Synthesis and antifungal activities of novel 2-aminotetralin derivatives

Article abstract of DOI:10.1021/jm0701167

Novel 2-aminotetralin derivatives were synthesized as antifungal agents. The 2-aminotetralin scaffold was chemically designed to mimic the tetrahydroisoquinoline ring of the lead molecule described before. Their antifungal activities were evaluated in vitro by measuring the minimal inhibitory concentrations (MICs). Compounds 10a, 12a, 12c, 13b, and 13d are more potent than fluconazole against seven testing human fungal pathogens. Compound 10b exhibits much higher antifungal activities against all of the four fluconazole-resistant clinic Candida albicans strains than the control drugs including amphotericin B, terbinafine, ketoconazole, and itraconazole. The mode of action of some compounds to the potential receptor lanosterol 14α-demethylase (CYP51) was investigated by molecular docking. The studies presented here provide a new structural type for the development of novel antifungal compounds. Furthermore, 10b was evaluated in vivo by a rat vaginal candidiasis model, and it was found that 10b significantly decreases the number of fungal colony counts.

Full text of DOI:10.1021/jm0701167

J. Med. Chem. 2007, 50, 5293-5300
5293
Synthesis and Antifungal Activities of Novel 2-Aminotetralin Derivatives
Bin Yao,† Haitao Ji,‡ Yongbin Cao,† Youjun Zhou,*,† Ju¨ Zhu,† Jiaguo Lu¨,† Yaowu Li,† Jun Chen,† Canhui Zheng,†
Yuanying Jiang,*,† Rongmei Liang,† and Hui Tang†
School of Pharmacy, Second Military Medical UniVersity, 325 Guohe Road, Shanghai 200433, People’s Republic of China, and Department of
Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, and Center for Drug DiscoVery and Chemical Biology,
Northwestern UniVersity, EVanston, Illinois 60208-3113
ReceiVed January 30, 2007
Novel 2-aminotetralin derivatives were synthesized as antifungal agents. The 2-aminotetralin scaffold was
chemically designed to mimic the tetrahydroisoquinoline ring of the lead molecule described before. Their
antifungal activities were evaluated in vitro by measuring the minimal inhibitory concentrations (MICs).
Compounds 10a, 12a, 12c, 13b, and 13d are more potent than fluconazole against seven testing human
fungal pathogens. Compound 10b exhibits much higher antifungal activities against all of the four fluconazole-
resistant clinic Candida albicans strains than the control drugs including amphotericin B, terbinafine,
ketoconazole, and itraconazole. The mode of action of some compounds to the potential receptor lanosterol
14R-demethylase (CYP51) was investigated by molecular docking. The studies presented here provide a
new structural type for the development of novel antifungal compounds. Furthermore, 10b was evaluated
in vivo by a rat vaginal candidiasis model, and it was found that 10b significantly decreases the number of
fungal colony counts.
Introduction
antifungals have led to resistance.15 Hence, the second-genera-
tion azole compounds16 such as voriconazole, posaconazole,
ravuconazole (BMS-207147; E-1224), and albaconazole (UR-
9825) have shown broad-spectrum antifungal activity compa-
rable or superior to itraconazole.17-19 (Chart 1). Voriconazole
has established a role in the antifungal armamentarium. It has
been the primary therapy for invasive aspergillosis. Based on
clinical studies, posaconazole appears to be a useful alternative
in the treatment of invasive aspergillosis, zygomycosis, can-
didiasis, and cryptococcal meningitis. It is already approved in
the EU and FDA. Ravuconazole is undergoing re-evaluation
and albaconazole is undergoing Phase II clinical trials.20 Azoles
exert antifungal activity through inhibiting the CYP51 by a
mechanism in which the heterocyclic nitrogen atom (N-3 of
imidazole and N-4 of 1,2,4-triazole) binds to the sixth coordina-
tion position of the heme iron atom of the prophyrin in the
substrate-binding site of the enzyme.21 The resulting ergosterol
depletion and the accumulation of the precursor 14R-methylated
sterols interfere with the function of ergosterol as a membrane
component. They affect the structure and functions of the plasma
membrane, resulting in an inhibition of the growth of fungi.
Over the past three decades the incidence of severe, invasive,
and systemic fungal infections has increased dramatically.
Among these, the widespread diffusion of topical and systematic
infectious fungal diseases is often related to the use of broad-
spectrum antibiotics, immunosuppressive agents, anticancer, and
anti-AIDS drugs.1-4 One of the principal problems in the
treatment of fungal infections is the spread of antifungal drug
resistance mainly in patients chronically subjected to antimycotic
therapy such as HIV-infected people and other immunosup-
pressed patients.3 Although the arsenal of antifungal drugs has
expanded, currently available antifungal drugs do not meet the
increasing requirements of managing infection in the complex
patient populations.5,6 The development of new antifungal drugs
has been constantly required in the clinical therapy.
