Naphthylisopropylamine and N-benzylamphetamine derivatives as monoamine oxidase inhibitors

Article abstract of DOI:10.1016/j.bmc.2009.01.074

A series of naphthylisopropylamine and N-benzyl-4-methylthioamphetamine derivatives were evaluated as monoamine oxidase inhibitors. Their potencies were compared with those of a series of amphetamine derivatives, to test if the increase of electron richness of the aromatic ring and overall size of the molecule might improve their potency as enzyme inhibitors. Molecular dockings were performed to gain insight regarding the binding mode of these inhibitors and rationalize their different potencies. In the case of naphthylisopropylamine derivatives, the increased electron-donating capacity and size of the aromatic moiety resulting from replacement of the phenyl ring of amphetamine derivatives by a naphthalene system resulted in more potent compounds. In the other case, extension of the arylisopropylamine molecule by N-benzylation of the amino group led to a decrease in potency as monoamine oxidase inhibitors.

Full text of DOI:10.1016/j.bmc.2009.01.074

Bioorganic & Medicinal Chemistry 17 (2009) 2452–2460
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Naphthylisopropylamine and N-benzylamphetamine derivatives
as monoamine oxidase inhibitors
Marcelo Vilches-Herrera a, Juan Miranda-Sepúlveda b, Marco Rebolledo-Fuentes a,c, Angélica Fierro c,d
,
Susan Lühr a, Patricio Iturriaga-Vasquez a,c, Bruce K. Cassels a,c, Miguel Reyes-Parada b,c,
*
a Department of Chemistry, Faculty of Sciences, University of Chile, Casilla 653, Santiago, Chile
b School of Medicine, Faculty of Medical Sciences, University of Santiago de Chile, Alameda 3363, Santiago, Chile
c Millennium Institute for Cell Dynamics and Biotechnology, Beauchef 861, Santiago, Chile
d Faculty of Chemistry and Biology, University of Santiago de Chile, Alameda 3363, Santiago, Chile
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of naphthylisopropylamine and N-benzyl-4-methylthioamphetamine derivatives were evaluated
as monoamine oxidase inhibitors. Their potencies were compared with those of a series of amphetamine
derivatives, to test if the increase of electron richness of the aromatic ring and overall size of the molecule
might improve their potency as enzyme inhibitors. Molecular dockings were performed to gain insight
regarding the binding mode of these inhibitors and rationalize their different potencies. In the case of
naphthylisopropylamine derivatives, the increased electron-donating capacity and size of the aromatic
moiety resulting from replacement of the phenyl ring of amphetamine derivatives by a naphthalene sys-
tem resulted in more potent compounds. In the other case, extension of the arylisopropylamine molecule
by N-benzylation of the amino group led to a decrease in potency as monoamine oxidase inhibitors.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 November 2008
Revised 30 January 2009
Accepted 31 January 2009
Available online 8 February 2009
Keywords:
Monoamine oxidase
MAO inhibitors
Naphthylisopropylamine derivatives
Amphetamine derivatives
PAL-287
Docking
1. Introduction
would favor charge-transfer interactions with the isoalloxazine
ring of the enzyme’s cofactor. Nevertheless, our current knowledge
The two isoforms of monoamine oxidase (MAO, E.C. 1.4.3.4),
namely MAO-A and MAO-B, are targets for a series of therapeuti-
cally valuable drugs. Thus, selective MAO-A inhibitors (MAOI-A)
are used as antidepressants while selective MAOI-B are used in
the treatment of Parkinson’s disease.1,2
The availability of high resolution crystal structures of both
MAO isoforms,3–6 and the concomitant use of molecular simulation
approaches are leading to a better understanding of the main bind-
ing interactions of several inhibitors at the enzymes’ active sites,
and have facilitated the interpretation of their structure–activity
relationships (SARs).7–10
Many phenylisopropylamine derivatives, often referred to in
the literature as ‘substituted amphetamines’, have been shown
by us and others to be potent and selective MAOI-A.11–13 In a pre-
vious QSAR study based on quantum-chemical calculations at the
AM1 level of theory,14 we reported that electron-rich aromatic
rings and higher HOMO energies correlated with an increased
activity of substituted amphetamines as MAOI-A. In that work, this
effect was interpreted as suggesting that these characteristics
of the MAO structures and with regard to the putative binding
modes of this class of compounds,15 indicates that increased MAOI
activity might be better rationalized as a consequence of stronger
p
type interactions with aromatic and non-aromatic residues present
in the active site of the protein.16 In this regard, it seemed interest-
ing to test the effect of replacing the phenyl ring of the amphet-
amine derivatives by
a naphthalene moiety, as a way of
increasing the electron richness and HOMO energy and therefore
their inhibitory activity.
Structural and molecular simulation data on MAO-A, on the
other hand, suggest that the substrate/inhibitor binding site (both
in human and rat MAO-A) could accommodate larger molecules
than substituted phenylisopropylamines.4–6 Thus, recent studies
have shown that molecules such as 4-phenyl-2-thiazolylhydraz-
one,9 N,N0-bis[2-oxo-2H-1-benzopyran]-3-carboxamide,17 or 4-
(40-bromo-N-imidazolyl)-aryloxazolidinone derivatives,18 fit into
this binding site and are potent (although not necessarily selective)
inhibitors of MAO-A activity. Therefore, replacement of a phenyl by
a naphthyl group could improve the inhibitory potency of these
compounds not only because of the greater ability of the latter
family to interact with aromatic residues in the enzyme’s active
site but also as a consequence of the increased size of the ligand.
* Corresponding author. Tel.: +56 2 718 3526; fax: +56 2 681 7602.
E-mail address: miguel.reyes@usach.cl (M. Reyes-Parada).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.01.074

M. Vilches-Herrera et al. / Bioorg. Med. Chem. 17 (2009) 2452–2460
2453
Table 2
Amphetamine derivatives
In addition, based on the putative binding mode of the potent and
selective inhibitor 4-methylthioamphetamine (3g),15 we decided
to explore if the inhibitory activity of the parent molecule might
increase by virtue of the introduction of bulky, substituted benzyl
groups on the amine function of this compound. In order to test
these hypotheses, the present study describes the synthesis, MAO
inhibitory properties and molecular docking results for a series of
naphthylisopropylamine and N-benzyl-4-methylthioamphetamine
derivatives.
NH2
CH3
R1
3
a
Compound
R1
Ki
(lM)
MAO-A
MAO-B
2. Results and discussion
2.1. Chemistry
3a
3b
3c
3d
3e
3f
H
CH3O
12.2 2.72
0.25 0.04
0.22 0.02
0.13 0.02
0.32 0.04
3.42 0.17
0.25 0.02
NE
NE
CH3CH2O
CH3CH2CH2O
CH3CH2CH2CH2O
PhCH2O
CH3S
>100
>100
>100
0.71 0.11
NE
Racemic 1-(1-) (1) and 1-(2-naphthyl)-2-aminopropane (2a),
and 1-(6-methoxy- (2b), ethoxy- (2c), propoxy- (2d), butoxy-
(2e), benzyloxy- (2f), and methylthio- (2g) 2-naphthyl)-2-amino-
propanes, the N-benzyl derivatives of 2b and 2e (2h and 2i, respec-
tively) (Table 1), 1-(4-methoxy- (3b), ethoxy- (3c), propoxy- (3d),
butoxy- (3e), benzyloxy- (3f) and methylthio- (3g) phenyl)-2-
aminopropanes (Table 2), and the N-benzyl- (4a), N-4-hydroxyben-
zyl- (4b), N-4-methoxybenzyl- (4c), N-4-butoxybenzyl- (4d), and
N-4-benzyloxybenzyl- (4e) derivatives of 3g (Table 3) were synthe-
sized following published methodology (see Section 4).
3g
a
Calculated from IC50 values using the Cheng–Prusoff equation; Km (5-HT, MAO-
M, Km (DMAPEA, MAO-B) = 5 M. NE: no effect at 100 M.
A) = 100
l
l
l
values in the low micromolar or submicromolar range. In agree-
ment with one of our hypotheses, in the case of the ring-unsubsti-
tuted compounds the extension of the
p system from a phenyl
(amphetamine; 3a) to a naphthyl ring (1 and 2a) induced an in-
crease of the inhibitory potency. According to Vallejos et al.,14 this
finding could be expected on the basis of the higher HOMO energy
of naphthalene as compared with benzene,19,20 as well as the neg-
ative charge-descriptor coefficients of both. Indeed, AM1 semiem-
pirical calculations performed for amphetamine (3a) and 2-
naphthylisopropylamine (2a) resulted in HOMO energy values of
ꢀ9.31 eV and ꢀ8.69 eV, respectively. These results further support
the notion that charge-transfer interactions might be important
contributors to the affinity of these types of compounds at the
MAO-A active site. As discussed below, however, steric factors also
appear to play a crucial role in determining MAO inhibitory
potency.
