation of
our work on the development of new antitubercular
OH
1
R
-
-
+
Cl
Cl
-
Br
NH
Cl
H
Br
NH
2
N
H
2
+
+
Br
Br
Bromhexine
A
Amboxol
Figure 1. Antitubercular benzylamines.
H
NaBH4/MeOH/ 0-30 ˚C
anhyd. CH2Cl2
ArCH2NHR
NR
ArCHO
+
RNH2
4Å mol. Sieves, 0-25 oC
Ar
1-19
Compds Ar
R
1.
2.
3.
4.
4-Hydroxy - 3-methoxy phenyl
4-Hydroxy-3-methoxy phenyl
4-Hydroxy - 3-methoxy phenyl
4-Florophenyl
cycloproyl
n-Hexadecyl
n-Octadec-9-enyl
n-Hexdecyl
5.
6.
7.
8.
4-Florophenyl
n-Octadec-9-enyl
n-Octadec-9-enyl
n-Dodecyl
3,4-Dimethoxyphenyl
2-Hydroxyphenyl
2-Hydroxy phenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
2-Nitrophenyl
n-Octadec-9-enyl
n-Octyl
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
n-Dodecyl
n-Hexadecyl
n-Octadec-9-enyl
n-Octyl
4-Pyridyl
n-Octyl
4-Pyridyl
n-Hexadecyl
n-Octadec-9-enyl
n-Hexadecyl
n-Octadec-9-enyl
n-Dodecyl
4-Pyridyl
3-Pyridyl
3-Pyridyl
2-Pyridyl
Scheme 1. Synthesis of phenyl (pyridyl) methyl amines.

8188
R. P. Tripathi et al. / Bioorg. Med. Chem. 14 (2006) 8186–8196
(CH2)n
(CH2)n
anhyd. CH2Cl2
ArCHO
N
N
+
NH2
NH2
4Å mol. Sieves, 0-25 oC
Ar
Ar
NaBH4/MeOH/ 0-30 oC
Compds Ar
n
3
20.
21.
22.
23.
24.
2-Hydroxyphenyl
2-Hydroxyphenyl
2-Hydroxyphenyl
2-Hydroxyphenyl
3-Hydroxyphenyl
5
7
12
5
Ar
HN
20-24
n N
H
Ar
Scheme 2. Synthesis of diphenyl methyl diamines.
characterized on the basis of spectral data and
microanalysis.
were not isolated, however characterized in few instanc-
es. As the esters were not very active against M. tubercu-
losis we reduced the ester group into alcohols in some
selected compounds to see its effect on antitubercular
profile. Thus compounds 32, 37 and 38 on reduction
with lithium aluminium hydride in tetrahydrofuran led
to the formation of respective alcohols 46–48 in good
yields (Scheme 3). The structures of all the compounds
were established on the basis of spectroscopic analysis
and analytical data.
Since diamines and polyamines based on the structure of
spermine and spermidine are known to have antiparasit-
ic and antimicrobial activities and that the antitubercu-
lar activity is enhanced by increase in hydrophobic
character, hence in the next attempt diaryl diamines
were prepared to see their effect on the bacterium. Thus
reaction of two equivalents of aromatic aldehydes with
one equivalent of selected diamines separately using
the above reductive amination strategy led to the forma-
tion of respective N1,Nn-diarylmethyl-diamines (20–24)
in excellent yields (Scheme 2).
2.2. Biological activity
All the synthesized compounds were evaluated against
M. tuberculosis H37 Ra and M. tuberculosis H37 Rv
strains following earlier protocol.15,16 Among all the
42 compounds screened for anti-TB activity except com-
pounds 11, 14, 20, 21, 22, 31, 33, 36, 37, 39, 41, 42, 43, 44
and 45 other compounds of the series were found to be
active at one or the other concentration ranging from
12.5 to 1.56 lg/mL. By closer look into structure–activ-
ity relationship of the compounds, it is evident that
The cinnamates 25–30 were prepared by literature meth-
ods.14 Thus conjugate addition of selected amines with
the above cinnamates separately led to the formation
of respective ethyl 3-amino-3-phenyl propionates 31–
45 in moderate to good yields (Scheme 3). It is appropri-
ate to mention here that in the above reaction very low
yields of the propenamides were also obtained which
R
O
O
HN
DBU/ Ethanol
80-100 oC
OC2H5
OC2H5
( 32, 37, 38 )
Ar
25-30
Ar
31-45
Compds Ar
R
LiAlH4/THF, 0-30 o
C
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
3-Chlorophenyl
3-Chlorophenyl
3-Chlorophenyl
3-Chlorophenyl
3-Chlorophenyl
3-Nitrophenyl
3-Nitrophenyl
3-Nitrophenyl
3-Nitrophenyl
3-Nitrophenyl
4-Nitrophenyl
4-Nitrophenyl
2-Nitrophenyl
4-Florophenyl
Phenyl
n-Butyl
n-Octyl
n-Dodecyl
Pyrrolididene
Phenylmethyl
n-Butyl
R
HN
n-Octyl
OH
n-Dodecyl
Pyrrolididene
Phenylmethyl
n-Octyl
n-Dodecyl
n-Dodecyl
n-Octyl
Ar
46-48
Compds Ar
R
46.
47.
48.
3-Chlorophenyl n-Octyl
n-Octyl
3-Nitrophenyl
3-Nitrophenyl
n-Octyl
n-Dodecyl
Scheme 3. Synthesis of phenylmethyl amino esters and amino alcohols.

R. P. Tripathi et al. / Bioorg. Med. Chem. 14 (2006) 8186–8196
8189
Table 1. Antitubercular activities of synthesized phenylmethyl- and pyridylmethyl amines against M. tuberculosis H37Ra and M. tuberculosis H37Rv
Compound
R1
NR2
MIC H37Ra
(lg/mL)
MIC H37Rv
(lg/mL)
R
1
2
3
3-Methoxy-4-hydroxyphenyl
3-Methoxy-4-hydroxyphenyl
3-Methoxy-4-hydroxyphenyl
H
H
H
>25
>25
>25
12.5a
3.12a
1.56a
25b
NH
n-Hexadecyl-NH–
n-(9-Octadecenyl)-NH–
4
5
6
4-Fluorophenyl
4-Fluorophenyl
3,4-Dimethoxyphenyl
H
H
H
n-Hexadecyl-NH–
n-(9-Octadecenyl)-NH–
n-(9-Octadecenyl)-NH–
<25
>25
<25
12.5a
12.5a
3.12a
6.25b
6.25a
25b
1.56a
3.12b
12.5a
3.12a
25a
3.12a
25b
12.5a
25a
3.12a
3.12b
6.25a
50b
3.12a
3.12b
3.12a
25b
1.56a
25a
25a
25a
7
8
2-Hydroxyphenyl
2-Hydroxyphenyl
H
H
n-Dodecyl-NH–
<25
<25
n-(9-Octadecenyl)-NH–
9
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
H
H
H
H
n-Octyl-NH–
n-Dodecyl-NH–
<25
<25
>25
<25
10
11
12
n-Hexadecyl-NH–
n-(9-Octadecenyl)-NH–
13
14
15
2-Nitrophenyl
4-Pyridyl
4-Pyridyl
H
H
H
n-Octyl-NH–
n-Octyl-NH–
n-Hexadecyl-NH–
<25
>25
<25
16
17
18
4-Pyridyl
3-Pyridyl
3-Pyridyl
H
H
H
n-(9-Octadecenyl)-NH–
n-Hexadecyl-NH–
<25
<25
<25
n-(9-Octadecenyl)-NH–
19
20
21
22
23
24
31
32
33
2-Pyridyl
H
n-Dodecyl-NH–
–NH(CH2)3NH–
–NH(CH2)5NH–
–NH(CH2)7NH–
–NH(CH2)12NH–
–NH(CH2)5NH–
n-Butyl-NH–
<25
>25
>25
<25
<25
>25
>25
>25
>25
2-Hydroxyphenyl
2-Hydroxyphenyl
2-Hydroxyphenyl
2-Hydroxyphenyl
3-Hydroxyphenyl
3-Chlorophenyl
3-Chlorophenyl
3-Chlorophenyl
H
H
H
H
3.12a
6.25a
25a
12.5a
25a
H
2-Carbethoxymethyl
2-Carbethoxymethyl
2-Carbethoxymethyl
n-Octyl-NH–
n-Dodecyl-NH–
34
3-Chlorophenyl
2-Carbethoxymethyl
>25
12.5a
N
35
36
37
38
3-Chlorophenyl
3-Nitrophenyl
3-Nitrophenyl
3-Nitrophenyl
2-Carbethoxymethyl
2-Carbethoxymethyl
2-Carbethoxymethyl
2-Carbethoxymethyl
C6H5CH2NH–
n-Butyl-NH–
n-Octyl-NH–
n-Dodecyl-NH–
>25
>25
>25
12.5a
25a
25a
6.25a
39
3-Nitrophenyl
2-Carbethoxymethyl
>25
25a
N
40
41
3-Nitrophenyl
4-Nitrophenyl
4-Nitrophenyl
2-Nitrophenyl
4-Fluorophenyl
Phenyl
2-Carbethoxymethyl
2-Carbethoxymethyl
2-Carbethoxymethyl
2-Carbethoxymethyl
2-Carbethoxymethyl
2-Carbethoxymethyl
2-Hydroxyethyl
C6H5CH2NH–
n-Octyl-NH–
n-Dodecyl-NH–
n-Dodecyl-NH–
n-Octyl-NH–
n-Octyl-NH–
n-Octyl-NH–
n-Octyl-NH–
n-Dodecyl-NH–
>25
<25
>25
<25
>25
<25
<25
<25
<25
12.5a
25a
42
43
25a
25a
44
45
25a
25a
46
47
3-Chlorophenyl
3-Nitrophenyl
3-Nitrophenyl
12.5a
12.5a
12.5a
0.65a
>1.56b
0.75a
>40b
3.25a
2-Hydroxyethyl
2-Hydroxyethyl
48
INH
Rifmp
Ethm
MIC, Minimum inhibitory concentration, the concentration of the test compound at which complete (>99%) inhibition of the bacterial colonies was
observed. INH, isoniazid; Rifmp, rifampicin; Ethm, ethambutol.
a MIC against sensitive strains.
b MIC against clinical isolates of MDR TB.