The antifungal agents currently marketed are mainly inhibitors
of ergosterol biosynthesis7 except amphotericin B, which
antifungal activity originates from its damaging binding to
ergosterol of fungal cell membranes8 and Echinocandins,9 such
as caspofungin, micafungin, and anidulafungin, which inhibit
the biosynthesis â-1,3-glucans,10 an important structural com-
ponent of the fungal cell wall. Three different types of inhibitors
of ergosterol biosynthetic pathway have been proven to be
clinically effective. These are azoles (N-substituted imidazoles
or 1,2,4-triazoles), which inhibit lanosterol 14R-demethylase
(CYP51);11 allylamines such as terbinafine, which act as a
squalene epoxidase inhibitor;12 and morpholines such as amo-
rolfine, ∆14-reductase and ∆8-7-isomerase inhibitors.13 Among
them, lanosterol 14R-demethylase has been proven to be a prime
target for antifungal therapy. Fluconazole and itraconzole are
the drugs of choice for the treatment of severe systemic mycoses.
Ketoconazole is widely used in the therapy of superficial
mycoses.14 Extensive use and prolonged therapy with azole
Differential inhibition of this cytochrome P-450 enzyme
between pathogenic fungi and human is the basis for the
clinically important activity of azole antifungal agents. The
specificity of the inhibitors is determined by the differential
complementary between the structure of the azole compound
and the active site of the fungal and host enzymes. In fact, one
of the reasons to continue the search for better antifungal agents
is to increase their specificity toward fungal enzyme. Because
CYP51 is a member of the cytochrome P450 superfamily, which
exists not only in fungi but in mammals; azole antifungal agents
are generally toxic and are hampered in the treatment of deep-
seated mycosis and life-threatening systemic infections because
of their ability to coordinate with the heme of a lot of host
cytochrome P450 enzymes, particularly mammalian CYP3A4.22,23
Cases of fatal hepatotoxicity have been reported.24-35 Although
the azole ring has been demonstrated to be one of the important
pharmacophores for antifungal activity,36,37 and it is also a key
toxicophore for the hepatotoxicity of azole antifungal agents.
* To whom correspondence should be addressed. Y.Z.: Phone: 86-21-
25070383. Fax: 86-21-25074587. E-mail: zhouyoujun2006@yahoo.com.cn.
Y.J.: Phone: 86-21-25070371. Fax: 86-21-65490641. E-mail: jiangyy@
smmu.edu.com.
† Second Military Medical University.
‡ Northwestern University.
10.1021/jm0701167 CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/28/2007

5294 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Yao et al.
Chart 1
On the basis of the analysis for the toxicity and activity of
azole antifungal agents, we believe that the search of novel
nonazole antifungal compounds with structural specificity to
the amino acids within the substrate-binding site of fungal
CYP51 (by the removal of the coordination binding to the heme
iron atom of CYP51) is meaningful in the separation of
antifungal activity from their hepatotoxicity. In the previous
study,38 we reported the design of nonazole antifungal lead
compounds based on the constructed three-dimensional model
of Candida albicans CYP51 by coupling structure-based de
novo design and found nonazole lead molecules with a
benzopyran scaffold. The biological evaluation of these com-
pounds illustrates that the benzopyran derivatives are the novel
nonazole inhibitors specific for the CYP51 of fungi. The affinity
of the lead molecules for CYP51 was mainly attributed to their
nonbonding interaction with the residues of apoprotein without
binding with the heme.38
Subsequently, another series of nonazole tetrahydroisoquino-
line compounds were designed and synthesized, and I-6 and
I-7 in Chart 1 are the most potent compounds discovered.39 The
antifungal activities of tetrahydroisoquinoline compounds were
better compared to those of the benzopyran derivatives, which
encouraged us to make further effort to explore more potent
nonazole antifungal lead compounds. Herein, the tetrahydroiso-
quinoline scaffold described in previous study was replaced with
a 2-aminotetralin nucleus, and novel derivatives were designed
based on the constructed structure of the active site of CYP51
of Candida albicans in the previous study.40,41 The antifungal
activities were evaluated in vitro and their structure-activity
relationship (SAR) was discussed.
4a-4d were obtained followed by a condensation reaction of
tetralones with hydroxylamine hydrochloride and a reduction
with metal hydrides, such as LiAlH4. N-Substituted 2-ami-
nomethoxy tetralin compounds 6a-6d, 8a-8d, 10a-10d, 12a-
12d, 14a-14d, 16a-16d, 18a-18d, 20a-20d, 22a-22d, 24a-
24d, and 26a-26d were prepared in high yields by a direct
reductive amination reaction of appropriate intermediates 3a-
3d with primary amines in anhydrous solvent. Sodium triac-
etoxyborohydride was used as the reductive reagent. N-Substi-
tuted 2-amino hydroxyltetralin compounds 7a-7d, 9a-9d,
11a-11d, 13a-13d, 15a-15d, 17a-17d, 19a-19d, 21a-21d,
23a-23d, 25a-25d, and 27a-27d were obtained by the
demethylating of the appropriate N-substituted 2-amino-meth-
oxytetralins 6a-6d, 8a-8d, 10a-10d, 12a-12d, 14a-14d,
16a-16d, 18a-18d, 20a-20d, 22a-22d, 24a-24d, and 26a-
26d with 48% hydrobromic acid under reflux.
