Synthesis and antifungal evaluation of 6-hydroxy-1H-carbazole-1,4(9H)- diones

Article abstract of DOI:10.1016/j.bmcl.2010.10.124

6-Hydroxy-1H-carbazole-1,4(9H)-diones were synthesized and tested for in vitro antifungal activity against two pathogenic strains of fungi. Among them tested, many compounds showed good antifungal activity. The results suggest that 6-hydroxy-1H-carbazole-

Full text of DOI:10.1016/j.bmcl.2010.10.124

Bioorganic & Medicinal Chemistry Letters 21 (2011) 427–430
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antifungal evaluation of 6-hydroxy-1H-carbazole-1,4(9H)-diones
⇑
Chung-Kyu Ryu , Seung-Yon Lee, Na Young Kim, Jung An Hong, Joo Hee Yoon, Aram Kim
College of Pharmacy, Ewha Womans University, Seodaemun-ku, Seoul 120-750, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
6-Hydroxy-1H-carbazole-1,4(9H)-diones were synthesized and tested for in vitro antifungal activity
against two pathogenic strains of fungi. Among them tested, many compounds showed good antifungal
activity. The results suggest that 6-hydroxy-1H-carbazole-1,4(9H)-diones would be potent antifungal
agents.
Received 13 August 2010
Revised 12 October 2010
Accepted 25 October 2010
Available online 30 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
6-Hydroxy-1H-carbazole-1,4(9H)-diones
Antimicrobial compounds
Antifungal
Fungi
Substitution effects
O
O
O
O
Heterocyclic quinone compounds represent an important class
of biologically active molecules.1 4,7-Dioxobenzothiazole deriva-
tive, a heterocyclic quinone, inhibits cytochrome B-complex by
the blockade of mitochondrial electron transport in Saccaromyces
cerevisiae, which is different from commonly used antifungal
drugs.2 UHDBT as a 4,7-dioxobenzothiazole has been reported as
an inhibitor of mitochondrial cytochrome complex in yeast3 and
bacteria.4 In our previous Letters5–8, heterocyclic quinone com-
pounds such as arylamino- or arylthio-4,7-dioxobenzothiazoles,5
benzo[d]oxazole-4,7-diones,6 4,7-benzimidazolediones,7 7-diox-
obenzo[b]thiophenes8 1, and bis(arylthio)-benzo[d]oxazole-4,-
7-diones6 2 have demonstrated potent antifungal activity against
pathogenic fungi (Fig. 1).
X
Y
R1
R2
S
S
R1
R2
W
Z
Y
X
R3
R3
1
2
3
1: R , R , R = H, F, ..
X = NH
R1
R2
1
2
3
Y = Cl, Br or H
Z, W = N, CH, O or S
2: R , R , R = H, F, ..
X, Y = N, CH, O or S
HO
HO
O
S
O
X
R1
R2
Structure–activity relationship studies from quinonoid com-
pounds indicated that the ring number and the position of nitrogen
atoms substituted in the heterocyclic ring were considerably
important factors to affect the biological activities.9–11
R1
R2
N
S
N
Y
R3
O
R3
O
We speculated that incorporation of a nitrogen atom into the
ring of the quinone skeleton would change the physicochemical
properties and lead to a new pharmacophore with a different bio-
logical profile from quinone compounds 1 and 2. The presence of
arylamino, arylthio, or alkyl moiety to the quinones was consider-
ably an important factor to affect their antifungal activity.10,11
Based on this speculation, 3-arylamino-6-hydroxy-1H-carba-
zole-1,4(9H)-diones 3, 3-arylthio-6-hydroxy-1H-carbazole-1,4-
(9H)-diones 4, and 3,4-bis(arylthio)-6-hydroxy-1H-carbazole-
1,4(9H)-diones 5 which would be analogs of quinones 1 and 2, were
R1
3: X = NH
4: X = S
R2
1
2
1
2
5: R , R = H, F, ..
R , R = H, F, ..
3
3
R = Alkyl
R = Alkyl, Y = H
Figure 1. Antifungal heterocyclic quinone compounds and 6-hydroxy-1H-carba-
zole-1,4(9H)-dione derivatives.
synthesized and evaluated for their antifungal activity (Fig. 1). There
have been a few Letters12 on 1H-carbazole-1,4(9H)-diones that
exhibit inhibitors of Toxoplasma gondii purine nucleoside
⇑
Corresponding author. Tel.: +82 2 3277 3027; fax: +82 2 3277 3051.
E-mail address: ckryu@ewha.ac.kr (C.-K. Ryu).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.124