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R. P. Tripathi et al. / Bioorg. Med. Chem. 14 (2006) 8186–8196
substitution in aromatic ring by any of the group like
hydroxy, methoxy, fluoro, chloro and nitro affects the
activity profile. Compounds with aromatic ring having
fluoro group are more active than the compounds with
chloro group. Substitution of the benzylic carbon in
these compounds either with carbethoxy or hydroxyl
ethyl substituent results in loss of activity. Among the
2-hydroxy phenylmethyl amine derivatives, compound
7 with 12-carbon chain substituent was found to be
active as MIC 6.25 lg/mL. Introduction of another 2-
hydroxy phenylmethyl amine (compound 23) moiety
leads to an increase in the activity profile of the com-
pounds against M. tuberculosis H37 Rv as the MIC
was found to be 3.12 lg/mL. In general, hydroxyl substi-
tuent in the aromatic ring at position-2 leads to measur-
able increase in activity profile as compared to
substitution at the other positions. Among the disubsti-
tuted compounds in benzene ring the best compound is
3 with 4-hydroxy-3-methoxy phenyl ring having MIC
1.56 lg/mL. Substitution of the hydroxyl group with
methoxy group in the disubstituted phenyl ring, for
example, compound 6 results in deterioration of its
activity profile as MIC is higher (3.12 lg/mL). Among
the pyridyl methyl amines almost all the compounds dis-
played activity at one or other concentration ranging
from 25 to 1.56 lg/mL. Among the compounds of
pyridyl series the activity trend is in the order of
2-pyridyl > 3-pyridyl > 4-pyridyl as evident from the
antitubercular activity of compounds 14–18. It is also
evident that most of these compounds are active in
infectious strain (M. tuberculosis H37 Rv) only and inac-
tive against avirulent strain (M. tuberculosis H37 Ra),
indicating that they are more specific to the virulent
strain. Many compounds having MIC < 6.25 mg/mL
were screened against clinical isolates of drug resistant
tuberculosis strain also and found to be active either
at the same concentration used for H37Rv or higher
than that shown in Table 1.
to monitor the reactions. IR (KBr) spectra were recorded
using Perkin-Elmer 881 spectrophotometer and the
values are expressed as mmax cmꢀ1. Mass spectral data
were recorded on a Jeol (Japan) SX 102/DA-6000 Mass
Spectrometer/Data system. The 1H NMR and 13C
NMR spectra were recorded on Bruker Spectrospin
spectrometer at 200 or 300 and 50 MHz, respectively,
using TMS as internal standard. The chemical shift values
are on d scale and the coupling constants (J) are in Hz.
4.2. Synthesis of compounds 1–19
4.2.1. 4-(Cyclopropylaminomethyl)-2-methoxyphenol (1).
Typical procedure: To a magnetically stirred solution of
4-hydroxy-3-methoxybenzaldehyde (2.0 g, 13.10 mmol)
˚
and 4 A mol Sieves. in dichloromethane (7 mL), cyclo-
propyl amine (0.90 mL, 13.10 mmol) was added and
stirring continued for 3.0 h untill the disappearance of
starting material (TLC). The solvent was evaporated
under reduced pressure and the residue, so obtained,
was dissolved in methanol (5 mL). NaBH4 (0.18 g,
4.98 mmol) was added slowly at 0 ꢁC and stirring con-
tinued for additional 4 h. The reaction mixture was
quenched with saturated ammonium chloride solution.
The reaction mixture was filtered, solvent evaporated
under reduced pressure and the residue, so obtained,
was dissolved in ethyl acetate (60 mL), washed with
water (2 · 20 mL) followed by saturated aqueous NaCl
solution (2 · 20 mL) and organic layer dried over anhyd
Na2SO4. The organic layer was concentrated under re-
duced pressure to obtain a crude product which was
chromatographed over SiO2 using hexane/ethyl acetate
(7:3) to give compound 1 as colourless liquid (yield,
2.31 g, 92%); IR (KBr): mmax 3450, 3276, 2940 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 6.86–6.79 (m, 3H,
ArH), 3.85 (s, 3H, OCH3), 3.50 (br s, 1H, OH), 3.75
(s, 2H, CH2Ar), 2.17–2.13 (m, 1H, CH), 0.45–0.40 (m,
4H, 2· CH2); FABMS m/z 194 [M+H]+; Anal. Calcd
for C11H15NO2: C, 68.39; H, 7.77; N, 7.25. Found: C,
68.42; H, 7.78; N, 7.30.
3. Conclusion
4.2.2. 4-(Hexadecylaminomethyl)-2-methoxyphenol (2).
Obtained by reaction of 4-hydroxy-3-methoxybenzalde-
hyde (1.68 g, 11.05 mmol) and hexadecylamine (2.58 g,
11.05 mmol) as described above gave (2) as colourless
solid (3.55 g, 90%); mp 130 ꢁC IR (KBr): mmax 3459,
In conclusion we have synthesized different phenylmeth-
yl and pyridylmethyl amines in a straightforward
manner using reductive amination or Michael type
1,4-conjugate addition of amines followed by further
desired manipulations. All the compounds were
screened against avirulent and virulent strains of
M. tuberculosis. Most of the compounds displayed high
order of activity and the selected compounds were also
evaluated against clinical isolates of MDR TB showing
potent activity.
1
3287 cmꢀ1; H NMR (300 MHz, CDCl3): d 6.86–6.78
(m, 3H, ArH), 3.89 (br s, 1H, OH), 3.86 (s, 3H,
OCH3), 3.70 (s, 2H, CH2Ar), 2.62 (t, J = 6.0 Hz, 2H,
NCH2), 1.51 (br s, 1H, NH), 1.26–1.24 (m, 28H, 14·
CH2), 0.88 (t, J = 6.0 Hz, 3H, CH3); 13C NMR
(50 MHz, CDCl3): d 147.3, 145.4, 132.2, 121.4, 114.9,
111.4, 75.2, 75.0, 56.1, 54.3, 49.8, 32.3, 32.1, 30.2, 30.1,
30.0, 30.0, 30.0, 29.9, 29.7, 27.7, 27.5 23.0, 14.5; FABMS
m/z 378 (M+H)+; Anal. Calcd for C24H43NO2: C, 76.39;
H, 11.40; N, 3.71. Found: C, 76.42; H, 11.48; N, 3.74.
4. Experimental
4.1. General methods
4.2.3. 2-Methoxy-4-(octadec-9-enylamino) phenol (3).
Obtained by reaction of 4-hydroxy-3-methoxybenzalde-
hyde (1.42 g, 9.34 mmol) and octadec-9-enylamine
(3.03 mL, 9.34 mmol) as described above. Colourless li-
quid in (3.37 g, 90%) yield; IR (KBr): mmax 3398,
Melting points were determined on a Buchi 510 appara-
tus. Elemental analyses for all compounds were per-
formed on a Carlo Erba Model EA-1108 elemental
analyzer and data of C, H and N are within 0.4% of
calculated values. Thin-layer chromatography was used
3020 cmꢀ1 1H NMR (200 MHz, CDCl3) d 7.26–6.78
;

R. P. Tripathi et al. / Bioorg. Med. Chem. 14 (2006) 8186–8196
8191
1
(m, 3H, ArH), 5.36–5.34 (m, 2H, –CH@), 3.86 (s, 3H,
OCH3), 3.70 (s, 2H, CH2Ar), 3.20 (br s, 1H, OH), 2.62
(t, J = 7.0 Hz, 2H, NCH2), 2.01–1.99 (m, 4H, 2· CH2),
1.51 (br s, 1H, NH), 1.27–1.25 (m, 24H, 12· CH2),
0.87 (t, J = 6.7 Hz, 3H, CH3), 13C NMR (50 MHz,
CDCl3): d 147.1, 145.2, 132.3, 130.8, 130.3, 130.2,
121.4, 114.7, 111.3, 56.2, 54.3, 49.7, 32.9, 32.3, 31.9,
30.8, 30.2, 30.1, 30.0, 29.9, 29.7, 29.6, 27.7, 27.6, 23.0,
14.4; FABMS m/z 404 [M+H]+; Anal. Calcd for
C26H45NO2: C, 77.41; H, 11.16; N, 3.47. Found: C,
77.48; H, 11.19; N, 3.41.