2.2. Biochemistry and molecular docking
Tables 1–3 summarize the effects of the aforementioned com-
pounds, plus amphetamine (3a), upon rat MAO-A and MAO-B.
Competitive inhibition of MAO-A was shown previously for sev-
eral phenylisopropylamine analogues,15 and has now been demon-
strated for 6-methoxynaphthylisopropylamine (2b) (Fig. 1). This
type of inhibition was assumed in the remaining cases studied
here.
Similarly to that seen in previous studies with amphetamine
derivatives, most of the naphthylisopropylamine analogues shown
in Table 1 exhibited selective MAO-A inhibitory properties with Ki
Table 1
Naphthylisopropylamine derivatives
NH2
CH3
NHR1
CH3
R2
1
2
Compound
R1
R2
Kia
(lM)
MAO-A
MAO-B
1
—
H
H
H
H
H
H
H
—
H
CH3O
CH3CH2O
CH3CH2CH2O
CH3CH2CH2CH2O
PhCH2O
CH3S
5.63 0.21
0.42 0.04
0.18 0.05
0.45 0.09
0.68 0.11
1.53 0.07
3.78 0.21
0.50 0.04
6.93 0.83
14.5 0.50
>100
>100
2a
2b
2c
2d
2e
2f
2g
2h
2i
16.3 7.78
13.6 3.33
13.5 0.038
ND
2.56 0.35
ND
PhCH2
PhCH2
CH3O
CH3CH2CH2CH2O
24.7 1.21
22.2 5.83
a
Calculated from IC50 values using the Cheng–Prusoff equation; Km (5-HT, MAO-A) = 100 lM, Km (DMAPEA, MAO-B) = 5 lM. ND: not determined.

2454
M. Vilches-Herrera et al. / Bioorg. Med. Chem. 17 (2009) 2452–2460
Table 3
Although the substances synthesized by us are racemic mix-
N-Benzyl-4-methylthioamphetamine derivatives
tures, in a few instances it has been shown that (S)-arylisopropyl-
amines are the eutomers for MAO inhibition,21–24 and therefore
our docking experiments were performed with the (S) isomers.
As shown in Figure 2, docking experiments revealed that com-
pound 2a as well as 3a exhibit binding modes where their aromatic
R1
H
N
rings are oriented in such a way as to establish
pꢀp interactions
with the aromatic groups of Phe208, Tyr69 and Phe352, whereas
the amino group points away from the flavin ring forming a hydro-
gen bond with the carbonyl group of Phe208. It should be noted
that in both cases (and also for the remaining naphthylisopropyl-
amines) a majority of the AUTODOCK runs showed the lowest docking
energies associated with this orientation. The relevance of the
aforementioned aromatic residues, particularly Phe208, to the
establishment of molecular interactions with aromatic rings pres-
ent in structurally diverse MAOI-A has been highlighted in previ-
ous QSAR and molecular modeling studies.9,17,25,26
CH3
H3CS
4
a
Compound
R1
Ki
(lM)
MAO-A
MAO-B
4a
4b
4c
4d
4e
H
OH
OCH3
>100
>100
>100
90 2.12
>100
>100
>100
NE
NE
NE
OCH2CH2CH2CH3
OCH2Ph
As discussed in previous reports,15,27 this binding mode pro-
vides a rationale for the inhibitory activity of these classes of com-
pounds, since they would block the access of substrates to the
active site while avoiding their own deamination by locating the
amino group far from the influence of the flavin ring. Nevertheless,
not only does the electron richness of the aromatic ring increase by
a
Calculated from IC50 values using the Cheng–Prusoff equation; Km (5-HT, MAO-
M, Km (DMAPEA, MAO-B) = 5 M. NE: no effect at 100 M.
A) = 100
l
l
l
extending the aromatic
p system, but also its size. The analysis of
the aromatic environment surrounding the binding poses of 2a and
3a into the active site of MAO-A, shows that Tyr444, Tyr407,
Phe177 and the isoalloxazine ring of FAD are located in the close
vicinity (less than 6 Å) of ring B (distal to the aminopropyl moiety)
of the naphthyl derivative, while these residues are approximately
2 Å further from the phenyl group of 3a, which coincides with ring
A (i.e., the one linked to the alkylamino chain) of compound 2a
(Fig. 2). Furthermore, the second aromatic ring of 2a establishes
an additional interaction with Gln215, at a distance of 3.4 Å. Thus,
the 30-fold difference in potency between 2a and 3a could be as-
cribed to an increased probability of establishing dispersive short
length interactions common to both compounds and also to a
greater number of interactions.
Interestingly, 1 and 2a which showed a difference of more than
an order of magnitude in their potency as MAOI-A, differed only
slightly in their binding poses (RMSD 0.5 Å, data not shown). Even
though energy parameters obtained with the docking program cor-
related well with the experimental data, further studies are neces-
sary to interpret the differential activity of these two positional
isomers.
Figure 1. Lineweaver–Burk plot for the inhibition of rat MAO-A by 2b.
It is worth pointing out that compound 2a, previously referred
to as PAL-287,28 has been shown to suppress cocaine self-adminis-
tration in rhesus monkeys.28,29 This effect has been attributed to
the dopamine and serotonin releasing properties of the drug. Con-
sidering the well documented overlap between depression and
addiction,30 and the potent effect of the drug upon MAO-A demon-
strated here, it is enticing to suggest that at least part of the anti-
addictive properties of PAL-287 might be related to its MAOI-A
activity.
Data from previous SAR studies with amphetamine derivatives
had shown that para-alkoxy,12 alkylthio13,15 and alkylamino11 sub-
stituents increase the activity of the parent compound versus
MAO-A, and that this increase was maximal with alkyl substituents
containing 2–3 carbon atoms and decreases with longer chains
(Refs. 11–15 and compounds 3a–3e, Table 2). Therefore, we ex-
plored the effect of a similar substitution pattern in the naphthyl-
isopropylamine derivatives. As shown in Table 1, compound 2b,
which has a methoxyl group at position 6 of the aromatic ring,
was twice as potent as its unsubstituted analogue, and slightly
more active than p-methoxyamphetamine (3b). However, when
the alkoxyl chain attached to C6 of the naphthyl moiety is length-
ened, a decrease of the inhibitory activity is observed (compounds
Figure 2. Superimposed structures of compounds 2a (orange) and 3a (blue),
docked into the active site of MAO-A. For the sake of clarity, some residues are not
shown.

M. Vilches-Herrera et al. / Bioorg. Med. Chem. 17 (2009) 2452–2460
2455
Figure 3. Comparison of the binding modes of compounds 2b (left panel) and 2e (right panel), which exemplifies the appearance of a steric repulsion and the lack of a
hydrogen bond when trying to accommodate substituents longer than methoxyl between Tyr407 and Tyr444.
Unexpectedly, when the oxygen atom of compound 2b was re-
2c–2e). The docking poses of 2b–2e suggest the appearance of a
placed by a sulfur atom to give compound 2g, this produced a de-
crease in potency versus MAO-A. In previous studies with several
steric repulsion when trying to accommodate substituents longer
than methoxyl between Tyr407 and Tyr444 (Fig. 3). It should be
4-substituted amphetamine derivatives such an isosteric replace-
pointed out that, lacking such steric repulsion, a hydrogen bond
ment always resulted in improved inhibitory activities.12,13 Again,
involving the hydroxyl group of Tyr407 and the ether oxygen atom
the greater length of the S–C bond as compared with the O–C bond
further stabilizes the interaction of 2a with the enzyme.
Indeed, compounds 2b and 3d, which were the most potent of
their corresponding series, occupied virtually the same region of
(about 1.8 vs 1.4 Å) might be enough to exceed the optimal size of
the ligand, thus explaining the lower activity of compound 2g.