428
C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 427–430
HO
HO
O
O
O
O
H
N
R1
R2
HO
O
c
a
b
N
N
R
OH
R3
O
O
O
3a-q
9a: R = Me
9b: R = Et
9c: R = n-Pr
8
7
d
f
e
HO
HO
HO
O
O
O
O
O
R1
R2
R1
R2
S
S
S
S
N
N
N
R3
R3
O
R1
R2
4a-i
6
5a-f
Scheme 1. Synthesis of 1H-carbazole-1,4(9H)-dione derivatives. Reagents and conditions: (a) PbO2/70% HClO4/AcCN/0.5 h/0 °C/56%; (b) R-NH2/CHCl3/2 h/rt/59–82%; (c) 9a,
9b, or 9c/arylamine (1 equiv)/CeCl3 (0.1 equiv)/EtOH/3 h/rt/42–95%; (d) 9a or 9b/arylthiol (1 equiv)/CeCl3 (0.1 equiv)/EtOH/3 h/rt/63–86%; (e) 9a or 9b/arylthiol (2 equiv)/
EtOH/18 h/reflux/45–81%; (f) 9b/ethylthiol (1 equiv)/CeCl3 (0.1 equiv)/EtOH/48 h/60 °C/25%.
phosphorylase. The antifungal activity of 1H-carbazole-1,4(9H)-
diones 3–6 and 9 on fungi has not been reported to the best of our
knowledge. Therefore, 1H-carbazole-1,4(9H)-diones 3–6 and 9 with
various substituents were designed and synthesized to elucidate
their contribution to the antifungal activity (Scheme 1). We describe
herein our results on the synthesis of 1H-carbazole-1,4(9H)-diones
3–6 and 9 with their antifungal activity on the pathogenic fungal
strains.
The compound 6 was synthesized through the addition of com-
pound 9b with 1 equiv of ethylthiol in the presence of CeCl3.
The compounds 3–6 were identified by 1H NMR, 13C NMR, or
mass spectra. The mechanism of formation of compounds 3–6
was cited in Ref. 15. The experimental data of representative com-
pounds 3a, 4a, 5a, and 6 was provided in Ref. 16.
The synthesized 1H-carbazole-1,4(9H)-diones 3a–q, 4a–i, 5a–f,
6, and 9a–c were tested in vitro for their growth inhibitory activity
against pathogenic fungi using the standard twofold broth dilution
method.17 The MIC (minimum inhibitory concentration) values
were determined by a comparison with fluconazole and 5-fluoro-
cytosine as standard agents.17 As indicated in Table 1, most of 9-al-
kyl-3-arylthio-6-hydroxy-1H-carbazole-1,4(9H)-diones 4a–i, 9-
alkyl-3,4-bis(arylthio)-6-hydroxy-1H-carbazole-1,4(9H)-diones
5a–f, and quinones 9a–c generally showed potent antifungal activ-
ity against all pathogenic fungal strain tested. In contrast, 9-alkyl-
3-arylamino-6-hydroxy-1H-carbazole-1,4(9H)-diones 3a–q did
not show significant antifungal activity against all pathogenic fun-
gal strain tested, although many of the compounds 3a–q also
showed potent antifungal activity against Candida krusei and
Cryptococcus neoformans.
A convenient method for synthesis of 1H-carbazole-1,4(9H)-
diones 3a–m, 4a–i, 5a–f, and 6 is shown in Scheme 1 and Table 1.
9-Alkyl-6-hydroxy-1H-carbazole-1,4(9H)-diones 9a, 9b, and 9c
were prepared in two steps from commercially available [1,10-
biphenyl]-2,20-diol (7) through its oxidation to [1,10-bi(cyclohex-
ane)]-3,30,6,60-tetraene-2,20,5,50-tetraone (8)13 followed by the
reaction of compound 8 with methyl-, ethyl-, or n-propylamine
according to the reported method12 with minor modification. The
compound 8 was synthesized through the oxidation of compound
7 with PbO2 in the presence of HClO4 in 56% yield. To prepare 1H-
carbazole-1,4(9H)-diones 9a, 9b, and 9c by nucleophilic addition of
alkylamine and to avoid a further nucleophilic addition of alkyla-
mine to 9, an equivalent amount of each metyl-, ethyl-, or n-pro-
pylamine was treated with compound 8. 9-Alkyl-3-arylamino-6-
hydroxy-1H-carbazole-1,4(9H)-diones 3a–q were synthesized by
regioselective nucleophilic addition of compound 9a, 9b, or 9c with
appropriate arylamines and subsequent oxidation. When com-
pound 9a, 9b, or 9c with 1 equiv amount of appropriate arylamines
in EtOH were refluxed for 3 h in the presence of CeCl314, com-
pounds 3a–q were formed. Most of these additions went as ex-
pected and had overall high yields of 42–95%.
In similar manner, 9-alkyl-3-arylthio-6-hydroxy-1H-carbazole-
1,4(9H)-diones 4a–i were synthesized by nucleophilic addition of
compound 9a or 9b with arylthiols and subsequent oxidation.
When compound 9a or 9b with 1 equiv of appropriate arylthiols
in EtOH were refluxed for 3 h, compounds 4a–i were formed in
overall high yields of 63–86%.
9-Alkyl-3,4-bis(arylthio)-6-hydroxy-1H-carbazole-1,4(9H)-diones
5a–f were synthesized by nucleophilic addition on compound 9a or
9b with 2 equiv of appropriate arylthiols in EtOH by reflux for 18 h
and had overall yields of 45–81%.
Actually, the activity of compounds 4c, 4h, and 9b was superior
or comparable to those of 5-fluorocytosine against all tested fungi.
The compounds 4c, 4h, and 9b completely inhibited the growth of
all fungal species tested at the MIC level of 1.6–25 lg/mL. The
activity of many tested compounds were superior to those of 5-flu-
orocytosine against all fungi.
In terms of structure–activity relationship, the 3-arylthio-6-hy-
droxy-1H-carbazole-1,4(9H)-diones 4, 3,4-bis(arylthio)-6-hydro-
xy-1H-carbazole-1,4(9H)-diones 5, and 6-hydroxy-1H-carbazole-
1,4(9H)-diones 9 showed, in general, more potent antifungal
activity than the other 3-arylamino-6-hydroxy-1H-carbazole-
1,4(9H)-diones 3. The 3-arylthio-compounds 4 and 3,4-bis(aryl-
thio)-compounds 5 exhibited good activity, indicating a correlation
that may offer insight into the mode of action of these compounds.
The substituents (R1, R2, R3: H, F, Me, Et, ...) for the 3-arylthio,
3-arylamino, and 9-alkyl moieties of compounds 3, 4, and 5 may
not contribute partially toward biological potency. Thus, the sub-
stituents (R1, R2, R3: H, F, Me, Et, ...) for the 3-arylamino and 9-alkyl