2919 cmꢀ1; H NMR (200 MHz, CDCl3): d 7.25–6.75
(m, 5H, OH, ArH), 3.97 (s, 2H, CH2Ar), 2.66 (t,
J = 7.1 Hz, 2H, NCH2), 1.52 (br s, 1H, NH) 1.35–1.16
(m, 20H, 10· CH2), 0.88 (t, J = 6.4 Hz, 3H, CH3), 13C
NMR (50 MHz, CDCl3): d 158.8, 129.0, 128.5, 123.0,
119.2, 116.7, 53.1, 49.2, 32.3, 30.3, 30.3, 30.2, 30.0,
29.7, 29.8, 29.7, 27.5, 23.0, 14.5; FABMS: m/z 292
[M+H]+; Anal. Calcd for C19H33NO: C, 78.35; H,
11.34; N, 4.81. Found: C, 78.33; H, 11.30; N, 4.81.
4.2.8. 2-(Octadec-9-en-1-yl-amino-methyl)-phenol (8).
Obtained by reaction of 2-hydroxybenzaldehyde
(1.50 g, 12.2 mmol) and octadec-9-enylamine (4.0 mL,
12.2 mmol), viscous liquid in (4.10 g, 90%); IR (KBr):
4.2.4. (4-Fluorophenylmethyl)hexadecylamine (4). Ob-
tained by reaction of 4-fluorobenzaldehyde (1.50 g,
14.28 mmol) and hexadecylamine (3.54 g, 14.47 mmol)
as described above gave 4 as colourless liquid in
mmax 3020, 2929 cmꢀ1; H NMR (200 MHz, CDCl3): d
1
8.30 (s, 1H, OH), 7.25–6.79 (m, 4H, ArH), 5.36–5.34
(m, 2H, –CH@), 3.96 (s, 2H, CH2Ar), 2.64 (t,
J = 6.9 Hz, 2H, NCH2), 2.02–1.99 (m, 4H, 2· CH2),
1.54 (br s, 1H, NH), 1.28–1.15 (m, 24H, 12· CH2),
0.87 (t, J = 6.7 Hz, 3H, CH3), 13C NMR (50 MHz,
CDCl3): d 158, 131.2, 130.8, 130.7, 128.2, 123.4, 123.0,
116.7, 116.6, 53.1, 49.0, 33.0, 32.2, 30.1, 30.1, 30.0,
30.0, 29.9, 29.8, 29.6, 27.6, 27.6, 27.5, 23.0, 14.5; FAB-
MS: m/z 374 [M+H]+; Anal. Calcd for C25H43NO: C,
80.42; H, 11.52; N, 3.75. Found: C, 80.48; H, 11.49;
N, 3.81.
(4.70 g, 95%) yield; IR (KBr): mmax 3393, 2926 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.29 (d, J = 8.2 Hz,
1H, ArH), 7.25 (d, J = 8.2 Hz, 1H, ArH), 7.04 (d,
J = 8.6 Hz, 1H, ArH), 6.97 (d, J = 8.6 Hz, 1H, ArH),
3.74 (s, 2H, CH2Ar), 2.60 (t, J = 7.1 Hz, 2H, NCH2),
1.66 (br s, 1H, NH), 1.48–1.49 (m, 2H, CH2), 1.27–
1.22 (m, 26H, 13· CH2), 0.87 (t, J = 6.6 Hz, 3H, CH3);
FABMS: m/z 350 [M+H]+; Anal. Calcd for C23H40FN:
C, 79.08; H, 11.46; N, 4.01. Found: C, 79.00; H, 11.50;
N, 4.08.
4.2.5. (4-Fluorophenylmethyl)-octadeca-9-enyl amine (5).
Obtained by reaction of 4-fluorobenzaldehyde (1.50 g,
14.28 mmol) and octadec-9-enylamine (4.67 mL,
14.28 mmol) as described above. Colourless liquid
(4.70 g, 90%) yield; IR (KBr): mmax 3400, 3020,
4.2.9. N-(4-Chlorobenzyl)octylamine (9). The reaction of
4-chlorobenzaldehyde (1.8 g, 12.85 mmol) and octyl-
amine (2.16 mL, 12.2 mmol) gave 9 as colourless solid
in (2.96 g, 92%) yield; mp 142–143 ꢁC; IR (KBr): mmax
1
3400, 3020, 2928 cmꢀ1; H NMR (200 MHz, CDCl3):
1
2928 cmꢀ1; H NMR (200 MHz, CDCl3): d 7.27–7.02
d 7.46 (d, J = 8.4, Hz, 2H, ArH), 7.33 (d, J = 8.4, Hz,
2H, ArH) 3.92 (s, 2H, CH2Ar), 2.69 (t, J = 8.0 Hz, 2H,
NCH2), 1.74–1.67 (m, 2H, CH2), 1.26–1.22 (m, 10H,
5· CH2), 0.87 (t, J = 6.7 Hz, 3H, CH3). FABMS: m/z
254 [M+H]+; Anal. Calcd for C15H24ClN: C, 71.14; H,
9.48; N, 5.53. Found: C, 71.18; H, 9.44; N, 5.55.
(m, 4H, ArH), 5.36–5.32 (m, 2H, –CH@CH–), 3.72 (s,
2H, CH2Ar), 2.58 (t, J = 7.1 Hz, 2H, NCH2), 2.02–
1.96 (m, 4H, 2· CH2), 1.48 (br s, 1H, NH), 1.28–1.24
(m, 24H, 12· CH2), 0.87 (t, J = 6.7 Hz, 3H, CH3); FAB-
MS: m/z 376 [M+H]+; Anal. Calcd for C25H42FN: C,
80.00; H, 11.27; N, 3.73. Found: C, 80.05; H, 11.19;
N, 3.78.
4.2.10. N-(4-Chlorobenzyl)dodecylamine (10). Obtained
by
14.20 mmol) and dodecylamine (3.27 mL, 14.2 mmol).
reaction
of
4-chlorobenzaldehyde
(2.00 g,
4.2.6. (3,4-Dimethoxyphenylmethyl)octadec-9-enyl amine
(6). Obtained by reaction of 3,4-dimethoxybenzaldehyde
(1.7 g, 10.24 mmol) and octadec-9-enylamine (3.3 mL,
10.24 mmol). Colourless oil (3.90 g, 92%) yield; IR
Colourless solid, yield (3.90 g, 90%); mp 150–151 ꢁC;
IR (KBr): mmax 3400, 3020, 2928 cmꢀ1
;
1H NMR
(200 MHz, CDCl3): d 7.54 (d, J = 8.4, Hz, 2H, ArH),
7.35 (d, J = 8.4 Hz, 2H, ArH), 3.98 (s, 2H, CH2Ar),
2.72 (t, J = 8.2, Hz, 2H, NCH2), 1.8–1.79 (m, 2H,
CH2), 1.25–1.16 (m, 18H, 9· CH2), 0.87 (t, J = 6.7 Hz,
3H, CH3); FABMS: m/z 310 [M+H]+; Anal. Calcd for
C19H32ClN: C, 73.78; H, 10.35; N, 4.53. Found: C,
73.75; H, 10.29; N, 4.52.
(KBr): mmax 3425, 3002 cmꢀ1 1H NMR (200 MHz,
;
CDCl3): d 7.26 (s, 1H, ArH), 6.89 (two d, J = 11.6 Hz,
1.6 Hz, 2H, ArH), 5.36–5.34 (m, 2H, –CH@CH), 3.88,
3.86 (s, 6H, 2· OCH3), 3.73 (s, 2H, CH2Ar), 2.62 (t,
J = 7.1 Hz, 2H, NCH2), 2.02–1.97 (m, 4H, 2· CH2),
1.63 (bs, 1H, NH), 1.26–1.23 (m, 24H, 12· CH2), 0.87
(t, J = 6.7 Hz, 3H, CH3), 13C NMR (50 MHz, CDCl3):
d 149.3, 148.4, 133.5, 130.6, 130.1, 120.5, 111.8, 111.4,
56.1, 56.2, 54.2, 49.8, 32.9, 32.2, 32.1, 30.4, 30.2, 30.0,
30.0, 29.9, 29.8, 29.6, 27.9, 27.7, 27.5, 23.0, 14.4; FAB-
MS: m/z 418 [M+H]+; Anal. Calcd for C27H47NO2: C,
77.69; H, 11.27; N, 3.35. Found: C, 77.55; H, 11.32;
N, 3.41.