Previous studies had shown that 4-substituted amphetamine
the MAO-A active site (Fig. 4), giving a clear indication about the
derivatives generally show little or no activity versus MAO-B.12,13
optimal length of the ligand required to attain maximal inhibitory
activity. In fact, the maximal hydrogen–hydrogen distances in the
most favorable binding conformations of 2b and 3d are 10.5 and
Interestingly, compound 3f, which was the least potent MAOI-A
of the phenylisopropylamine series with the exception of amphet-
amine itself (Table 2), showed a considerable effect upon MAO-B, a
10.3 Å, respectively.
behavior that was similar to that exhibited by the corresponding
naphthylisopropylamine analogue (2f, Table 1), indicating that
the benzyloxy group is an attractive substituent to modulate the
selectivity of this type of drugs.
None of the N-benzyl-4-methylthioamphetamine derivatives
studied (compounds 4a–4e, Table 3) showed significant effects
upon MAO activities. A similar, though lesser decrease in potency
regarding the parent compound was also observed in the case of
the two N-benzyl-naphthylisopropylamine derivatives (2h and 2i,
Table 1). Although for amphetamine derivatives it has been re-
ported that the presence of relatively small alkyl substituents on
the amino group leads to a decrease of MAO-A inhibitory activ-
ity,12,24 there were no data about the influence of the introduction
of aromatic substituents that might establish additional interac-
tions with protein residues. The present results indicate that, in
line with previous data, N-benzyl substitution also produces a de-
crease in potency of either amphetamine or naphthylisopropyl-
amine derivatives. This lack of activity could indicate that either
the ligand does not reach the active site or that, once there, it is un-
able to establish attractive interactions with certain amino acid
residues. In agreement with our experimental results, the docking
data showed that high interaction energies (positive values in most
cases) were obtained for all binding poses of the ligands at the
MAO-A active site. Besides providing a possible explanation for
the lack of inhibitory activity of this kind of compounds, these the-
oretical results give further support to the predictive value of
Figure 4. Superimposed structures of compounds 2b (purple) and 3d (green),
docked into the active site of MAO-A. Some residues are not shown.

2456
M. Vilches-Herrera et al. / Bioorg. Med. Chem. 17 (2009) 2452–2460
molecular simulation when analyzing their interactions with
MAOs.
(400 ml) where the product precipitated as a pink powder. Yield
64%, mp 124.5–127.5 °C (lit.35 123–127 °C). 1H NMR (CDCl3) d
7.92 (s, H, ArH), 7.67 (d, 1H, J = 9.6 Hz, ArH), 7.56 (d, 1H, J = 8.8
Hz, ArH), 7.49 (d, 1H, J = 8.9 Hz, ArH), 7.12 (s, 2H, ArH), 5.03 (s,
1H, OH).
3. Conclusions
Two hypotheses, based on the published MAO crystal struc-
tures, considering modifications of the amphetamine scaffold,
were evaluated. In one case, an increased electron-donating capac-
ity and size of the aromatic moiety by replacing the phenyl ring of
amphetamine (3a) by naphthalene (1 and 2a), resulted in more po-
tent compounds. Nevertheless, this effect can be offset by the
introduction of substituents at C6 of the naphthalene ring leading
to molecules that exceed an optimal length. Aside from specific
considerations for the naphthylisopropylamine series, the replace-
ment of a phenyl by a naphthyl ring provides heretofore unused
positions on the aromatic moiety, which can be exploited for drug
design. In the other case, extension of the arylisopropylamine mol-
ecule by N-benzylation of the amino group led to a decrease in po-
tency as MAOI.
4.1.2. General procedure for the preparation of 6-alkoxy-2-bro-
monaphthalenes
To a stirred solution of 6-bromo-2-naphthol (1 mmol) in CH3CN
(100 ml), K2CO3 (3 mmol) and the appropriate alkyl halide
(2 mmol) were added. The reaction mixture was refluxed and stir-
red for 24 h and then the solvent was removed by rotary evapora-
tion. The product (a white solid) was extracted with EtOAc and 25%
NaOH (2 ꢁ 100 ml) and then with H2O (2 ꢁ 100 ml). The organic
layer was dried over Na2SO4 and concentrated. The product crys-
tallized after adding methanol.
4.1.2.1. 2-Bromo-6-methoxynaphthalene. Yield 81%, mp 102.5–
104.0 °C. 1H NMR (CDCl3) d 7.89 (s, 1H, ArH), 7.62 (d, 1H, J = 9.1
Hz, ArH), 7.58 (d, 1H, J = 8.8 Hz, ArH), 7.47 (dd, 1H, J1 = 8.6 Hz,
J2 = 1.9 Hz, ArH), 7.14 (dd, 1H, J1 = 9.1 Hz, J2 = 2.4 Hz, ArH), 7.08
(d, 1H, J = 2.1 Hz, ArH), 3.89 (s, 3H, OCH3).
Finally, further studies are desirable to assess the possible role
of MAO-A inhibition in the antiaddictive properties of PAL-287
and, presumably, its analogues.
4.1.2.2. 2-Bromo-6-ethoxynaphthalene. Yield 67%, mp 72.9–
76.3 °C. 1H NMR (CDCl3) d 7.91 (s, 1H, ArH), 7.64 (d, 1H, J = 9.1
Hz, ArH), 7.58 (d, 1H, J = 8.8 Hz, ArH), 7.49 (d, 1H, J = 8.6 Hz,
ArH), 7.16 (dd, 1H, J1 = 9.1 Hz, J2 = 2.3 Hz, ArH), 7.09 (s, 1H, ArH),
4.14 (q, 2H, J = 7.1 Hz, CH3CH2O), 1.48 (t, 3H, J = 6.8 Hz, CH3CH2O).
4. Experimental
4.1. Chemistry
All reagents and solvents were commercially available and were
used without further purification. Amphetamine sulfate (3a) was
purchased from Sigma (St. Louis, MO). The naphthylisopropylam-
ines (1, 2a–2g) and amphetamines (3b–3g) were synthesized fol-
lowing standard published methods,24,31–33 which involved the
condensation of appropriately substituted aromatic aldehydes
with nitroethane, the subsequent reduction of the corresponding
nitrostyrenes with LiAlH4 and the final preparation of the amine
hydrochloride. The 6-substituted-2-naphthaldehydes were ob-
tained by Grignard reaction of O-alkylated derivatives of 6-bro-
mo-2-naphthol,34 which, in turn, was prepared by selective
debromination of 1,6-dibromo-2-naphthol with tin.35 2-Bromo-6-
methythionaphthalene was obtained via 2-O-(6-bromonaphthyl)-
dimethylthiocarbamate,36 and subsequent Newman–Kwart rear-
rangement to afford 2-S-(6-bromonaphthyl)-dimethylthiocarba-
mate,37,38 followed by hydrolysis and S-methylation. An
alternative, higher-yielding route to 6-methylthio-2-naphthalde-
hyde involved substitution of the aromatic bromine atom by a cy-
ano group using CuCN,39 followed by reduction with DIBAH,40 and
hydrolysis of the resulting imine. All N-benzyl derivatives (4a–4e,
2h and 2i) were obtained by reductive amination with NaBH3CN
of the corresponding arylisopropylamine in the presence of the
appropriately substituted benzaldehyde. Melting points are uncor-
rected and were determined with a Reichert Galen III hot plate
microscope. 1H NMR spectra were recorded using Bruker AMX
400 and AMX 300 spectrometers at 400 or 300 MHz, respectively.
Chemical shifts are reported relative to TMS (d = 0.00) or HDO
(d = 4.79) and coupling constants (J) are given in Hertz. The ele-
mental analyses for C, H, N, O and S were performed on a CE Instru-
ments (model EA 1108) analyzer.
4.1.2.3. 2-Bromo-6-propoxynaphthalene. Yield 80%, mp 64.7–
65.1 °C. 1H NMR (CDCl3) d 7.95 (s, 1H, ArH), 7.68 (d, 1H, J = 8.9
Hz, ArH), 7.62 (d, 1H, J = 8.6 Hz, ArH), 7.53 (dd, 1H, J1 = 8.9 Hz,
J2 = 2.1 Hz, ArH), 7.21 (dd, 1H, J1 = 8.8 Hz, J2 = 2.5 Hz, ArH), 7.13
(d, 1H, J = 2.3 Hz, ArH), 4.07 (t, 2H, J = 6.6 Hz, CH3CH2CH2O), 1.92
(m, 2H, CH3CH2CH2O), 1.13 (t, 3H, J = 7.6 Hz, CH3CH2CH2O).