Results and Discussion
In Vitro Antifungal Activities. The in vitro antifungal
activities of all the title compounds were listed in Table 1, in
which fluconazole and I-6 were used as the controls. All of the
title compounds exhibit potent antifungal activities against seven
pathogenic fungi, which were found in dermatomycoses (Tri-
chophyton rubrum, Fonsecaea compacta, and Microsporum
gypseum) and systemic mycoses (Candida albicans, Candida
parapsilosis, Cryptococcus neoformans, and Aspergillus fumi-
gatus). Compared to I-6, compounds 10a-11d, in which the
length of N-alkyl side chains at position 2 is as long as that of
I-6, exhibit much more potent antifungal activities against seven
pathogenic fungi.
In the previous study we presented that compound I-6
exhibited comparable or superior antifungal activities in com-
parison with fluconazole except against Candida albicans.39
However, 8b, 8c, 9b-13d, 14b-15b, 16c, 16d, and 17b-17d
in Table 1 exhibit higher antifungal activities than fluconazole
against Candida albicans. Compounds 8a, 8c, 8d, 9d-12a, 12c,
12d, 13b-13d, 14c, 14d, 15d, and 17d exhibit high antifungal
activities against Aspergillus fumigatus. Especially, compounds
Chemistry
A series of novel 2-aminotetralin compounds were synthe-
sized according to Scheme 1. The appropriate dihydroxy
naphthalenes 1a-1d were methylated with dimethyl sulfate to
generate 2a-2d, which were subsequently reduced according
to the method of Cornforth et al. to afford the desired methoxy
substituted-2-tetralones 3a-3d.42 The 2-amino methoxytetralins

2-Aminotetralins as Antifungal Agents
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5295
Scheme 1
8b, 9b, 10a, 10b, 11b, 12a, 12c, 13a, 13b, and 13d show their
MIC values lower than 0.125 µmol/L against Candida albicans.
Compounds 10a and 13d showed a MIC value of 8 µmol/L
against Aspergillus fumigatus. Compounds 10a, 12a, 12c, 13b,
and 13d exhibit more potent antifungal activities against all
seven pathogenic fungi than fluconazole.
Structure-Activity Relationship Analysis. The antifungal
activities of the compounds with N-substituted aromatic groups
(20a-21d and 24a-27d) are lower than those of the compounds
that contain N-substituted alkyl side chains and the correspond-
ing carbon atom number of the alkyl side chain is between 7
and 13. The antifungal activities of the N-unsubstituted com-
pounds 4a-5d are very low. Similarly, compounds 6a-7d, in
which the carbon atom numbers of the N-substituted alkyl side
chain are less than four, exhibit low antifungal activities as well.
Compared to 8a-15d, the antifungal activities of compounds
16a-19d, in which the carbon atom numbers of the N-
substituted alkyl side chain are more than 12, are decreased
linearly with the increase of the length of N-substituted alkyl
side chain. Compounds 10a-13d, in which the carbon atom
numbers of N-substituted alkyl side chains are between 9 and
10, are of the highest antifungal activity compared to all of the
other compounds. Compounds substituted with a hydroxyl or
methoxy group at positions 5 and 6 of the tetralin ring, such as
8a, 8b, 9a, 9b, 10a, and 10b, exhibit higher antifungal activities
than those of compounds with a hydroxyl or methoxy group at
positions 7 and 8, such as 8c, 8d, 9c, 9d, 10c, and 10d. The
primary SAR analysis above provides the structural basis for
the modification of 2-aminotetralin antifungal derivatives in the
future.
The compounds in which antifungal MIC values against the
standard Candida albicans strain were lower than 0.125 µmol/L
were further tested against four fluconazole-resistant clinic
Candida albicans strains. The results are listed in Table 2. All
tested compounds exhibit much more potent antifungal activities
than that of fluconazole or itraconazole. Compounds 9b, 11b,
12a, 12c, and 13b exhibit comparable or superior antifungal
activities than that of terbinafine or ketoconazole. The antifungal
activities of compounds 10b against fluconazole-resistant strains
are higher than those of the other testing compounds including

5296 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Table 1. In Vitro Antifungal Activities of 2-Aminotetralin Compoundsa
Yao et al.