4.2.11. N-(4-Chlorobenzyl)-hexadecylamine (11). Ob-
tained by reaction of 4-chlorobenzaldehyde (1.50 g,
10.70 mmol) hexadecylamine (2.58 g, 10.00 mmol). Col-
ourless granules, (3.50 g, 90%); mp 158–159 ꢁC; IR
(KBr): mmax 3393, 2926, 1605 cmꢀ1
;
1H NMR
(200 MHz, CDCl3): d 7.34–7.24 (m, 4H, ArH), 3.70 (s,
2H, CH2Ar), 2.60 (t, J = 8.1 Hz, 2H, NCH2), 1.95–
1.92 (m, 2H, CH2), 1.29–1.19 (m, 26H, 13· CH2), 0.87
(t, J = 6.6 Hz, 3H, CH3). FABMS: m/z 366 [M+H]+;
Anal. Calcd for C23H40ClN: C, 75.61; H, 10.95; N,
3.83. Found: C, 75.58; H, 10.98; N, 3.80.
4.2.7. 2-(Dodecylaminomethyl)-phenol (7). Obtained by
reaction of 2-hydroxybenzaldehyde (2.00 g, 16.3 mmol)
and dodecylamine (3.76 mL, 16.2 mmol) as colourless li-
quid (4.02 g, 85%) yield; IR (KBr): mmax 3266,

8192
R. P. Tripathi et al. / Bioorg. Med. Chem. 14 (2006) 8186–8196
4.2.12.
N-(4-Chlorobenzyl)-octadec-9-ene-1-yl-amine
(m, 2H, CH2), 1.40–1.18 (m, 26H, 13· CH2), 0.88 (t,
J = 5.8 Hz, 3H, CH3); FABMS: m/z 358 (M+H)+; Anal.
Calcd for C24H42N2: C, 80.44: H, 11.73: N, 7.82. Found:
C, 80.40: H, 11.69: N, 7.85.
(12). Obtained by reaction of 4-chlorobenzaldehyde
(1.50 g, 10.7 mmol) and octadec-9-enylamine (3.52 mL,
10.4 mmol) as described above as colourless liquid yield
(3.83 g, 92%); IR (KBr): mmax 3400, 3020, 2928,
1511 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.28 (d,
4.2.17. N-(3-Pyridylmethyl)hexadecylamine (17). Ob-
tained by reaction of 3-pyridylcarboxaldehyde (2.0 g,
18.6 mmol) and hexadecylamine (4.48 g, 18.8 mmol).
Colourless solid, yield (5.55 g, 90%); mp 89–90 ꢁC; IR
J = 8.0 Hz, 2H, ArH), 7.25 (d, J = 8.0 Hz, 2H, ArH),
5.38–5.32 (m, 2H, –CH@CH), 3.74 (s, 2H, CH2Ar),
2.59 (t, J = 6.5 Hz, 2H, NCH2), 2.01–1.97 (m, 4H, 2·
CH2), 1.37–1.15 (m, 24H, 12· CH2), 0.87 (t,
J = 6.7 Hz, 3H, CH3). FABMS: m/z 392 [M+H]+; Anal.
Calcd for C25H42ClN: C, 76.72; H, 10.74; N, 3.58.
Found: C, 76.77; H, 10.70; N, 3.55.
(KBr): mmax 3267, 2920, 1578 cmꢀ1
;
1H NMR
(200 MHz, CDCl3): d 8.61 (m, 2H, PyH), 7.61 (m, 1H,
PyH), 7.30 (m, 1H, PyH), 3.81 (s, 2H, NCH2), 2.61 (t,
J = 4.0 Hz, 2H, CH2), 1.72 (s, 1H, NH), 1.49 (m, 2H,
CH2), 1.35–120 (m, 26H, 13· CH2), 0.88 (t,
J = 4.0 Hz, 3H, CH3). FABMS: m/z 333 (M+H)+; Anal.
Calcd for C22H40N2: C, 79.51: H, 12.04: N, 8.43. Found:
C, 79.45: H, 11.99: N, 8.48.
4.2.13. N-(2-Nitrobenzyl)octylamine (13). Obtained by
reaction of 2-nitrobenzaldehyde (2.0 g, 13.2 mmol) and
octylamine (2.1 mL, 13.3 mmol) as colourless liquid,
yield (3.12 g, 90%); IR (KBr): mmax 2926, 1529,
1461 cmꢀ1; H NMR (200 MHz, CDCl3): d 8.21 (br s,
4.2.18. N-(3-Pyridylmethyl)octadec-9-ene-1-ylamine (18).
Obtained by reaction of 3-pyridylcarboxaldehyde (2.0 g,
18.6 mmol) and hexadecylamine (6.13 mL, 18.6 mmol).
Viscous oil, yield (5.90 g, 90%); IR (KBr): mmax 3267,
1
1H, ArH), 8.09 (d, J = 8.0 Hz, 1H, ArH), 7.70 (d,
J = 7.6 Hz, 1H, ArH), 7.46 (dd, J = 7.9 Hz, 1H, ArH),
3.89 (s, 2H, CH2Ar), 2.62 (t, J = 7.1 Hz, 2H, NCH2),
1.51 (br s, 1H, NH) 1.34–1.12 (m, 12H, 6· CH2), 0.87
(t, J = 6.7 Hz, 3H, CH3), 13C NMR (50 MHz, CDCl3):
d 148.7, 143.3, 134.5, 129.5, 123.2, 122.3, 53.5, 49.9,
32.2, 30.4, 29.8, 29.6, 27.6, 23.0, 14.4; FABMS: m/z
265 [M+H]+; Anal. Calcd for C15H24N2O2: C, 68.18:
H, 9.09: N, 10.60. Found: C, 68.23: H, 9.15: N, 10.66.
1
2920, 1578 cmꢀ1; H NMR (200 MHz, CDCl3): d 8.53
(two d, J = 8.7 and 4.0 Hz, 2H, PyH), 7.68 (d,
J = 7.7 Hz, 1H, PyH), 7.26 (two d, J = 7.7 and 3.4 Hz,
1H, PyH), 5.34 (m, 2H, –CH@CH–), 3.78 (s, 2H,
NCH2), 2.61 (t, J = 4.0 Hz, 2H, NCH2), 1.72 (s, 1H,
NH), 1.49–1.46 (m, 2H, CH2), 1.35–1.18 (m, 26H, 13·
CH2), 0.88 (t, J = 4.0 Hz, 3H, CH3); FABMS: m/z 358
(M+H)+; Anal. Calcd for C24H42N2: C, 80.44; H,
11.73; N, 7.82. Found: C, 79.99: H, 11.99: N, 7.88.
4.2.14. N-(4-Pridylmethyl)-octylamine (14). Obtained by
reaction of 4-pyridylcarboxaldehyde (2.0 g, 18.6 mmol)
and octylamine (3.09 mL, 18.8 mmol) as viscous liquid
yield (3.70 g, 92%);; IR (KBr): mmax 3267, 2920,
4.2.19. N-(2-Pyridylmethyl)dodecylamine (19). Obtained
by reaction of 2-pyridylcarboxaldehyde (2.0 g,
18.6 mmol) and dodecylamine (4.3 mL, 18.8 mmol).
Colourless oil, yield (4.60 g, 90%); (KBr): mmax 3266,
1578 cmꢀ1 1H NMR (200 MHz, CDCl3): d 8.45 (m,
;
2H, PyH), 7.65 (m, 1H, PyH), 7.20 (m, 1H, PyH) 3.81
(s, 2H, NCH2), 2.61 (t, J = 4.0 Hz, 2H, CH2), 1.72 (s,
1H, NH), 1.49 (m, 2H, CH2), 1.35–120 (m, 10H, 5·
CH2), 0.88 (t, J = 4.0 Hz, 3H, CH3). FABMS: m/z 221
(M+H)+; Anal. Calcd for C14H24N2: C, 76.36: H,
10.90: N, 12.72. Found: C, 76.35: H, 10.96: N, 12.68.
2930 cmꢀ1 1H NMR (200 MHz, CDCl3): d 8.53 (d,
;
J = 4.8 Hz, 1H, PyH), 7.67 (dd, J = 7.4 Hz, 1.4 Hz,
1H, PyH), 7.28 (d, J = 7.7 Hz, 1H, PyH), 7.16 (m, 1H,
PyH), 4.75 (s, 2H, PyCH2), 3.89 (s, 2H,CH2), 3.10 (br
s, 1H, NH), 2.63 (t, J = 7.2 Hz, 2H, NCH2), 1.35–115
(m, 20H, 10· CH2), 0.88 (t, J = 5.6 Hz, 3H, CH3); 13C
NMR (50 MHz, CDCl3): d 150.0, 148.7, 136.1, 136.0,
123.6, 51.7, 49.9, 32.3, 30.4, 30.3, 30.2, 30.1, 30.0, 29.7,
29.6, 27.7, 23.0, 14.5; FABMS: m/z 277 (M+H)+; Anal.
Calcd for C18H32N2: C, 78.26: H, 11.59: N, 10.14.