4.1.2.4. 2-Bromo-6-butoxynaphthalene. Yield 54% mp 54.0–
55.3 °C. 1H NMR (CDCl3) d 7.90 (s, 1H, ArH), 7.63 (d, 1H, J = 8.8
Hz, ArH), 7.58 (d, 1H, J = 8.6 Hz, ArH), 7.48 (dd, 1H, J1 = 8.8 Hz,
J2 = 1.8 Hz, ArH), 7.15 (dd, 1H, J1 = 9.1 Hz, J2 = 2.5 Hz, ArH), 7.08
(d, 1H, J = 2.3 Hz, ArH), 4.06 (t, 2H, J = 6.6 Hz, CH3CH2CH2CH2O),
1.83 (m, 2H, CH3CH2CH2CH2O), 1.53 (m, 2H, CH3CH2CH2CH2O),
1.00 (t, 3H, J = 7.7 Hz, CH3CH2CH2CH2O).
4.1.2.5. 6-Benzyloxy-2-bromonaphthalene. Yield 50%, mp 89.5–
94.8 °C. 1H NMR (CDCl3) d 7.97 (s,1H, ArH), 7.71 (d, 1H, J = 9.1 Hz,
ArH), 7.64 (d, 1H, J = 8.6 Hz, ArH), 7.53 (m, 3H, ArH), 7.46 (m, 2H,
ArH), 7.40 (d, 1H, J = 7.6 Hz, ArH), 7.28 (d, 1H, J = 2.5 Hz, ArH),
7.23 (d, 1H, J = 2.5 Hz, ArH), 5.22 (s, 2H, ArCH2O).
4.1.3. General procedure for the preparation of 6-alkoxy-2-nap-
hthaldehydes
The appropriate 6-alkoxy-2-bromonaphthalene (1 mmol) dis-
solved in dry tetrahydrofuran (THF; 50 ml), was added dropwise
to a mixture of 1.2 g of Mg and an I2 crystal in dry THF (100 ml)
and refluxed under N2 for 4 h. After cooling to 0 °C, DMF
(1.2 mmol) was added, and the mixture was left at room tempera-
ture for 24 h. After evaporating the solvent, acetic acid (10%, 60 ml)
was added and the mixture was extracted with DCM. The organic
layer was dried over Na2SO4 and concentrated. The product crys-
tallized after adding methanol.
4.1.1. Preparation of 6-bromo-2-naphthol
To a solution of 2-naphthol (140 mmol) in acetic acid (60 ml)
was added Br2 (14 ml) in acetic acid (14 ml). The reaction mixture
was refluxed for 3 h during which three portions of Sn
(2 ꢁ 0.03 mol and 0.12 mol) were added. Then, the mixture was
cooled to 50 °C, and the Sn salts formed were filtered and dis-
carded. The remaining solution was poured into cold water
4.1.3.1. 6-Methoxy-2-naphthaldehyde. Yield 40%, mp 77.0–
80.8 °C (yellow crystals). 1H NMR (CDCl3) d 10.07 (s,1H, CHO),
8.23 (s, 1H, ArH), 7.90 (dd, 1H, J1 = 8.5 Hz, J2 = 1.2 Hz, ArH), 7.87
(d, 1H, J = 8.8 Hz, ArH), 7.78 (d, 1H, J = 8.5 Hz, ArH), 7.21 (dd, 1H,

M. Vilches-Herrera et al. / Bioorg. Med. Chem. 17 (2009) 2452–2460
2457
J1 = 8.8 Hz, J2 = 2.8 Hz, ArH), 7.16 (d, 1H, J = 2.1 Hz, ArH), 3.94 (s, 3H,
OCH3).
4.1.4.5. 1-Nitro-2-(6-propoxynaphthyl)-propene. Yield 76%, mp
70.0–71.3 °C (yellow crystals). 1H NMR (CDCl3) d 8.22 (s, 1H, ArCH),
7.84 (s, 1H, ArH), 7.76 (d, 1H, J = 3.5 Hz, ArH), 7.74 (d, 1H, J = 3.0 Hz,
ArH), 7.47 (d, 1H, J = 8.6 Hz, ArH), 7.19 (dd, 1H, J1 = 8.9 Hz, J2 = 2.0
Hz, ArH), 7.12 (s, 1H, ArH), 4.05 (t, 2H, J = 6.3 Hz, CH2CH2CH2O),
2.54 (s, 3H, CH3CNO2), 1.88 (m, 2H, CH2CH2CH2O), 1.08 (t, 3H,
J = 7.3 Hz, CH3CH2CH2O).
4.1.3.2. 6-Ethoxy-2-naphthaldehyde. Yield 21%, mp 67.3–68.1 °C
(yellow crystals). 1H NMR (CDCl3) d 10.07 (s, 1H, CHO), 8.22 (s, 1H,
ArH), 7.89 (dd, 1H, J1 = 8.8 Hz, J2 = 1.8 Hz, ArH), 7.87 (d, 1H, J = 9.3
Hz, ArH), 7.76 (d, 1H, J = 8.3 Hz, ArH), 7.21 (dd, 1H, J1 = 8.8 Hz,
J2 = 2.6 Hz, ArH), 7.14 (d, 1H, J = 2.3 Hz, ArH), 4.17 (q, J = 7.1 Hz,
CH3CH2O), 1.48 (t, 3H, J = 6.8 Hz, CH3CH2O).
4.1.4.6. 2-(6-Butoxynaphthyl)-1-nitropropene. Yield 70%, mp
50.8–51.8 °C (yellow crystals). 1H NMR (CDCl3) d 8.21 (s, 1H,
ArCH), 7.83 (s, 1H, ArH), 7.75 (d, 2H, J = 8.3 Hz, ArH), 7.47 (dd,
1H, J1 = 8.6 Hz, J2 = 1.3 Hz, ArH), 7.18 (dd, 1H, J1 = 8.8 Hz, J2 = 2.3
Hz, ArH), 7.13 (d, 1H, J = 2.0 Hz, ArH), 4.09 (t, 2H, J = 6.6 Hz,
CH3CH2CH2CH2O), 2.53 (s, 3H, CH3CNO2), 1.83 (m, 2H, CH3CH2
CH2CH2O), 1.53 (m, 2H, CH3CH2CH2CH2O), 1.00 (t, 3H, J = 7.3 Hz,
CH3CH2CH2CH2O).
4.1.3.3. 6-Propoxy-2-naphthaldehyde. Yield 25%, mp 43.0–
44.5 °C (yellow crystals). 1H NMR (CDCl3) d 10.08 (s, 1H, CHO),
8.24 (s, 1H, ArH), 7.91 (d, 1H, J = 7.4, ArH), 7.88 (d, 1H, J = 9.0 Hz,
ArH), 7.77 (d, 1H, J = 8.6 Hz, ArH), 7.23 (dd, 1H, J1 = 9.0 Hz,
J2 = 2.4 Hz, ArH), 7.16 (d, 1H, J = 1.8 Hz, ArH), 4.07 (t, 2H, J = 6.4
Hz, CH3CH2CH2O), 1.89 (m, 2H, CH3CH2CH2O), 1.09 (t, 3H, J = 7.4
Hz, CH3CH2CH2O).
4.1.4.7. 2-(6-Benzyloxynaphthyl)-1-nitropropene. Yield 76% mp
151.0–153.3 °C (yellow crystals). 1H NMR (CDCl3) d 8.22 (s, 1H,
ArCH), 7.85 (s, 1H, ArH), 7.77 (m, 2H, ArH), 7.48 (d, 3H, J = 8.1 Hz,
ArCH2), 7.40 (m, 2H, ArH), 7.35 (d, 1H, J = 7.1 Hz, ArH), 7.27 (dd,
1H, J1 = 8.8 Hz, J2 = 2.3 Hz, ArH), 7.22 (d, 1H, J = 1.8 Hz, ArH), 5.19
(s, 2H, ArCH2O), 2.53 (s, 3H, CH3CNO2).
4.1.3.4. 6-Butoxy-2-naphthaldehyde. Yield 43%, mp 31.5–33.0 °C
(yellow crystals). 1H NMR (CDCl3) d 10.09 (s, 1H, CHO), 8.24 (s, 1H,
ArH), 7.91 (dd, 1H, J1 = 9.0 Hz, J2 = 1.6 Hz, ArH), 7.89 (d, 1H, J = 9.4
Hz, ArH), 7.78 (d, 1H, J = 8.6 Hz, ArH), 7.23 (dd, 1H, J1 = 8.9 Hz,
J2 = 2.5 Hz, ArH), 7.16 (d, 1H, J = 2.4 Hz, ArH), 4.12 (t, 2H, J = 6.4
Hz, CH3CH2CH2 CH2O), 1.86 (m, 2H, CH3CH2 CH2CH2O), 1.55 (m,
2H, CH3CH2CH2CH2O), 1.01 (t, 3H, J = 7.3 Hz, CH3CH2CH2CH2O).