cmpd
C. alb.
C. par. C. neo. T. rub. F. com. A. fum. M. gyp. cmpd C. alb. C. par. C. neo. T. rub. F. com. A. fum. M. gyp.
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
8a
8b
8c
8d
9a
9b
9c
9d
10a
10b
10c
10d
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
13c
13d
14a
14b
14c
14d
15a
15b
15c
15d
16a
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
16
16
32
32
64
16
32
8
0.5
0.5
4
1
32
4
16
8
8
8
0.25
2
32
2
4
4
16
32
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
>64
16
16
16
16
32
8
16
8
2
4
4
4
8
0.5
8
8
8
64
64
64
64
>64
>64
>64
32
32
32
32
>64
>64
4
0.25
64
>64
64
>64
4
8
4
8
8
2
8
4
0.5
2
2
2
4
1
8
4
1
8
1
1
1
0.25
8
2
8
64
8
8
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
16
>64
64
32
>64
>64
>64
16
8
64
16
16
64
32
64
16
16
>64
16
16
>64
16
32
8
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
32
>64
>64
64
64
>64
8
8
8
8
16
4
4
4
4
4
64
8
0.5
8
4
2
4
2
2
1
8
2
4
16
>64
2
64
2
8
4
16b
16c
16d
17a
17b
17c
17d
18a
18b
18c
18d
19a
19b
19c
19d
20a
20b
20c
20d
21a
21b
21c
21d
22a
22b
22c
22d
23a
23b
23c
23d
24a
24b
24c
24d
25a
25b
25c
25d
26a
26b
26c
26d
27a
27b
27c
27d
I-6
32
4
4
8
2
4
16
>64
64
>64
>64
64
32
16
>64
>64
>64
>64
>64
>64
64
32
>64
32
30
64
>64
64
64
64
64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
2
>64
>64
16
>64
32
4
64
64
16
32
8
4
8
32
>64
>64
>64
64
>64
>64
>64
>64
>64
>64
64
>64
>64
64
16
32
16
0.0625
0.5
0.5
0.5
0.5
0.125
32
8
8
2
16
8
2
2
2
0.5
4
4
8
8
8
4
>64
64
32
>64
>64
8
>64
>64
>64
>64
>64
>64
16
>64
4
2
4
2
4
4
>64
>64
>64
16
64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
32
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
16
>64
64
64
>64
64
>64
>64
32
32
64
32
>64
32
16
32
64
>64
>64
4
64
>64
>64
>64
>64
>64
64
64
4
16
64
64
>64
>64
8
8
4
4
4
4
8
8
64
>64
>64
>64
>64
>64
8
0.0625
1
16
64
>64
>64
>64
>64
>64
64
32
64
32
>64
>64
>64
>64
>64
>64
32
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
16
8
0.0625
4
2
0.0625
0.0625
0.25
0.5
64
16
16
4
32
0.125
8
16
0.5
2
2
1
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
>64
8
0.0625
2
4
0.25
4
4
1
1
8
1
>64
>64
32
8
0.0625
1
1
0.031 25
0.25
0.0625
0.25
0.031 25
0.0625
1
0.0625
8
4
2
4
1
16
1
1
1
1
4
1
8
8
8
0.5
32
0.25
0.5
0.5
2
2
1
16
>64
2
0.25
2
16
16
16
16
32
16
16
16
16
32
0.5
4
1
1
4
64
64
0.0625
2
0.25
0.5
4
2
4
32
2
1
>64
>64
>64
>64
>64
8
32
32
32
0.5
>64
>64
16
4
1
1
16
>64
8
>64
32
>64
16
>64
2
32
32
32
32
4
1
16
16
>64
4
32
8
64
>64
>64
>64
32
8
8
16
>64
8
16
16
32
1
32
32
64
16
64
64
>64
16
4
8
>64
16
8
1
1
4
8
>64
>64
64
>64
Flu
0.5
2
16
>64
a MIC, µmol/L. Abbreviations: C. alb., Candida albicans; C. par., Candida parapsilosis; C. neo., Cryptococcus neoformans; T. rub., Trichophyton
rubrum; F. com., Fonsecaea compacta; A. fum., Aspergillus fumigatus; M. gyp., Microsporum gypseum; Flu, fluconazole.
Table 2. In Vitro Antifungal Activities of Some 2-Aminotetralin
presented here suggest that 2-aminotetralin derivatives have no
cross resistance with azoles antifungal agents.
Binding Mode of the 2-Aminotetralins. The binding mode
Compounds against Four Fluconazole-Resistant Candida albicans
Strainsa
cmpd
0511655
01010
18
25
of 2-aminoteralin derivatives to the active site of CYP51 is
explained by the flexible docking using the Affinity module
within the Insight II software package (Figure 1). The active
site of CYP51 was constructed in the previous studies.38,40
Because all the title compounds were the racemates, both the
R- and S-isomers were docked into the active site and the
interaction energies of the R- and S-isomers were calculated,
respectively. The results show that the overall trend of the
interaction energies of both the S- and R-isomers are in good
qualitative agreement with the in vitro antifungal activities.
Because the interaction energies of the R-isomer of each docked
compounds were lower than that of the corresponding S-isomers,
only the binding mode of the R-conformation was displayed in
Figure 1.
8b
9b
8
4
16
4
16
0.125
4
8
4
8
4
16
0.0625
4
4
4
32
2
16
>64
8
8
2
8
10a
10b
11b
12a
12c
13a
13b
13d
16
0.0625
4
8
4
32
2
16
>64
8
0.25
64
8
0.0625
2
4
2
32
2
16
>64
4
0.5
>64
8
16
4
16
>64
32
0.64
>64
8
fluconazole
terbinafine
amphoterican B
itraconazole
ketoconazole
2
>64
4
a MIC, µmol/L.
In previous studies, we found that the regions in the active
site of CYP51 for ligand noncovalent binding can be divided
into four subsites S1-S4, besides the site coordinating to the
the control drug amphotericin B, which is often used in the clinic
to treat fluconazole-resistant fungal infection. The results

2-Aminotetralins as Antifungal Agents
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5297
Figure 2. Outcome of vaginal infection by C. albicans in oophorec-
tomized, oestradiol-treated rats inoculated intravaginally with
compound 10b: 1% mg/L (white triangles), 4% mg/L (white squares),
10% mg/L (white circles), itraconazole 4% mg/L (black circles), blank
suppository (control; black squares) at 1, 2, 4, and 7 days after the
drugs were administered. Each curve represents the mean of cfu of
six rats.