Found: C, 78.22: H, 11.62: N, 10.20.
4.2.15. N-(4-Pyridylmethyl)-hexadecylamine (15). Ob-
tained by reaction of 4-pyridylcarboxaldehyde (2.0 g,
18.6 mmol) and hexadecylamine (4.8 g, 18.8 mmol) as
colourless solid yield (5.50 g, 90%); mp 143–144 ꢁC; IR
(KBr): mmax 3453, 3286, 2919, 1600 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 8.54 (d, J = 6.0 Hz, 2H, PyH),
7.26 (d, J = 6.0 Hz, 2H, ArH), 3.81 (s, 2H, NCH2),
2.61 (t, J = 6.0 Hz, 2H, NCH2), 1.72 (s, 1H, NH),
1.53–1.43 (m, 2H, CH2), 1.31–1.18 (m, 26H, 13· CH2),
0.88 (t, J = 6.0 Hz, 3H, CH3); FABMS: m/z 334
[M+H]+; Anal. Calcd for C22H40N2: C, 79.51: H,
12.04: N, 8.43. Found: C, 79.45: H, 11.99: N, 8.48.
4.3. Synthesis of compounds 20–24
4.3.1. N,N(Bis-2-hydroxybenzyl)-1,3-diaminopropane (20).
The reaction of 2-hydroxybenzaldehyde (3.0 g,
24.5 mmol) and 1,3 diaminopropane (1.0 mL,
12.2 mmol) as above gave 20 as light yellow granules,
yield (5.90 g, 85%); mp 65–66 ꢁC; IR (KBr): mmax 3481,
4.2.16. N-(4-Pyridylmethyl)-octadec-9-enylamine (16).
Obtained by reaction of 4-pyridylcarboxaldehyde
(2.0 g, 18.6 mmol) and octadec-9-enylamine (6.15 mL,
18.5 mmol). Viscous liquid (5.80 g, 90%); IR (KBr): mmax
1
3274, 2925, 1593 cmꢀ1; H NMR (200 MHz, CDCl3),
7.18–6.67 (m, 8H, ArH), 3.95 (s, 4H, CH2Ar), 2.71 (m,
4H, NCH2), 1.78–1.71 (m, 2H, CH2); 13C NMR
(50 MHz, CDCl3): d 158.5, 157.9, 129.1, 128.8, 123.0,
122.8, 119.8, 119.5, 119.1, 118.8, 116.7, 53.1, 52.7,
46.7, 30.0; FABMS: m/z 287 [M+H]+; Anal. Calcd for
C17H22N2O2: C, 71.32: H, 7.69: N, 9.79. Found: C,
71.36: H, 7.72,: N, 9.74.
3265, 2929 cmꢀ1; H NMR (200 MHz, CDCl3): d 8.52
1
(dd, J = 8.7 Hz, 4.7 Hz, 2H, PyH), 7.67 (d, J = 7.7 Hz,
1H, PyH), 7.28–7.24 (m, J = 7.7 Hz, 1H, PyH), 5.36–
5.32 (m, 2H, 2· –CH@) 3.81 (s, 2H, NCH2), 2.61 (t,
J = 4.0 Hz, 2H, NCH2), 1.72 (s, 1H, NH), 1.49–1.46

R. P. Tripathi et al. / Bioorg. Med. Chem. 14 (2006) 8186–8196
8193
4.3.2. N1,N5(Bis-2-hydroxybenzyl)-1,5-diaminopentane
(21). Obtained by reaction of 2-hydroxybenzaldehyde
(3.0 g, 24.5 mmol) and 1,5 diaminopentane (1.4 mL,
12.2 mmol). Colourless powder yield (6.13 g, 80%); mp
105–106 ꢁC; IR (KBr): mmax 3481, 3274, 2925,
2.0 g, 9.50 mmol) in ethanol was added butylamine
(0.9 mL, 9.50 mmol) followed by the addition of DBU
20 mol%. The reaction mixture was stirred for 8 h at
80 ꢁC, cooled and the solvent was evaporated under re-
duced pressure to give a crude mass.The latter was dis-
solved in ethyl acetate (65 mL) and washed with brine
(2 · 20 mL) followed by water (2 · 25 mL). The organic
layer dried (anhyd Na2SO4) was evaporated under re-
duced pressure to give a brown gum, which was chro-
matographed over SiO2 column, using hexane/ethyl
acetate (7:1) as eluent to give desired product 31 as vis-
cous liquid. Yield (1.6 g, 60%); IR (KBr): mmax 3338,
1593 cmꢀ1 1H NMR (200 MHz, CDCl3), 7.25–6.72
;
(m, 8H, ArH), 6.25 (br s, 2H, OH) 3.97–3.87 (m, 4H,
CH2Ar), 2.69–2.56 (m, 4H, NCH2), 1.76–1.70 (m, 2H,
CH2); 13C NMR (50 MHz, CDCl3): d 158.5, 157.9,
129.1, 128.8, 123.0, 122.8, 119.8, 119.5, 119.1, 118.8,
116.7, 53.1, 52.7, 46.7, 30.0. FABMS: m/z 314
[M+H]+; Anal. Calcd for C19H26N2O2: C, 72.61; H,
8.28; N, 8.91. Found: C, 72.66; H, 8.22; N, 8.94.
1731 cmꢀ1 1H NMR (200 MHz, CDCl3): d 7.33 (s,
;
1H, ArH); 7.23 (m, 3H, ArH), 4.07 (m, 3H, ArCH
and OCH2), 2.60 (t, J = 6.02 Hz, 2H, CH2), 2.40 (m,
2H, NCH2), 1.79 (s, 1H, NH), 1.40 (m, 4H, 2· CH2);
1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 0.86 (t,
J = 6.9 Hz, 3H, CH2CH3); 13C NMR (50 MHz, CDCl3):
d 171.9, 145.6, 134.7, 130.7, 127.9, 127.6, 125.6, 60.9,
59.7, 47.6, 43.2, 32.5, 20.7, 14.5, 14.3; FABMS: m/z
284 (M+H)+; Anal. Calcd for C15H22ClNO2: C, 63.60;
H, 7.77; N, 4.94. Found: C, 63.65; H, 7.80; N, 4.90.
4.3.3. N1,N7(Bis-2-hydroxybenzyl)-1,7-diaminoheptane
(22). Obtained by reaction of 2-hydroxybenzaldehyde
(3.0 g, 24.5 mmol) and 1,7 diaminoheptane (1.59 g,
12.2 mmol). Colourless granules yield (7.1 g, 85%); mp
1
108–109 ꢁC; IR (KBr): mmax 3266, 2919, 1603 cmꢀ1; H
NMR (200 MHz, CDCl3): d 7.15 (two d, J = 7.5 Hz,
2H, ArH), 7.15 (two d, J = 7.7 Hz, 4H, ArH), 4.86 (br
s, 2H, OH) 3.95 (s, 4H, CH2Ar), 2.63 (t, J = 6.7 Hz,
4H, NCH2), 1.48 (m, 4H, 2· CH2) 1.30 (m, 6H, 3·
CH2); 13C NMR (50 MHz, CDCl3): d 158.2, 129.1,
128.5, 128.1, 127.7, 125.0, 122.5, 119.7, 118.8, 116.2,
64.2, 52.6, 48.5, 29.3, 29.0, 26.9. FABMS: m/z 343
[M+H]+; Anal. Calcd for C21H30N2O2: C, 73.68; H,
8.77; N, 8.18. Found: C, 73.62; H, 8.75; N, 8.22.
4.4.2. Ethyl 3-octylamino-3-(3-chlorophenyl)-propionate
(32). Obtained by reaction of 3-(3-chlorophenyl)acrylic
acid ethyl ester (25, 2.00 g, 9.50 mmol) and octylamine
(1.57 mL, 9.5 mmol) as above. Colourless oil, yield
(2.24 g, 70%); IR (KBr): mmax 3336, 1731 cmꢀ1 1H
;
NMR (200 MHz, CDCl3): d 7.30 (m, 4H, ArH), 4.08
(m, 3H, ArCH and OCH2), 2.66 (m, 2H, NCH2),
2.40 (m, 2H, CH2CO–), 1.68 (br s, 1H, NH), 1.24
(m, 15H, 6· CH2 and CH3), 0.86 (t, J = 6.9 Hz, 3H,
CH3); 13CNMR (50 MHz, CDCl3): d 171.9, 145.6,
134.7, 130.1, 127.9, 127.6, 125.6, 60.9, 59.7, 47.9,
43.3, 32.2, 31.3, 30.4, 29.8, 29.6, 27.6, 23.0, 14.5; FAB-
MS: m/z 341 (M+H)+; Anal. Calcd for C19H30ClNO2:
C, 67.25; H, 8.84; N, 4.12. Found: C, 67.27; H, 8.88;
N, 4.10.