4.1.5. General procedure for the preparation of naphthylisopro-
pylamine hydrochlorides (1 and 2a–2f)
4.1.3.5. 6-Benzyloxy-2-naphthaldehyde. Yield 15%, mp 94.5–
97.8 °C (yellow crystals). 1H NMR (CDCl3) d 10.08 (s, 1H, CHO),
8.24 (s, 1H, ArH), 7.89 (dd, 2H, J1 = 8.3 Hz, J2 = 2.5 Hz, ArH), 7.78
(d, 1H, J = 9.0 Hz, ArH), 7.47 (d, 2H, J = 7.3 Hz, ArCH2), 7.42 (d, 1H,
J = 7.4 Hz, ArCH2), 7.40 (d, 1H, J = 7.5 Hz, ArCH2), 7.35 (d, 1H, J
=7.4 Hz, ArCH2), 7.30 (dd, 1H, J1 = 8.8 Hz, J2 = 2.2 Hz, ArH), 7.25
(d, 1H, J = 2.0 Hz, ArH), 5.20 (s, 2H, ArCH2O).
LiAlH4 (10 mmol) was carefully suspended in dry THF (60 ml)
with good stirring. Then, the corresponding nitrostyrene (1 mmol)
dissolved in THF (30 ml) was added dropwise. The reaction mix-
ture was refluxed and stirred for 3 days. After cooling to room tem-
perature, excess hydride was destroyed by careful dropwise
addition of water and then NaOH (15%; 3:1 in relation to the hy-
dride). The mixture was filtered to remove the insoluble salts, dried
with MgSO4 and the solvent evaporated under reduced pressure. In
all cases the amine was obtained as an oil that was purified by dis-
tillation using a Kugelrohr device. The product was taken up into a
minimal quantity (3 ml) of 2-propanol and converted to the hydro-
chloride by adding concentrated HCl (4–5 drops). The solution was
diluted with anhydrous ether, which resulted in the formation of
white crystals.
4.1.4. General procedure for the preparation of naphthylnitro-
propenes
The appropriate naphthaldehyde (1 mmol), nitroethane
(10 mmol) and cyclohexylamine (5 mmol) were dissolved in acetic
acid (50 ml). This reaction mixture was kept at 100 °C for 24 h,
after which the solvent was evaporated. Boiling methanol (30 ml)
was added to the product obtained, and after cooling to 4 °C, the
corresponding nitrostyrenes crystallized.
4.1.5.1. 1-(1-Naphthyl)-2-aminopropane hydrochloride (1). Yield
11%, mp 215.0–218.5 °C. 1H NMR (D2O) d 7.98 (d, 1H, J = 8.1 Hz,
ArH), 7.89 (d, 1H, J = 8.1 Hz, ArH), 7.81 (d, 1H, J = 8.1 Hz, ArH), 7.52
(m, 2H, ArH), 7.42 (t, 1H, J = 7.58 Hz, ArH), 7.36 (d, 1H, J = 7.07 Hz,
ArH), 3.68 (m, 1H, ArCH2CH(CH3)NH3þ), 3.29 (m, 2H, ArCH2), 1.24
(d, 3H, J = 6.6 Hz, ArCH2CH(CH3)NH3þ). Anal. Calcd for C13H16ClN: C,
70.42; H, 7.27; N, 6.32. Found: C, 66.91; H, 8.27; N, 6.35.
4.1.4.1. 1-(1-Naphthyl)-2-nitropropene. Yield 80%, mp 59.8–
60.5 °C (yellow crystals). 1H NMR (CDCl3) d 8.68 (s, 1H, ArCH),
7.96 (m, 3H, ArH), 7.62 (m, 3H, ArH), 7.07 (d, 1H, J = 7.1 Hz, ArH),
2.41 (s, 3H, CH3CNO2).
4.1.4.2. 1-(2-Naphthyl)-2-nitropropene. Yield 75%, mp 81.0–
83.5 °C (yellow crystals). 1H NMR (CDCl3) d 8.30 (s, 1H, ArCH),
7.94 (m, 4H, ArH), 7.59 (m, 3H, ArH), 2.59 (s, 3H, CH3CNO2).
4.1.5.2. 1-(2-Naphthyl)-2-aminopropane hydrochloride (2a).
Yield 40%, mp 205.0–207.0 °C (lit.28 205.2–205.5 °C). 1H NMR
(D2O) d 7.82 (t, 3H, ArH), 7.69 (s, 1H, ArH), 7.46 (m, 2H, ArH),
7.33 (d, 1H, J = 8.1 Hz, ArH), 3.62 (m, 1H, ArCH2CH(CH3)NH3þ),
2.98 (d, 2H, J = 7.1 Hz, ArCH2), 1.22 (d, 3H, J = 6.6 Hz, ArCH2-
CH(CH3)NH3þ). Elemental analysis of this compound was re-
ported previously.28
4.1.4.3. 2-(6-Methoxynaphthyl)-1-nitropropene. Yield 77%, mp
87.5–88.3 °C (yellow crystals). 1H NMR (CDCl3) d 8.21 (s, 1H, ArCH),
7.84 (s, 1H, ArH), 7.77 (d, 1H, J = 3.8 Hz, ArH), 7.75 (d, 1H, J = 4.0 Hz,
ArH), 7.48 (dd, 1H, J1 = 8.6 Hz, J2 = 1.3 Hz, ArH), 7.19 (dd, 1H, J1 = 9.1
Hz, J2 = 2.2 Hz, ArH), 7.13 (d, 1Hg, J = 2.3 Hz, ArH), 3.93 (s, 3H,
OCH3), 2.53 (s, 3H, CH3CNO2).
4.1.5.3. (6-Methoxy-2-naphthyl)-2-aminopropane hydrochlo-
ride (2b). Yield 47%, mp 237.8–238.2 °C. 1H NMR (D2O) d 7.69 (d,
2H, J = 7.6 Hz, ArH), 7.58 (s, 1H, ArH), 7.27 (d, 1H, J = 8.3 Hz,
ArH), 7.20 (s, 1H, ArH), 7.08 (dd, 1H, J1 = 9.1 Hz, J2 = 1.5 Hz, ArH),
3.80 (s, 3H, OCH3), 3.57 (m, 1H, ArCH2CH(CH3)NH3þ), 2.93 (d, 2H,
J = 7.3 Hz, ArCH2), 1.20 (d, 3H, J = 6.6 Hz, ArCH2CH(CH3)NH3þ). Anal.
Calcd for C14H18ClNO: C, 66.79; H, 7.21; N, 5.56. Found: C, 65.01; H,
7.80; N, 5.40.
4.1.4.4. 2-(6-Ethoxynaphthyl)-1-nitropropene. Yield 69%, mp
108.0–109.8 °C (yellow crystals). 1H NMR (CDCl3) d 8.21 (s, 1H,
ArCH), 7.84 (s, 1H, ArH), 7.77 (d, 1H, J = 3.5 Hz, ArH), 7.74 (d, 1H,
J = 3.03 Hz, ArH), 7.47 (d, 1H, J = 8.6 Hz, ArH), 7.19 (dd, 1H,
J1 = 8.8 Hz, J2 = 2.2 Hz, ArH), 7.12 (d, 1H, J = 1.8 Hz, ArH), 4.16 (q,
2H, J = 6.8 Hz, CH3CH2O), 2.53 (s, 3H, CH3CNO2), 1.48 (t, 3H,
J = 6.8 Hz, CH3CH2O).

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M. Vilches-Herrera et al. / Bioorg. Med. Chem. 17 (2009) 2452–2460
4.1.5.4. (6-Ethoxy-2-naphthyl)-2-aminopropane hydrochloride
(2c). Yield 30%, mp 252.9–254.5 °C. 1H NMR (D2O) d 7.63 (d, 2H,
J = 8.9 Hz, ArH), 7.52 (s, 1H, ArH), 7.20 (dd, 1H, J1 = 8.3 Hz, J2 = 1.3
Hz, ArH), 7.15 (d, 1H, J = 2.3 Hz, ArH), 7.01 (dd, 1H, J1 = 8.9 Hz,
J2 = 2.3 Hz, ArH), 4.01 (q, 2H, J = 6.8 Hz, OCH2CH3), 3.48 (m, 1H,
ArCH2CH(CH3)NH3þ), 2.85 (d, 2H, J = 7.1 Hz, ArCH2), 1.23 (t, 3H,
J = 7.1 Hz, OCH2CH3), 1.11 (d, 3H, J = 6.8 Hz, ArCH2CH(CH3)NH3þ).