Figure 1. (A) Binding of compound 12c to the active site of CYP51
from C. albicans. Yellow indicates the S1 subsite. Green indicates the
S2 subsite. Pale purple indicates the S3 subsite. Pink indicates the S4
subsite. (B) A comparison of the calculated interaction energies of the
R-isomers of 6c, 8c, 10c, 12c, 14c, and 16c with CYP51.
heme.38,40 The S1 subsite is a hydrophilic hydrogen-bonding
region; the S2 subsite is a hydrophobic region; the S3 subsite
is a narrow hydrophobic cleft formed by the residues in the
helix B′-Meander1 loop and the N terminus of helix I; and the
S4 subsite adjacent to the â6-1/â1-4 sheet is another hydrogen-
bonding region in the active site.
The binding mode of the 2-aminotetralin derivatives to
CYP51 suggests that the tetralin ring interacts with the hydro-
phibic S2 subsite. The methoxy group in the benzene ring forms
H-bonding interactions with the residues Tyr69 and Ser378 in
the S4 subsite. The long lipophilic alkyl side chain interacts
with the hydrophobic S3 subsite. No interaction was found
between the compound and the heme. It suggests that the affinity
of 2-aminotetralin derivatives to the potential receptor CYP51
might be mainly attributed to their nonbonding interaction with
the apoprotein part of the active site.
activities than those compounds with substituents at positions
7 and 8 of the tetralin ring (8c, 8d, 9c, 9d, 10c, and 10d).
Experimental Vaginal Infection. After establishing activity
in vitro, we examined the activity of compound 10b in vivo.
As shown in Figure 2, compound 10b exerted a marked
acceleration of clearance of the yeast, as demonstrated by a
statistically significant decrease in colony forming units (cfu)
counts throughout the study, compared with the blank control.
The parallel curves of clearance with different compound 10b
concentrations suggest a substantial compound 10b dose
dependence of fungus clearance, although the difference was
not statistically significant. As with all dose regimens, the
infection was cleared in 1 week, whereas the blank control rats
remained infected. Itraconazole treatment, as a positive control,
shows a pattern of clearance comparable to that induced by 10b.
The binding mode of the 2-aminotetralin derivatives with the
active site of CYP51 provides reasonable explanation for their
antifungal activities. The antifungal activities of compounds 4a-
7d and 20a-27d are very low. That is because either none of
the alkyl side chains was presented in 4a-5d or N-substituted
alkyl (6a-7d) or the aromatic (20a-27d) side chains are too
short to interact firmly with the hydrophobic S3 region. The
low antifungal activities of compounds 14a-19d are due to their
very long N-substituted alkyl side chains that are out of the
accommodation by the hydrophobic S3 subsite. Compounds
10a-13d, which N-substituted alkyl side chains have 9 to 10
carbon atoms, exhibit the highest antifungal activities, and the
antifungal activities of 10a, 12c, 13b, and 13d are particularly
interesting. This result suggests that the appropriate length of
the substituents on the amino group of 2-aminotetralin deriva-
tives is important for antifungal activities, and the alkyl side
chains with 9 to 10 carbon atoms are optimal for the binding
of these types of inhibitors to the receptor.
The S4 subsite is a hydrogen bond donor and acceptor region,
which interacts with the functional groups on the phenyl group
of the tetralin ring. To study the effect of substitution at different
positions of the phenyl ring on their antifungal activities, the
analogues with hydroxyl or methoxy group at different positions
of the phenyl ring were designed and synthesized. The binding
mode of the docked molecules to CYP51 and their correspond-
ing antifungal activities suggest that compounds with hydrogen
bonding donor or acceptor substituents at positions 5 and 6,
such as 8a, 8b, 9a, 9b, 10a, and 10b, exhibit higher antifungal
Conclusion
In the present study, a novel series of 2-aminotetralin
compounds were designed, synthesized and their antifungal
activities were evaluated in vitro. The results show that the
2-aminotetralin derivatives exhibit potent antifungal activities,
in which the antifungal activities of compounds 10a, 12a, 12c,
13b, and 13d against seven pathogenic fungi are higher than
those of fluconazole, especially against Candida albicans (MIC
< 0.125 µmol/L) and Aspergillus fumigatus (MIC e 16 µmol/
L). Compound 10b exhibits better antifungal activities against
four fluconazole-resistant clinic strains (MIC < 0.125 µmol/L)
than amphotericin B, which is often used in the clinic to treat
fluconazole-resistant fungal infection. A molecular docking
study showed that the affinity of 2-aminotetralin derivatives for
CYP51 was mainly attributed to their nonbonding interaction
with the apoprotein. The primary SAR analysis provides the
reliable clues about how to optimize the structures of 2-ami-
notetralin compounds. The research presented here affords a
new structural type as an antifungal agent, which has some
distinguished advantages, such as high antifungal activity, broad
antifungal spectra, and potentially low toxicity. Compound 10b
was evaluated in vivo by a rat vaginal candidiasis model, and
it was found to have a marked acceleration of clearance of the
yeast, as demonstrated by a statistically significant decrease in
colony forming unit (cfu) counts. The infection was cleared in
one week with all dose regimens.