4.3.4. N1,N12(Bis-2-hydroxybenzyl)-1,12-diaminodode-
cane (23). Obtained by reaction of 2-hydroxybenzalde-
hyde (2.0 g, 16.3 mmol) and 1,12 diaminododecane
(1.62 g, 8.0 mmol). Colourless crystalline solid, yield
(5.70 g, 85%); mp 131–132 ꢁC; IR (KBr): mmax
1
3481 cmꢀ1; H NMR (200 MHz, CDCl3): d 7.19 (dd,
J = 7.4 Hz, 1.5 Hz, 2H, ArH), 6.94 (d, J = 6.8 Hz, 2H,
ArH), 4.53 (br s, 2H, OH), 3.98 (s, 4H, CH2Ar), 2.66
0
(t, J = 6.9 Hz, 4H, NCH2), 1.52 (m, 4H, CH2 s), 1.27–
0
1.23 (m, 16H, CH2 s); 13C NMR (50 MHz, CDCl3): d
158.7, 129.0, 128.6, 128.2, 123.0, 120.2, 119.3, 116.7,
64.8, 53.1, 49.1, 29.9, 27.5; FABMS: m/z 413 [M+H]+;
Anal. Calcd for C26H40N2O2: C, 75.72; H, 9.70; N,
6.79. Found: C, 75.76; H, 9.77; N, 6.79.
4.4.3. Ethyl 3-(3-chlorophenyl)-3-dodecylamino-propio-
nate (33). Obtained by reaction of 3-(3-chlorophe-
nyl)acrylic acid ethyl ester (25, 2.0 g, 9.50 mmol) and
dodecylamine (2.18 mL, 9.5 mmol) gave compound 33
as colourless liquid, yield (2.6 g, 70%); IR (KBr): mmax
4.3.5. N1,N5(Bis-3-hydroxybenzyl)-1,5-diaminopentane
(24). Obtained by reaction of 3-hydroxybenzaldehyde
(2.0 g, 16.3 mmol) and 1,5 diaminopentane (0.9 mL,
8.00 mmol). Viscous oil, yield (4.30 g, 85%); IR (KBr):
3335, 1733 cmꢀ1; H NMR (200 MHz, CDCl3): d 7.26
1
(m, 4H, ArH), 4.11 (m, 3H, ArCH and OCH2), 2.61
(m, 2H, CH2CO–), 2.41 (m, 2H, NCH2), 1.73 (br s,
1H, NH), 1.24 (m, 23H, 10· CH2 and CH3), 0.87 (t,
J = 6.9 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d
171.9, 145.6, 134.7, 130.1, 128.5, 127.9, 127.6, 125.6,
60.9, 59.7, 56.1, 47.9, 43.2, 41.4, 32.3, 30.4, 30.3, 30.2,
30.0, 29.7, 27.6, 23.0, 14.5; FABMS: m/z 396 (M+H)+;
Anal. Calcd for C23H38Cl NO2: C, 69.87; H, 9.62; N,
3.54. Found: C, 69.82; H, 9.59; N, 3.59.
1
mmax 3481, 3274 cmꢀ1; H NMR (200 MHz, CDCl3): d
7.19 (m, 3H, ArH), 6.94 (m, 3H, ArH), 6.83 (m, 2H,
ArH), 4.53 (br s, 2H, OH), 3.95 (s, 4H, CH2Ar), 2.78 (t,
J = 7.5 Hz, 4H, NCH2), 1.64 (m, 4H, 2· CH2), 1.35 (m,
2H, CH2); 13C NMR (50 MHz, CDCl3): d 160.9, 157.8,
135.0, 129.8, 120.4 119.5, 117.1, 116.9, 115.8, 114.1,
60.7, 50.6, 50.5, 46.7, 46.6, 30.6, 25.7, 25.6, 23.7; FABMS:
m/z 315 [M+H]+; Anal. Calcd for C19H26N2O2: C, 72.61:
H, 8.28: N, 8.91. Found: C, 72.60: H, 8.26: N, 8.82.
4.4.4. Ethyl 3-(3-chlorophenyl)-3-(pyrrolidin-1-yl)-propi-
onate (34). Obtained by reaction of 3-(3-chloro-phenyl)-
acrylic acid ethyl ester (25, 2.0 g, 9.50 mmol) and pyrrol-
idine (0.79 mL, 9.5 mmol). Colourless oil, yield (1.72 g,
4.4. Synthesis of compounds 31–45
65%); IR (KBr): mmax 3447, 1732 cmꢀ1 1H NMR
;
4.4.1. Ethyl-3-butylamino-3-(3-chlorophenyl)-propionate
(31). Typical procedure: To a magnetically stirred solu-
tion of 3-(3-chloro-phenyl)-acrylic acid ethyl ester (25,
(200 MHz, CDCl3): d 8.22 (d, J = 1.4 Hz, 1H, ArH),
8.14 (dd, J = 7.8, 1.4 Hz, 1H, ArH), 7.70 (d, J = 6.8,
1H, ArH), 8.22 (two d, J = 7.4 Hz, 1H, ArH), 3.99 (q,

8194
R. P. Tripathi et al. / Bioorg. Med. Chem. 14 (2006) 8186–8196
J = 7.1 Hz, 2H, OCH2), 3.82 (dd, J = 5.4 Hz, 1H,
ArCH), 3.07–2.37 (m, 6H, NCH2, CH2CO–), 1.85 (m,
5H, 2· CH2, NH), 1.09 (t, J = 7.0 Hz, 3H, CH3); 13C
NMR (50 MHz, CDCl3): d 171.6, 144.3, 134.4, 129.8,
127.9, 127.2, 66.3, 60.7, 52.5, 52.1, 41.9, 30.0, 23.6,
23.5, 14.3; FABMS m/z 282 (M+H)+; Anal. Calcd for
C15H20 Cl NO2: C, 64.05; H, 7.11; N, 4.98. Found: C,
64.10; H, 7.06; N, 4.98.
70%); IR (KBr): mmax cmꢀ13310, 1732; 1H NMR
(200 MHz, CDCl3): d 8.18 (m, 2H, ArH), 7.66 (m, 2H,
ArH), 7.70 (d, J = 7.6 Hz, 1H, ArH), 7.48 (two d,
J = 7.8 Hz, 1H, ArH), 3.97 (q, J = 7.1 Hz, 2H, OCH2),
8.11 (two d, J = 5.4 Hz, 1H, ArCH), 3.07–2.37 (m, 6H,
NCH2, –CH2CO–), 1.77 (m, 5H, NH, pyrroldine CH2),
1.09 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (50 MHz,
CDCl3): d 171.9, 148.9, 145.9, 133.7, 129.7, 122.8,
122.5, 61.0, 59.6, 48.0, 43.1, 39.8, 37.3, 32.2, 31.2, 30.4,
29.9, 29.7, 27.5, 27.3, 26.2, 23.0, 14.4; FABMS m/z 407
(M+H)+; Anal. Calcd for C23H38N2O4: C, 67.98; H,
9.35; N, 6.89. Found: C, 67.82; H, 9.33; N, 6.82.
4.4.5. Ethyl 3-benzylamino-3-(3-nitrophenyl)-propionate
(35). Obtained by reaction of 3-(3-chloro-phenyl)-acrylic
acid ethyl ester (25, 2.5 g, 1.19 mmol) and benzylamine
(1.29 mL, 1.19 mmol). Viscous liquid, yield (2.50 g,
68%); IR (KBr): mmax 3336, 1730 cmꢀ1
;
1H NMR
4.4.9. Ethyl 3-(3-nitrophenyl)-3-(pyrrolidin-1-yl)-propio-
nate (39). Obtained by reaction of 3-(3-nitro-phenyl)-
acrylic acid ethyl ester (26, 2.0 g, 9.0 mmol) and pyrrol-
idine (0.75 mL, 9.05 mmol) gave compound 39 as col-
ourless liquid yield (1.70 g, 65%); IR (KBr): mmax
(200 MHz, CDCl3): d 7.37–7.20 (m, 9H, ArH), 4.14–
4.04 (m, 3H, ArCH and O–CH2), 3.69–3.49 (m, 2H,
ArCH2), 2.75–2.55 (m, 2H, OCH2), 1.89 (br s, 1H,
NH), 1.65 (t, J = 6.9 Hz, 3H, CH3); 13C NMR
(50 MHz, CDCl3): d 171.9, 145.6, 142.2, 134.7, 130.7,
129.5, 127.9, 127.6, 125.6, 122.6, 60.9, 59.7, 47.6, 43.2,
32.5, 20.7, 14.5, 14.3; FABMS: m/z 318 (M+H)+; Anal.
Calcd for C18H20 Cl NO2: C, 68.13; H, 6.30; N, 4.41.
Found: C, 68.17; H, 6.32; N, 4.44.