Anal. Calcd for C15H20ClNO: C, 67.79; H, 7.58; N, 5.27. Found: C,
66.81; H, 8.39; N, 5.14.
chromatography on Silica Gel 60, eluting with DCM. After recrys-
tallization in methanol the product was obtained as yellow crys-
tals. Yield 50%, mp 111.3–113.5 °C. 1H NMR (CDCl3) d 8.00 (d, 2H,
J = 9.4 Hz, ArH), 7.76 (d, 1H, J = 8.6 Hz, ArH), 7.69 (d, 1H, J = 8.6
Hz, ArH), 7.57 (d, 2H, J = 8.6 Hz, ArH), 3.09 (s, 6H, N(CH3)2).
4.1.8. Preparation of 6-bromo-2-mercaptonaphthalene
A mixture of the compound prepared in the previous step
(1 mmol) in methanol (50 ml) and KOH (10 mmol) was refluxed
for 24 h. After cooling to room temperature, the mixture was made
acid with concentrated HCl, extracted with DCM, dried with
MgSO4, and filtered, and the solvent evaporated under reduced
pressure. Finally the product was recrystallized from methanol.
Yield 63%, mp 158.3–163.5 °C (white crystals). 1H NMR (CDCl3) d
7.93 (s, 1H, ArH), 7.70 (s, 1H, ArH), 7.63 (d, 1H, J = 8.6 Hz, ArH),
7.55 (d, 2H, J = 4.0, ArH), 7.35 (d, 1H, J = 8.6, ArH).
4.1.5.5. (6-Propoxy-2-naphthyl)-2-aminopropane hydrochlo-
ride (2d). Yield 68%, mp 232.6–236.6 °C. 1H NMR (DMSO-d6) d
7.72 (d, 2H, J = 8.6 Hz, ArH), 7.60 (s, 1H, ArH), 7.29 (dd, 1H,
J1 = 8.3 Hz, J2 = 1.5 Hz, ArH), 7.23 (d, 1H, J = 2.5 Hz, ArH), 7.10
(dd, 1H, J1 = 9.1 Hz, J2 = 2.5 Hz, ArH), 3.97 (t, 2H, J = 6.6 Hz,
CH3CH2CH2O), 3.40 (m,1H, ArCH2CH(CH3)NH3þ), 3.05 (dd, 1H,
J1 = 5.3 Hz, J2 = 13.4 Hz, ArCH2), 2.74 (dd, 1H, J1 = 8.8 Hz, J2 = 13.4
Hz, ArCH2), 1.74 (m, 2H, CH3CH2CH2O), 1.08 (d, 3H, J = 6.6 Hz,
ArCH2CH(CH3)NH3þ), 0.96 (t, 3H, J = 7.3 Hz, CH3CH2CH2O). Anal.
Calcd for C16H22ClNO: C, 68.68; H, 7.93; N, 5.01. Found: C, 68.37;
H, 9.31; N, 5.08.
4.1.9. Preparation of 2-bromo-6-methylthionaphthalene
This compound was prepared following the same general proce-
dure used for the synthesis of 2-bromo-6-alkoxynaphthalenes
(step 4.1.2.). Yield 86%, mp 87.6–88.9 °C (white crystals). 1H NMR
(CDCl3) d 7.97 (s, 1H, ArH), 7.68 (d, 1H, J = 9.1 Hz, ArH), 7.64 (d,
1H, J = 9.1 Hz, ArH), 7.57 (d, 2H, J = 8.6 Hz, ArH), 7.43 (dd, 1H,
J1 = 8.6 Hz, J2 = 1.5 Hz, ArH), 2.62 (s, 3H, SCH3).
4.1.5.6. (6-Butoxy-2-naphthyl)-2-aminopropane hydrochloride
(2e). Yield 14%, mp 234.5–237.0 °C. 1H NMR (DMSO-d6) d 7.71 (d,
2H, J = 7.8 Hz, ArH), 7.60 (s, 1H, ArH), 7.29 (dd, 1H, J1 = 8.3 Hz,
J2 = 1.5 Hz, ArH), 7.24 (d, 1H, J = 2.3 Hz, ArH), 7.09 (dd, 1H,
J1 = 8.9 Hz, J2 = 2.5 Hz, ArH), 4.01 (t, 2H, J = 6.6 Hz,
CH3CH2CH2CH2O), 3.42 (m, 1H, ArCH2CH(CH3)NH3þ), 3.07 (dd,
1H, J1 = 5.3 Hz, J2 = 13.4 Hz, ArCH), 2.73 (dd, 1H, J1 = 8.8 Hz,
J2 = 13.4 Hz, ArCH), 1.70 (m, 2H, CH3CH2CH2CH2O), 1.42 (m, 2H,
CH3CH2CH2CH2O), 1.08 (d, 3H, J = 6.6 Hz, ArCH2CH(CH3)NH3þ),
0.90 (t, 3H, J = 7.3 Hz, CH3CH2CH2CH2O). Anal. Calcd for
C17H24ClNO: C, 69.49; H, 8.23; N, 4.77. Found: C, 69.51; H, 9.88;
N, 4.87.
4.1.10. Preparation of 2-cyano-6-methylthionaphthalene
To a solution of the compound prepared in the previous step
(1 mmol) in DMF (70 ml), CuCN (1.5 mmol) was added and the
mixture was refluxed for 48 h. After cooling to room temperature,
the reaction mixture was poured into ice/water, made basic with
NH3, extracted with DCM, dried with Na2SO4, filtered and the sol-
vent evaporated under reduced pressure. The product crystallized
after adding methanol. Yield 32%, mp 98.8–100.3 °C (white crys-
tals). 1H RMN (CDCl3) d 8.19 (s, 1H, ArH), 7.81 (t, 2H, J = 9.1 Hz,
ArH), 7.63 (dd, 1H, J1 = 8.6 Hz, J2 = 1.5 Hz, ArH), 7.60 (s, 1H, ArH),
7.50 (dd, 1H, J1 = 9.1 Hz, J2 = 2.0 Hz, ArH), 2.52 (s, 3H, SCH3).
4.1.5.7. (6-Benzyloxy-2-naphthyl)-2-aminopropane hydrochlo-
ride (2f). Yield 33%, mp 236.2–238.2 °C. 1H NMR (DMSO-d6) d 7.77
(d, 2H, J = 8.3 Hz, ArH), 7.66 (s, 1H, ArH), 7.49 (d, 2H, J = 7.7 Hz,
ArH), 7.40 (m, 3H, ArCH2), 7.35 (d, 2H, J = 8.4 Hz, ArCH2), 7.22
(dd, 1H, J1 = 8.9 Hz, J2 = 2.5 Hz, ArH), 5.20 (s, 2H, ArCH2O), 3.45
(m, 1H, ArCH2CH(CH3)NH3þ), 3.09 (dd, 1H, J1 = 5.5 Hz, J2 = 13.4
Hz, ArCH2), 2.78 (dd, 1H, J1 = 8.8 Hz, J2 = 13.4 Hz, ArCH2), 1.12 (d,
3H, J = 6.4 Hz, ArCH2CH(CH3)NH3þ). Anal. Calcd for C20H22ClNO:
C, 73.27; H, 6.76; N, 4.27. Found: C, 72.95; H, 7.51; N, 4.34.
4.1.11. Preparation of 6-methylthio-2-naphthaldehyde
To a solution of the compound prepared in the previous step
(1 mmol) in THF (50 ml), 5 ml of DIBAH (1 M in THF) were added,
and the reaction mixture was kept at room temperature for 4 h.
Then, methanol and water made acid with drops of H2SO4 were
added giving a gelatinous product, which was filtered over Celite.
The solvent was evaporated under reduced pressure and the
product crystallized after adding methanol (yield 58.2%). The final
product was recognized by TLC, developing with 2,4-dinitrophen-
ylhydrazine, and used in the subsequent steps without further
purification.