5298 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Yao et al.
g (50.1%) of 4a as a white needle: mp 265-267 °C (lit.43,47 mp
266-267 °C). IR (KBr,ν/cm-1): 3445, 2920, 1585, 1470, 1259,
Experimental Section
Chemistry. General Methods. Melting points were determined
on an electrically heated RK-Z melting point apparatus and are
uncorrected. Infrared (IR) spectra were recorded on a Brucker
Vector II spectrometer. Mass spectra (MS) were measured on a
Micromass Qtof-Micro LC-MS instrument. 1H NMR spectra were
recorded at 300 MHz on a Bruker AC-300P spectrometer with Me4-
l
1078, 766, 685. H NMR (CD3OD, 300 MHz): δ 7.12 (t, J ) 8
Hz, 1H), 6.74 (dd, J ) 8, 8 Hz, 2H), 3.80 (s, 3H), 3.48 (m, 1H),
3.13 (m, 1H), 3.01∼2.90 (m, 1H), 2.80 (m, 1H), 2.65 (m, 1H),
2.30 (m, 1H), 1.88∼1.72 (m, 1H). MS (ESI) m/z: 178.12 (M +
1). Anal. (C11H16ClNO) C, H, N.
Similarly, 4b-4d were obtained from the appropriate methoxy-
2-tetralones 3b-3d. Compound 4b was obtained as a white
powder: mp 245-246 °C (lit.43 mp 243-246 °C). IR (KBr,
ν/cm-1): 3440, 3023, 2927, 2610, 1505, 1246, 1161, 1045, 824.
lH NMR (CD3OD, 300 MHz): δ 7.05 (d, J ) 8.4 Hz, 1H), 6.71
(dd, J ) 2.7, 8.4 Hz, 1H), 6.66 (d, J ) 2.7 Hz, 1H), 3.78 (s, 3H),
3.42 (m, 1H), 3.18∼3.08 (m, 1H), 3.01∼2.90 (m, 1H), 2.88∼2.76
(m, 1H), 2.72∼2.60 (m, 1H), 2.30∼2.16 (m, 1H), 1.88∼1.72 (m,
1H). MS (ESI) m/z: 178.09 (M + 1). Anal. (C11H16ClNO) C, H,
N.
1
Si as the internal standard. H NMR spectra of some compounds
were recorded at 500 MHz on a Bruker AC-500P spectrometer with
Me4Si as the internal standard. Chemical shifts are given in ppm
(δ), and the spectral data are consistent with the assigned structures.
Elemental analyses were performed with a MOD-1106 instrument
and were consistent with theoretical values within 0.4%. Silica gel
thin-layer chromatography was performed on precoated plates GF254
(Qindao Haiyang Chemical, China). Silica gel column chromatog-
raphy was performed with Silica gel 60 G (Qindao Haiyang
Chemical, China). All compounds were routinely checked by TLC
by using silica gel plates GF254 (Qindao Haiyang Chemical, China).
Commercial solvents and reagents were of reagent grade and, when
necessary, were purified and dried by standard protocols. All starting
materials were commercially available unless otherwise indicated.
Yields of purified products were not optimized. A concentration
of solutions after reactions and extractions was executed on a rotary
vaporator (Bu¨chi) operating under reduced pressure. Brine is a
saturated solution of sodium chloride in water. Organic solutions
were dried over anhydrous sodium sulfate.
Compound 4c was obtained as a white powder: mp 251-
253 °C (lit.43 mp 213-214 °C). IR (KBr, ν/cm-1): 3436, 2924,
l
1615, 1493, 1453, 1265, 698. H NMR (CD3OD, 300 MHz): δ
7.16 (d, J ) 8.4 Hz, 1H), 6.85 (d, J ) 8.4 Hz, 1H), 6.81 (s, 1H),
3.80 (s, 3H), 3.52 (m, 1H), 3.15 (m, 1H), 2.97 (m, 1H), 2.78 (m,
1H), 2.62 (m, 1H), 2.32 (m, 1H), 1.81 (m, 1H). MS (ESI) m/z:
178.10 (M + 1). Anal. (C11H16ClNO) C, H, N.
Compound 4d was obtained as a white needle: mp 275-
277 °C (lit.43 mp 273-275 °C). IR (KBr, ν/cm-1): 3418, 2918,
l
1586, 1098, 764, 696. H NMR (CD3OD, 300 MHz): δ 7.15 (dd,
General Method for the Synthesis of the Methoxy-2-tetralones
3a-3d. The method to synthesize 5-methoxy-2-tetralone (3a) is
described. 1,6-dimethoxynaphthalene42 2a (30.0 g, 0.16 mol) was
added to the refluxing anhydrous EtOH (300 mL) under mechanical
stirring. Sodium (28 g, 1.22 mol), cut in small pieces, was added
as rapidly as possible to the solution. Refluxing was continued until
all sodium disappeared. The reaction mixture was cooled to 10 °C
and then 2 N HCl was added dropwise until the pH value was
changed to 3. The reaction mixture continued to reflux for 30 min.