1
cmꢀ13450, 1669; H NMR (200 MHz, CDCl3): d 8.22
(s, 1H, ArH), 8.11 (d, J = 8.1 Hz, 1H, ArH), 7.70 (d,
J = 7.6 Hz, 1H, ArH), 7.48 (two d, J = 7.8 Hz, 1H,
ArH), 3.97 (q, J = 7.1 Hz, 2H, OCH2), 8.11 (two d,
J = 5.4 Hz, 1H, ArCH), 3.07–2.37 (m, 6 H, NCH2, –
CH2CO–), 1.77 (m, 5H, NH, pyrroldine CH2), 1.09 (t,
J = 7.1 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d
171.9, 145.6, 134.7, 130.7, 127.9, 127.6, 125.6, 60.9,
59.7, 47.6, 43.2, 32.5, 20.7, 14.5, 14.3; FABMS m/z 293
(M+H)+; Anal. Calcd for C15H20N2O4: C, 61.64; H,
6.84; N, 9.58. Found: C, 61.59; H, 6.80; N, 9.60.
4.4.6. Ethyl 3-butylamino-3-(3-nitrophenyl)-propionate
(36). Obtained by reaction of 3-(3-nitro-phenyl)-acrylic
acid ethyl ester (26, 2.0 g, 9.04 mmol) and pyrrolidine
(0.9 mL, 9.05 mmol) to give 36 as colourless oil. Yield
(1.90 g, 65%); IR (KBr): mmax cmꢀ13338, 1731; 1H
NMR (200 MHz, CDCl3): d 8.24 (d, J = 1.8 Hz, 1H,
ArH), d 8.11 (dd, J = 8.0, 1.0 Hz, 1H, ArH), d 7.70 (d,
J = 7.6 Hz, 1H, ArH), d 7.50 (dd, J = 7.9 Hz, 1H,
ArH), 4.12–4.05 (m, 3H, ArCH and O–CH2), 2.62–
2.60 (m, 2H, OCH2), 2.40–2.38 (m, 2H, NCH2), 1.74
(br s, 1H, NH), 1.29–1.19 (m, 7H, 2· CH2 and CH3),
0.86 (t, J = 6.9 Hz, 3H, CH3); 13C NMR (50 MHz,
CDCl3): d 171.9, 145.6, 134.7, 130.7, 127.9, 127.6,
125.6, 60.9, 59.7, 47.6, 43.2, 32.5, 20.7, 14.5, 14.3; FAB-
MS: m/z 284 (M+H)+; Anal. Calcd for C15H22Cl N2O4:
C, 54.71; H, 6.68; N, 8.51. Found: C, 54.73; H, 6.69; N,
8.49.
4.4.10. Ethyl 3-benzylamino-3-(3-nitrophenyl)-propionate
(40). Obtained by reaction of 3-(3-nitro-phenyl)-acrylic
acid ethyl ester (26, 2.00 g, 9.0 mmol) and benzylamine
(1.00 mL, 9.09 mmol) gave compound 40 as colourless
liquid in (2.0 g, 68%) yield; IR (KBr): mmax cmꢀ13336,
1730; 1H NMR (200 MHz, CDCl3):
d 8.27 (d,
J = 1.4 Hz, 1H, ArH), 8.13 (dd, J = 1.0 Hz, 8.1 Hz,
1H, ArH), 7.73 (d, J = 7.7 Hz, 1H, ArH), 7.33 (m, 6H,
ArH), 4.23 (two d, J = 5.6 Hz, 1H, ArCH), 4.11 (q,
J = 7.1 Hz, 2H, OCH2), 3.64 and 3.59 (d, J = 13.1 Hz,
2H, NHCH2Ph), 2.72 (m, 2H, –CH2CO–), 1.95 (br s,
1H, NH); 1.23 (t, J = 7.1 Hz, 3H, CH3); 13C NMR
(50 MHz, CDCl3): d 171.9, 145.6, 140.0, 133.9, 129.9,
128.8, 128.4, 127.5, 127.4, 125.2, 125.3, 123.0, 122.7,
61.1, 58.7, 51.8, 43.1, 14.5; FABMS: m/z 329 (M+H)+;
Anal. Calcd for C18H20N2O4: C, 65.85; H, 6.09; N,
8.53. Found: C, 65.80; H, 6.11; N, 8.55.
4.4.7. Ethyl 3-(3-nitrophenyl)-3-octylamino-propionate
(37). Obtained by reaction of 3-(3-nitro-phenyl)-acrylic
acid ethyl ester (26, 2.00 g, 9.09 mmol) and octylamine
(1.5 mL, 9.05 mmol). Viscous oil, yield (2.04 g, 70%);
1
IR (KBr): mmax cmꢀ13336, 1731; H NMR (200 MHz,
CDCl3): d 8.23 (s, 1H, ArH), 8.10 (d, J = 9.1 Hz, 1H,
ArH), 7.70 (d, J = 7.7 Hz, 1H, ArH), 7.50 (two d,
J = 7.8 Hz, 1H, ArH), 4.21–4.05 (m, 3H, ArCH and
O–CH2), 2.69–2.61 (m, 2H, OCH2), 2.42–2.38 (m, 2H,
NCH2), 1.74 (br s, 1H, NH), 1.30–1.18 (m, 15H, 6·
CH2 and CH3), 0.86 (t, J = 6.7 Hz, 3H, CH3); 13C
NMR (50 MHz, CDCl3): d 171.5, 148.9, 146.6, 133.8,
129.8, 122.8, 122.5, 61.1, 59.5, 48.0, 43.1, 32.1, 30.4,
29.8, 29.6, 27.5, 23.0, 14.5, 14.4; FABMS: m/z 351
(M+H)+; Anal. Calcd for C19H30N2O4: C, 65.14; H,
8.57; N, 8.00. Found: C, 65.19; H, 8.51; N, 8.00.
4.4.11. Ethyl 3-(4-nitrophenyl)-3-octylamino-propionate
(41). Obtained by reaction of 3-(4-nitro-phenyl)-acrylic
acid ethyl ester (27, 2.0 g, 9.09 mmol) and octylamine
(1.5 mL, 9.05 mmol) as colourless oil. yield (2.0 g,
65%); IR (KBr): mmax cmꢀ13336, 1731; 1H NMR
(200 MHz, CDCl3): d 8.18 and 7.54 (d, J = 8.7 Hz, e
4H, ArH), 4.20–4.05 (m, 3H, ArCH and O–CH2),
2.67–2.30 (m, 4H, NCH2, and –CH2CO–), 1.70 (br s,
1H, NH), 1.25 (m, 15H, 6· CH2 and OCH2CH3), 0.86
(t, J = 6.6 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3):
d 171.9, 145.6, 134.7, 130.7, 127.9, 127.6, 125.6, 60.96,
59.7, 47.6, 43.2, 32.5, 31.8, 31.0, 30.2, 23.5, 20.7, 14.5,
14.3; FABMS: m/z 351 (M+H)+; Anal. Calcd for
C19H30N2O4: C, 65.14; H, 8.57; N, 8.00. Found: C,
65.19; H, 8.51; N, 8.00.
4.4.8. Ethyl 3-dodecylamino-3-(3-nitrophenyl)-propionate
(38). Obtained by reaction of 3-(3-nitro-phenyl)-acrylic
acid ethyl ester (26, 2.0 g, 9.0 mmol) and dodecylamine
(2.08 mL, 9.05 mmol). Colourless oil, yield (2.45 g,

R. P. Tripathi et al. / Bioorg. Med. Chem. 14 (2006) 8186–8196
8195
4.4.12. Ethyl 3-dodecylamino-3-(4-nitrophenyl)-propio-
4.5. Synthesis of compounds 46–48
nate (42). Obtained by reaction of 3-(4-nitro-phenyl)-
acrylic acid ethyl ester (27, 2.00 g, 9.0 mmol) and
dodecylamine (2.08 mL, 9.05 mmol) as colourless oil,
yield (2.45 g, 70%); IR (KBr): mmax cmꢀ13335, 1733;
1H NMR (200 MHz, CDCl3): d 8.21–7.51 (m, 4H,
ArH), 4.18–4.09 (m, 3H, ArCH and O–CH2), 2.66–
2.61 (m, 2H, OCH2), 2.41–2.35 (m, 2H, NCH2), 1.72
(br s, 1H, NH), 1.33–1.15 (m, 23H, 10· CH2 and
CH3), 0.87 (t, J = 6.7 Hz, 3H, CH3); 13C NMR
4.5.1. 3-(3-Chlorophenyl)-3-octylaminopropan-1-ol (46).
Typical procedure: To a magnetically stirred slurry of
LiAlH4 (0.030 g, 0.81 mmol) in anhyd THF (10 mL) at
0 ꢁC, the above compound 32 (0.20 g, 0.58 mmol) dis-
solved in THF (5 mL) was slowly added and stirring
continued for 4 h at ambient temperature. Reaction
mixture was neutralized by saturated aq solution of
Na2SO4 at 0 ꢁC and filtered over Celite pad. The filtrate,
so obtained, was evaporated under reduced pressure to
give a crude mass. The latter was dissolved in chloro-
form (65 mL) and washed with saturated solution of
NaCl (2 · 20 mL) followed by water (2 · 25 mL), dried
(anhyd Na2SO4). The organic layer was evaporated un-
der reduced pressure to get a crude product, which was
chromatographed over SiO2 column using chloroform:
methanol, (98:2) as eluent to afford 46 as viscous oil,
(50 MHz, CDCl3):
d 171.5, 151.2, 147.7, 130.5,
128.4, 124.1, 123.8, 115.2, 61.1, 59.6, 48.5, 48.1,
43.0, 32.2, 31.5, 30.4, 30.0, 29.9, 29.7, 27.5, 23.0,
14.5, 14.4; FABMS: m/z 407 (M+H)+; Anal. Calcd
for C23H38N2O4: C, 67.98; H, 9.35; N, 6.89. Found:
C, 67.82; H, 9.33; N, 6.82.