4.1.6. Preparation of 6-O-(2-bromonaphthyl)-dimethylthiocar-
bamate
The previously prepared 6-bromo-2-naphthol (1 mmol) was
dissolved in DMF (100 ml) with good stirring at ꢀ10 °C, and then
NaH (1.5 mmol) was carefully added. Then, dimethylthiocarba-
moyl chloride (1.5 mmol) dissolved in DMF (50 ml) was added,
and this reaction mixture was kept at 80–90 °C for 48 h. After cool-
ing to room temperature, KOH (15%, 200 ml) was added and the
mixture extracted with DCM. The organic layer was dried with
Na2SO4 and after filtering, removal of the solvent in vacuo gave
the product, which was recrystallized from methanol. Yield 54%,
mp 128.3–129.5 °C (white crystals). 1H NMR (CDCl3) d 8.02 (s,
1H, ArH), 7.77 (d, 1H, J = 8.9 Hz, ArH), 7.68 (d, 1H, J = 8.9 Hz,
ArH), 7.56 (dd, 1H, J1 = 8.8 Hz, J2 = 2.0 Hz, ArH), 7.48 (d, 1H,
J = 2.02, ArH), 7.29 (dd, 1H, J1 = 8.8 Hz, J2 = 2.3 Hz, ArH), 3.49 (s,
3H, NCH3), 3.41 (s, 3H, NCH3).
4.1.12. Preparation of 1-(6-methylthio-2-naphthyl)-2-nitropro-
pene
This compound was prepared following the same general proce-
dure used for the synthesis of naphthyl-nitropropenes (step 4.1.4.).
Yield 42%, mp 99.6–101.6 °C (yellow crystals). 1H NMR (CDCl3) d
8.27 (s, 1H, ArCH), 7.91 (s, 1H, ArH), 7.82 (m, 2H, ArH), 7.62 (s,
1H, ArH), 7.56 (dd, 1H, J1 = 8.6 Hz, J2 = 1.5 Hz, ArH), 7.46 (dd, 1H,
J1 = 8.6 Hz, J2 = 2.0 Hz, ArH), 2.65 (s, 3H, CH3CNO2), 2.59 (s, 3H,
SCH3).
4.1.13. Preparation of (6-methylthio-2-naphthyl)
isopropylamine hydrochloride (2g)
This compound was prepared following the same general proce-
dure used for the synthesis of the other naphthylisopropylamine
hydrochlorides (step 4.1.5.). Yield 47%, mp 216–219 °C (yellow
crystals). 1H NMR (DMSO-d6) d 7.81 (m, 2H, ArH), 7.71 (s, 2H,
ArH), 7.40 (d, 2H, J = 8.6 Hz, ArH), 3.52 (m, 1H, ArCH2-
4.1.7. Preparation of 6-S-(2-bromonaphthyl)-dimethylthiocar-
bamate
The compound prepared in the previous step was melted and
kept at 220 °C for 6 h and the product was purified by column

M. Vilches-Herrera et al. / Bioorg. Med. Chem. 17 (2009) 2452–2460
2459
CH(CH3)NH3þ), 3.14 (dd, 1H, J1 = = 5.6 Hz, J2 = 13.1 Hz, ArCH), 2.83
(dd, 1H, J1 = 8.6 Hz, J2 = 13.1 Hz, ArCH), 2.58 (s, 3H, SCH3), 1.15 (d,
3H, J = 6.1 Hz, ArCH2CH(CH3)NH2). Anal. Calcd for C14H18ClNS: C,
62.79; H, 6.77; N, 5.23; S, 11.97. Found: C, 61.03; H, 7.62; N,
5.15; S, 13.17.
4.1.14.5. N-4-Methoxybenzyl-(4-methylthioamphetamine) hy-
drochloride (4c). Yield 86%, mp 172.7–173.2 °C, 1H NMR (CDCl3) d
9.85 (s, 2H, NH2þ), 7.55 (d, 2H, J = 8.5 Hz, ArH), 7.15 (d, 2H, J = 8.3
Hz ArH), 7.05 (d, 2H, J = 8.2 Hz, ArH), 6.88 (d, 2H, J = 8.7 Hz, ArH),
4.03 (m, 2H, ArCH2NH2þ), 3.65 (s, 3H, CH3OAr), 3.38 (dd, 2H,
J1 = 13.0, J2 = 3.4 Hz, ArCH2CH(CH3)NH2þCH2Ar), 3.13 (m, 1H,
ArCH2CH(CH3)NH2CH2Ar), 2.72 (dd, 1H, J = 12.8 Hz, ArCH2-
CH(CH3)NH2þCH2Ar), 2.45 (s, 3H, CH3S), 1.29 (d, 3H, J = 6.3 Hz,
CH(CH3)NH2). Anal. Calcd for C18H24ClNOS: C, 63.98; H, 7.16; N,
4.15; S, 9.49. Found: C, 60.39; H, 8.05; N, 4.04; S, 11.66.
4.1.14. General procedure for the preparation of N-benzyl
derivatives (2h and 2i and 4a–4e)
To a well stirred solution of the appropriate amine (compounds
2b, 2e or 3g; 1 mmol) as a free base in methanol (50 ml), was
added dropwise the corresponding benzaldehyde (1 mmol), stir-
ring at room temperature for 24 h. To this mixture was added
NaBH3CN (1.6 mmol) and stirring was continued for additional
20 min. NaOH 40% (3 ml) was added to terminate the reaction.
After removing the solvent under vacuum the product was purified
by preparative TLC (Silica Gel 60, EtOAc). In all cases the product
was obtained as an oil, which was dissolved in a minimal volume
(3 ml) of 2-propanol and converted to the hydrochloride by adding
concentrated HCl (1–3 drops). The solution was diluted with anhy-
drous ether, which resulted in the formation of white crystals.
4.1.14.6. N-4-Butoxybenzyl-(4-methylthioamphetamine) hy-
drochloride (4d). Yield 80%, mp 184.8–189.2 °C, 1H NMR (CDCl3)
d 9.89 (s, 2H, NH2þ), 7.55 (d, 2H, J = 8.6 Hz, ArH), 7.15 (d, 2H,
J = 8.2 Hz, ArH), 7.05 (d, 2H, J = 8.2 Hz, ArH), 6.85 (d, 2H, J = 8.5
Hz, ArH), 4.01 (1H, d, J = 13.2 Hz, ArCH2NH2þ), 3.92 (1H, d,
J = 13.2 Hz, ArCH2NH2þ), 3.75 (t, 2H, J = 6.5 Hz, ArOCH2(CH2)2CH3),
3.40 (dd, 1H, J1 = 13.0, J2 = 3.4 Hz, NH2þCH2Ar), 3.16 (m, 1H, ArCH2-
CH(CH3)NH2þCH2Ar), 2.76 (dd, 1H, J = 13.0 Hz, NH2CH2Ar), 2.47 (s,
3H, CH3S), 1.69 (qui, 2H, J = 6.5 Hz, ArOCH2CH2CH2CH3) 1.43 (sex,
2H, J = 7.5 Hz, ArOCH2CH2CH2CH3) 1.31 (d, 3H, J = 6.4 Hz,
CH(CH3)NH2þ), 0.96 (t, 3H, J = 7.5 Hz, ArOCH2CH2CH2CH3). Anal.
Calcd for C21H30ClNOS: C, 66.38; H, 7.96; N, 3.69; S, 8.44. Found:
C, 65.92; H, 8.44; N, 3.82; S, 11.54.
4.1.14.1.
N-Benzyl-(6-methoxy-2-naphthyl)-2-aminopropane
hydrochloride (2h). Yield 25%, mp 251.0–218.0 °C. 1H NMR
(CDCl3), d 7.65 (d, 2H, J = 8.3 Hz, ArH), 7.51 (s, 1H, ArH), 7.22 (m,
6H, ArH), 7.12 (d, 2H, J = 9.6 Hz, ArH), 3.90 (s, 3H, OCH3), 3.87 (d,
1H, J = 13.1 Hz, NHCHAr), 3.76 (d, 1H, J = 13.1 Hz, NHCHAr), 3.05
(m, 1H, ArCH2CH(CH3)NH3þ), 2.91 (dd, 1H, J1 = 7.1 Hz, J2 = 13.6
Hz, ArCH), 2.77 (dd, 1H, J1 = 6.6 Hz, J2 = 13.4 Hz, ArCH), 1.14 (d,
3H, J = 6.1 Hz, ArCH2CH(CH3)NH3þ). Anal. Calcd for C21H24ClNO:
C, 73.78; H, 7.08; N, 4.10. Found: C, 72.33; H, 7.36; N, 4.25.