After cooling, the reaction mixture was extracted with Et2O (100
mL × 3), the H2O/EtOH layer was concentrated under reduced
pressure, and then the H2O layer was extracted with Et2O (100 mL
× 3). The Et2O layers were combined and washed with brine (50
mL × 3), dried over anhydrous Na2SO4, and filtrated, and the
solvent was evaporated. The residual oil was purified by distillation
under reduced pressure to yield 18.3 g (65%) of 3a as a yellow
oil, which solidified under room temperature: bp 160-165 °C (10
mmHg). Recrystallization from petroleum ether (bp 60-90 °C) gave
3a as a light yellow solid: mp 35-37 [lit.43,44 bp 118-124 °C
J ) 8.1, 7.5 Hz, 1H), 6.79 (d, J ) 8.1 Hz, 1H), 6.71 (d, J ) 7.5
Hz, 1H), 3.78 (s, 3H), 3.39 (m, 1H), 3.16 (m, 1H), 3.01∼2.76 (m,
2H), 2.40 (m, 2H), 1.81 (m, 1H). MS (ESI) m/z: 178.06 (M + 1).
Anal. (C11H16ClNO) C, H, N.
General Method for the Synthesis of the 2-Amino-hydroxy-
1,2,3,4-tetrahydronaphthalene. The method adopted for the
synthesis of 2-amino-5-hydroxy-1,2,3,4-tetrahydronaphthalene hy-
drobromide (5a) is described. A mixture of 4a (1 g, 0.005mol) and
48% HBr (10 mL) was heated at 120-130 °C for 3 h. After removal
of solvent, the solid residue was recrystallized from methanol/ether,
giving 5a as a white solid (1 g, 87.7%): mp 250-252 °C (lit.47
mp 252-253 °C). IR (KBr, ν/cm-1): 3330, 3025, 2926, 1588, 1495,
l
1464, 1267, 770, 698. H NMR (CD3OD, 500 MHz): δ 6.97 (t, J
) 7.8, 7.8 Hz, 1H), 6.61∼6.63 (m, 2H), 3.35∼3.41 (m, 1H), 3.01
(m, 1H), 2.78 (m, 2H), 2.50 (m, 1H), 2.12 (m, 1H), 1.72 (m, 1H).
MS (ESI) m/z: 164.18 (M + 1). Anal. (C10H14BrNO) C, H, N.
Similarly, 5b-5d were obtained from the appropriate 4b-4d.
Compound 5b was a gray solid: mp > 280 °C. IR (KBr, ν/cm-1):
3324, 3027, 2926, 1613, 1501, 1449, 1285, 1215 1154, 972, 826,
1
l
(1.1 mmHg); mp 36-37 °C ]. H NMR (CDCl3, 300 MHz): δ
698. H NMR (CD3OD, 300 MHz): δ 6.90 (d, J ) 8.0 Hz, 1H),
6.50-7.52 (m, 3H, ArH), 3.82 (s, 3H, OCH3), 3.42 (s, 2H, CH2),
3.06 (t, 2H, CH2), 2.48 (t, 2H, CH2).
6.56 (dd, J ) 2.7, 8.0 Hz, 1H), 6.50 (d, J ) 2.4 Hz, 1H), 3.41 (m,
1H), 2.98 (m, 1H), 2.74 (m, 3H), 2.10 (m, 1H), 1.71 (m, 1H). MS
(ESI) m/z: 164.24 (M + 1). Anal. (C10H14BrNO) C, H, N.
Compound 5c was a gray solid: mp 180-182 °C. IR (KBr,
ν/cm-1): 3353, 3027, 2923, 1620, 1592, 1503, 1273, 696. lH NMR
(CD3OD, 300 MHz): δ 6.89 (d, J ) 8.4 Hz, 1H), 6.56 (dd, J )
2.4, 8.4 Hz, 1H), 6.50 (d, J ) 2.4 Hz, 1H), 3.40 (m, 1H), 3.06 (m,
1H), 2.74 (m, 2H), 2.42 (m, 2H), 1.72 (m, 1H). MS (ESI) m/z:
164.26 (M + 1). Anal. (C10H14BrNO) C, H, N.
Similarly, 3b-3d were synthesized from the appropriate
dimethoxy-naphthalenes 2b-2d. Compound 3b: mp 34-35 °C
(lit.42 mp 36 °C). Compound 3c: mp 26-27 °C [lit.43,45 bp
130-136 °C (2.3 mmHg); mp 27-28 °C]. Compound 3d: mp 56-
57 °C [lit.43,46 mp 58-59 °C; bp 120-123 °C (1.0 mmHg)].
General Method for the Synthesis of the 2-Amino-methoxy-
1,2,3,4-tetrahydro-naphthalene 4a-4d. The method to synthesize
2-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride
(4a) is described. Compound 3a (5.6 g, 0.032 mol) was added to
a solution of hydroxylamine hydrochloride (4.4 g, 0.063 mol) and
sodium acetate (8.5 g, 0.104 mol) in 60 mL of EtOH. The mixture
was refluxed for 2 h and then diluted with water and extracted
with Et2O. The ether extract was washed with water and dried over
anhydrous Na2SO4. After removal of solvent, a brown solid was
obtained. The crude oxime was dissolved in anhydrous tetrahy-
drofurane and then LiAlH4 (6 g, 0.158 mol) was added. The mixture
was refluxed for 8 h and cooled to 0 °C. Ice water was added
carefully to the mixture until no bubbles occurred. The mixture
was filtered and evaporated. The residue was dissolved in anhydrous
Et2O and filtered. The filtrate was chilled in an ice water bath, and
anhydrous HCl was passed through the solution. The precipitated
salt was collected and recrystallized from MeOH/Et2O to give 3.4
Compound 5d was a yellow crystal: mp 241-242 °C. IR (KBr,
ν/cm-1): 3332, 3013, 2928, 1588, 1493, 1468, 1316, 1275, 766,
l
698. H NMR (CD3OD, 300 MHz): δ 6.93 (t, J ) 7.8, 7.8 Hz,
1H), 6.61 (d, J ) 7.5 Hz, 1H), 6.59 (d, J ) 7.2 Hz, 1H), 3.39 (m,
1H), 3.06 (m, 1H), 2.74 (m, 2H), 2.40 (m, 2H), 1.71 (m, 1H). MS
(ESI) m/z: 164.21 (M + 1). Anal. (C10H14BrNO) C, H, N.