4.4.13. Ethyl 3-dodecylamino-3-(2-nitrophenyl)]-propio-
nate (43). Obtained by reaction of 3-(2-nitro-phenyl)-
acrylic acid ethyl ester (28, 2.0 g, 9.0 mmol) and
dodecylamine (2.08 mL, 9.05 mmol) as colourless oil,
yield (2.50 g, 70%); IR (KBr): mmax cmꢀ13344, 1729;
1H NMR (200 MHz, CDCl3): d 7.82–7.42 (m, 4H,
ArH), 4.31–4.11 (m, 3H, ArCH and O–CH2), 2.74–
2.79 (m, 2H, OCH2), 2.54–2.52 (m, 2H, NCH2), 1.85
(br s, 1H, NH), 1.32–1.16 (m, 23H, 10· CH2 and
CH3), 0.87 (t, J = 6.6 Hz, 3H, CH3); d; FABMS: m/z
407 (M+H)+; Anal. Calcd for C23H38N2O4: C, 67.98;
H, 9.35; N, 6.89. Found: C, 67.82; H, 9.33; N, 6.82.
yield (0.104 g, 60%); IR (KBr): mmax 3679, 3405 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.23 (m, 4H, ArH),
3.79 (m, 3H, ArCH and CH2OH), 2.47 (br s, 1H,
OH), 2.44 (t, J = 7.0 Hz, 2H, NCH2), 1.84 (m, 2H,
CH2), 1.54–1.23 (m, 12H, 6 xCH2), 0.86 (t, J = 6.4 Hz,
3H, CH3); FABMS: m/z 298 (M+H)+; Anal. Calcd for
C17H28ClNO: C, 68.68; H, 9.42; N, 4.71 Found: C,
68.70; H, 9.46; N, 4.77.
4.5.2. 3-(3-Nitrophenyl)-3-octylamino-propan-1-ol (47).
Obtained by reduction of the above compound 37
(0.20 g, 0.58 mmol) with LiAlH4 (0.030 g, 0.81 mmol)
as colourless oil. Yield (0.113 g, 65%); IR (KBr): mmax
1
3428, 1530 cmꢀ1; H NMR (200 MHz, CDCl3): d 8.15
4.4.14. Ethyl 3-(4-fluorophenyl)-3-octylamino-propionate
(44). Obtained by reaction of 3-(4-floro-phenyl)-acrylic
acid ethyl ester (29, 2.0 g, 1.03 mmol) and octylamine
(1.7 mL, 1.03 mmol). Colourless oil yield (2.3 g, 70%);
(m, 2H, ArH), 7.60 (m, 2H, ArH), 3.97 (m, H, ArCH),
3.79 (m, 2H, OCH2), 2.77 (br s, 1H, OH), 2.40 (m,
2H, NCH2), 1.68 (br s, 1H, NH), 1.23 (s, 12H, CH2’s),
0.79 (t, J = 6.9 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d 148.9, 146.0, 133.1, 130.0, 122.7, 121.9, 63.5, 62.3,
47.7, 39.1, 32.1, 30.3, 29.7, 29.5, 27.5, 23.0, 15.6, 14.4;
FABMS: m/z 309 (M+H)+; Anal. Calcd for
C17H28N2O3: C, 66.23; H, 9.09; N, 9.09. Found: C,
66.28; H, 9.11; N, 9.15.
1
IR (KBr): mmax cmꢀ13453, 1727; H NMR (200 MHz,
CDCl3): d 7.30 (dd, J = 6.5 Hz, 2.0 Hz, 2H, ArH), 7.03
(dd, J = 2.0 Hz, 8.7 Hz, 2H, ArH), 4.14–4.01 (m, 3H,
ArCH and O–CH2), 2.66–2.57 (m, 2H, OCH2), 2.37–
2.25 (m, 2H, NCH2), 1.75 (br s, 1H, NH), 1.31–1.12
(m, 15H, 6· CH2 and OCH2CH3), 0.86 (t, J = 6.7 Hz,
3H, CH3); 13C NMR (50 MHz, CDCl3): d 172.1,
164.8, 159.9, 139.0, 129.0, 128.8, 115.8, 60.8, 59.4,
47.9, 43.4, 32.2, 30.4, 29.8, 29.6, 27.6, 23.0, 14.5, 14.4;
FABMS: m/z 323 (M+H)+ Anal. Calcd for
C19H30FNO2: C, 70.80; H, 9.31; N, 4.34. Found: C,
70.75; H, 9.39; N, 4.39.
4.5.3.
3-Dodecylamino-3-(3-nitrophenyl)]-propan-1-ol
(48). Obtained by reduction of compound 38 (0.20 g,
0.49 mmol) with LiAlH4 (0.025 g, 0.67 mmol) as above.
Colourless gum, yield (0.105 g, 60%);; IR (KBr): mmax
1
cmꢀ13402, 1531; H NMR (200 MHz, CDCl3): d 8.18
(m, 2H, ArH), 7.68–7.28 (m, 2H, ArH), 4.13–3.82 (m,
3H, ArCH, O–CH2), 3.39 (m, 2H, NHCH2), 2.91 (br
s, 1H, OH), 2.44 (m, 2H, CH2), 1.40–1.12 (m, 23H,
NH, 11· CH2), 0.87 (t, J = 6.3 Hz, 3H, CH3); FABMS:
m/z 365 (M+H)+; Anal. Calcd for C21H36N2O3: C,
69.23; H, 9.89; N, 7.69. Found: C, 69.21; H, 9.88; N,
7.69.
4.4.15. Ethyl 3-octylamino-3-phenyl-propionate (45). Ob-
tained by reaction of 3-(phenyl)-acrylic acid ethyl ester
(30, 2.0 g, 1.13 mmol) and octylamine (1.8 mL,
1.13 mmol). Colourless oil, yield (2.3 g, 70%), IR
(KBr): mmax 3335, 1733 cmꢀ1 1H NMR (200 MHz,
;
CDCl3): d 7.31 (m, 5H, ArH), 4.05 (m, 3H, ArCH and
O–CH2), 2.63 (m, 2H, NCH2), 2.44–2.36 (m, 2H,
–CH2CO–), 1.68 (br s, 1H, NH), 1.23 (m, 15H, CH2
and CH3), 0.86 (t, J = 6.7 Hz, 3H, CH2CH3), 13C
NMR (50 MHz, CDCl3): d 172.0, 143.3, 128.8, 127.6,
127.3, 123.2, 122.8, 115.6, 60.4, 60.1, 47.9, 43.4, 32.2,
30.5, 30.0, 29.9, 29.6, 28.5, 27.6, 23.0, 14.3, 14.2; FAB-
MS: m/z 306 (M+H)+; Anal. Calcd for C19H31NO2: C,
75.00; H, 9.86; N, 4.60. Found: C, 75.09; H, 9.88; N,
4.55.
5. Biological activity
5.1. Activity against M. tuberculosis H37Ra strain14
All the compounds synthesized were evaluated for
their efficacy against M. tuberculosis H37Ra at concen-
tration ranging from 100 lg/mL to 1.56 lg/mL using

8196
R. P. Tripathi et al. / Bioorg. Med. Chem. 14 (2006) 8186–8196
twofold dilutions in the initial screen. Log phase cul-
ture of M. tuberculosis H37Ra is diluted so as to give
final OD550 nm of 0.05 in Sauton’s medium. In 96-well
white plate 190 ll of culture is dispensed in each well.
A dimethyl-sulfoxide (DMSO) solution of test com-
pounds is dispensed to 96-well plates so as to make
final test concentration 25 lg/mL (5 lg test compound
is dispensed in 10 ll DMSO). Then the plate is incu-
bated at 37 ꢁC/5% CO2 for 5 days. On fifth day
15 ll Alamar blue solution is added to the each well
of plate. The plate is again incubated overnight at
37 ꢁC/5% CO2 incubator. The fluorescence is read on
BMG polar star with excitation frequency at 544 nm
and emission frequency at 590 nm. The compounds,
which were found active (>90% inhibition as com-
pared with control) at this concentration, are then
tested at 6 serial dilutions starting from 50 to
1.56 lg/mL.
References and notes
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N. Saxena, S. S. Verma and V. K. Tiwari are thankful
to CSIR and UGC for providing the JRF and SRF.
We are thankful to Drs N. Tewari and D. Katiyar
for their help in preparing few compounds. Financial
assistance from ICMR, New Delhi, is gratefully
acknowledged.