4.1.14.7. N-4-Benzyloxybenzyl-(4-methylthioamphetamine) hy-
drochloride (4e). Yield 95%, mp 188.0–189.1 °C, 1H NMR (CDCl3) d
8.95 (s, 2H, NH2þ), 7.42 (d, 2H, J = 8.5 Hz, ArH), 7.38 (dd, 2H, J = 6.8
Hz, ArH), 7.34 (dddd, 2H, J = 7.2 Hz, ArH), 7.26 (dddd, 1H, J = 7.1 Hz,
ArH), 7.16 (d, 2H, J = 8.6 Hz, ArH), 7.10 (d, 2H, J = 8.3 Hz, ArH), 7.01
(d, 2H, J = 8.8 Hz, ArH), 5.08 (s, 2H, ArCH2O), 4.10 (1H, d, Japp = 13.3
Hz, ArCH2 NH2þ), 4.05 (1H, d, Japp = 13.3 Hz, ArCH2 NH2þ), 3.19 (dd,
1H, J1 = 13.0, J2 = 3.7 Hz, ArCH2CH(CH3)NH2þCH2Ar), 2.54 (dd, 1H,
J = 13.1 Hz, ArCH2CH(CH3)NH2þCH2Ar), 2.39 (s, 3H, CH3S), 1.25 (d,
3H, J = 6.0 Hz, CH(CH3)NH2þ). Anal. Calcd for C24H28ClNOS: C,
69.63; H, 6.82; N, 3.38; S, 7.75. Found: C, 69.62; H, 6.93; N, 3.50;
S, 10.69.
4.1.14.2. N-Benzyl-(6-butoxy-2-naphthyl)-2-aminopropane hy-
drochloride (2i). Yield 18% mp 210.0–214.0 °C. 1H NMR (D2O) d
7.72 (s,1H, ArH), 7.71 (d, 1H, J = 1.8 Hz, ArH), 7.61 (s, 1H, ArH),
7.57 (d, 2H, J = 6.6 Hz, ArH), 7.40 (m, 3H, ArH), 7.27 (d, 1H, J = 8.6
Hz, ArH), 7.24 (d, 1H, J = 2.0 Hz, ArH), 7.09 (dd, 1H, J1 = 9.1 Hz,
J2 = 2.5 Hz, ArH), 4.20 (m, 2H, NHCH2Ar), 4.02 (t, 2H, J = 6.6 Hz,
CH3CH2CH2CH2O), 3.40 (d, 2H, J = 13.4 Hz, ArCH2), 2.75 (m, 1H,
ArCH2CH(CH3)NH3þ), 1.70 (m, 2H, CH3CH2CH2CH2O), 1.42 (m, 2H,
CH3CH2CH2CH2O), 1.15 (d, 3H, J = 6.3 Hz, ArCH2CH(CH3)NH3þ),
0.90 (t, 3H, J = 7.3 Hz, CH3CH2CH2CH2O). Anal. Calcd for
C24H30ClNO: C, 75.08; H, 7.88; N, 3.65. Found: C, 74.59; H, 9.18;
N, 3.81.
4.2. Biochemistry
The effects of the compounds on MAO-A or MAO-B activities
were studied following previously reported methodologies,12,24
using a crude rat brain mitochondrial suspension as a source of en-
zyme. Serotonin (100
lM) and 4-dimethylaminophenethylamine
4.1.14.3. N-Benzyl-(4-methylthioamphetamine) hydrochloride
(4a). Yield 90%, mp 184.0–185.3 °C, 1H NMR (CDCl3) d 10.03 (s, 2H,
NH2þ), 7.65 (d, 2H, J = 7.0 Hz, ArH), 7.45–7.25 (m, 3H, ArH), 7.15 (d,
2H, J = 8.3 Hz, ArH), 7.01 (d, 2H, J = 8.3 Hz, ArH), 4.10 (d, 1H, J = 3.5
Hz, NH2þCH2Ar), 4.02 (d, 1H, J = 3.6 Hz, NH2þCH2Ar), 3.41 (dd, 2H,
J1 = 13.1, J2 = 3.6 Hz, ArCH2CH(CH3)NH2þCH2Ar), 3.45 (dd, 2H,
J = 3.6 Hz, NH2þCH2Ar), 3.13 (m, 1H, ArCH2CH(CH3)NH2þCH2Ar),
2.77 (dd, 1H, J = 12.9 Hz, NH2þCH2Ar), 2.45 (s, 3H, CH3S), 1.31 (d,
3H, J = 6.4 Hz, CH(CH3)NH2þ). Anal. Calcd for C17H22ClNS: C,
66.32; H, 7.20; N, 4.55; S, 10.41. Found: C, 66.41; H, 7.58; N,
4.74; S, 12.76.
(5 M) were used as selective substrates for MAO-A and -B, respec-
l
tively, and these compounds and their metabolites were detected
by HPLC with electrochemical detection as described previ-
ously.12,24 IC50 values (mean SD from at least two independent
experiments, each in triplicate) were determined using GRAPH PAD
PRISM software, from plots of inhibition percentages (calculated in
relation to a sample of the enzyme treated under the same condi-
tions without inhibitors) versus ꢀlog inhibitor concentration. Ki
were determined from the IC50 values using the Cheng–Prusoff
equation: Ki = IC50/(1 + [S]/Km),41 Km (5-HT, MAO-A) = 100
(DMAPEA, MAO-B) = 5 M. A kinetic study was carried out on 2b
to ascertain the type of inhibition, using four substrate concentra-
tions (25, 50, 100, and 125 M), and three inhibitor concentrations
(0.1, 0.5, and 1.0 M), incubating for five different times. Each
lM, Km
l
4.1.14.4. N-4-Hydroxybenzyl-(4-methylthioamphetamine) hy-
drochloride (4b). Yield 94%, mp 198.3–199.5 °C, 1H NMR (CDCl3/
DMSO-d6) d 9.63 (s, 2H, NH2þ), 9.36 (s, 1H, ArOH), 7.45 (d, 2H,
J = 8.5 Hz, ArH), 7.18 (d, 2H, J = 8.2 Hz ArH), 7.12 (d, 2H, J = 8.2
Hz, ArH), 6.87 (d, 2H, J = 8.4 Hz, ArH), 4.04 (m, 2H, NH2þCH2Ar),
3.38 (dd, 1H, J1 = 12.8, J2 = 3.6 Hz, ArCH2CH(CH3)NH2þCH2Ar),
3.26 (m, 1H, ArCH2CH(CH3)NH2þH2þCH2Ar), 2.78 (dd, 1H, J = 12.9
Hz, ArCH2CH(CH3)NH2þCH2Ar), 2.47 (s, 3H, CH3S), 1.29 (d, 3H,
J = 6.4 Hz, CH(CH3)NH2þ). Anal. Calcd for C17H22ClNOS: C, 63.04;
H, 6.85; N, 4.32; S, 9.90. Found: C, 61.27; H, 7.72; N, 4.30; S, 12.07.
l
l
experiment was performed in duplicate.
4.3. Molecular simulation
The crystallographic data of rat MAO-A (PDB: 1O5 W) were
used for all calculations. The AUTODOCK 3.05 suite42 was then used
to perform the docking simulations and conditions were as previ-
ously reported.15,27 Briefly, the hydrogen atoms of the protein and

2460
M. Vilches-Herrera et al. / Bioorg. Med. Chem. 17 (2009) 2452–2460
the FAD molecule were built using Insight II,43 and the structures
were relaxed following a minimization protocol using Discover_3
and the ESFF force field. The grid maps were calculated using the
autogrid3 option and were centered on the putative ligand-binding
site. The volumes chosen for the grid maps were made up of
40 ꢁ 40 ꢁ 40 points, with a grid-point spacing of 0.375 Å. The par-
tial charges of different compounds were corrected using RESP
methodology.44 The dielectric constant was adjusted to 2 in the
grid parameter file (gpf) of the AUTODOCK suite. The docked com-
pound complexes were built using the lowest docked-energy bind-
ing positions. Although both enantiomers of compounds were
studied, in all cases the results obtained for the (S)-isomers were
used for the analysis.
12. Scorza, M. C.; Carrau, C.; Silveira, R.; Zapata-Torres, G.; Cassels, B. K.; Reyes-
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Acknowledgments
We thank Dr. Silvia Sepúlveda and Ms. Claudia Sanhueza for
their assistance with the HPLC analysis, and Drs. Edwin Pérez
and Gerald Zapata-Torres for critical reading of the manuscript.
This work was partially funded by FONDECYT Grant 1060199 and
ICM P05-001-F.
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