N-Butyl-1,2,3,4-tetrahydro-5-methoxynaphthalen-2-amine Hy-
drochloride (6a). To a solution of 5-methoxy-2-tetralone (3a; 3.0
g, 0.017 mmol) in dichloroethane (60 mL) was added n-butylamine
(2 mL, 0.020 mol) followed by sodium triacetoxyborohydride (10.5
g, 0.05 mol) under an inert atmosphere. The reaction was allowed
to stir at room temperature for 24 h. The mixture was concentrated
and 2 N NaOH was added dropwise until pH ) 8 was obtained.
The solution was extracted with ethyl acetate (30 mL × 3). The
combined organic layers were washed with water and dried over

2-Aminotetralins as Antifungal Agents
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5299
anhydrous Na2SO4. After removal of solvent, the residue was taken
up in ether (125 mL) and treated with 1 N HCl in ether. The salt
was filtered and dried to afford 6a as a gray solid (5.0 g, 90.1%).
Mp 193-194 °C. IR (KBr, ν/cm-1): 3445, 2924, 2450, 1600, 1560
1270, 637. lH NMR (CD3OD, 300 MHz): δ 7.14 (dd, J ) 7.8, 7.8
Hz, 1H), 6.79 (d, J ) 8.4 Hz, 1H), 6.72 (d, J ) 7.5 Hz, 1H), 3.76
(s, 3H), 3.58 (m, 1H), 3.15∼3.25 (m, 3H), 2.85∼2.94 (m, 3H),
2.27 (m, 1H), 1.84 (m, 1H), 1.69 (m, 2H), 1.40 (m, 2H), 0.95 (t, J
) 7.2, 7.5 Hz, 3H). MS (ESI) m/z: 234.21 (M + 1). Anal. (C15H24-
ClNO) C, H, N.
dexamethasone in drinking water at a dose of 1 mg per liter
throughout the study. Seven days after the first oestradiol dose, all
animals were inoculated intravaginally with 107 yeast cells of
Candida albicans 0511655 in 0.05 mL of saline. The number of
cells in the vaginal fluid was counted with 0.05 mL saline by
washing the fluid three times up and down in the vagina. A total
of 1 µL of the fluid was then plated onto sabouraud dextrose agar
containing chloramphenicol (100 mg/L) and incubated for 48 h at
37 °C, and colony forming units (cfu) values were recorded.
Compound 10b was administered intravaginally with 50 µL
suppository based with PEG 1500 and PEG 4000 (1:2 [v/v]) at 1%
mg/L, 4% mg/L, and 10% mg/L, at 24 h after intravaginal Candida
albicans challenge and continued 7 days). Rats receiving itracona-
zole suppository at 4% or blank suppository served as positive or
negative controls, respectively. The infection was monitored just
before administering suppository as 0 day and 1, 2, 4, and 7 days
after the first suppository administered.
The synthetic methods for the following compounds 6c-6d, 8a-
8d, 10a-10d, 12a-12d, 14a-14d, 16a-16d, 18a-18d, 20a-20d,
22a-22d, 24a-24d, and 26a-26d were similar to the synthesis
of compound 6a.
N-Butyl-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-amine Hy-
drobromide (7a). A mixture of 6a (1.0 g, 0.0037 mol) and 48%
HBr (10 mL) was heated at 120-130 °C for 3 h. After removal of
solvent, the solid residue was recrystallized from ethanol-ether,
giving 7a as a gray solid (1 g, 90.1%). Mp 130-133 °C. IR (KBr,
ν/cm-1): 3300, 2654, 2450, 1600, 1560, 1270, 637. lH NMR (CD3-
OD, 500 MHz): δ 6.98 (t, J ) 7.8, 7.8 Hz, 1H), 6.61∼6.64 (m,
2H), 3.36∼3.40 (m, 1H), 2.95∼3.12 (m, 3H), 2.65∼2.78 (m, 3H),
2.19∼2.25 (m, 1H), 1.58∼1.72 (m, 3H), 1.32∼1.39 (m, 2H), 0.91
(t, J ) 7.2, 7.5 Hz, 3H). MS (ESI) m/z: 220.29 (M + 1). Anal.
(C14H22BrNO) C, H, N.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (Grant No. 30572257).
Supporting Information Available: IR, 1H NMR, MS, melting
point data, and elemental analysis data for the compounds in this
study. This material is available free of charge via the Internet at
http://pubs.acs.org.
The synthetic methods for the following compounds 7c-7d, 9a-
9d, 11a-11d, 13a-13d, 15a-15d, 17a-17d, 19a-19d, 21a-21d,
23a-23d, 25a-25d, and 27a-27d were similar to that for
compound 7a.
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