C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 427–430
429
Table 1
Structures and in vitro antifungal activity for 1H-carbazole-1,4(9H)-dione derivatives
HO
HO
HO
HO
O
O
O
O
O
O
H
N
R1
R2
R1
R2
R1
R2
R1
S
S
S
N
N
N
N
R3
R3
R3
R2
O
O
R1
3a-q
4a-i
6, 9a-c
5a-f
R2
Compound
R1
R2
R3
MICa
(
lg/mL)
b
C. albicans
C. tropicalis
C. krusei
C. neoformans
A. niger
A. flavus
3a
3b
3c
3d
3e
H
H
H
H
H
H
H
H
H
OH
F
H
H
H
H
H
H
H
H
H
CH3
H
CH3
H
F
CH3O
H
CH3
Br
Cl
CF3O
I
F
OH
H
H
F
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3
CH3
CH3
n-Pr
n-Pr
n-Pr
n-Pr
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3
CH3
CH3
CH3CH2
CH3CH2
CH3
CH3
CH3
CH3
—
—
—
—
—
>50.0
50.0
>100.0
25.0
25.0
50.0
25.0
50.0
6.3
25.0
12.5
12.5
6.3
25.0
1.6
3.2
6.3
1.6
6.3
1.6
0.8
0.8
12.5
3.2
3.2
12.5
12.5
3.2
3.2
6.3
12.5
6.3
6.3
>100.0
0.8
3.2
3.2
12.5
3.2
25.0
12.5
12.5
>100.0
>100.0
50.0
>100.0
50.0
25.0
25.0
25.0
12.5
25.0
>100.0
25.0
25.0
>100.0
25.0
50.0
3.2
25.0
25.0
50.0
12.5
3.2
25.0
12.5
12.5
25.0
50.0
12.5
25.0
25.0
12.5
12.5
25.0
25.0
25.0
>100.0
25.0
12.5
>100.0
6.3
>100.0
25.0
50.0
25.0
6.3
50.0
50.0
50.0
25.0
12.5
12.5
6.3
50.0
25.0
50.0
>100.0
50.0
12.5
50.0
>100.0
50.0
25.0
25.0
25.0
12.5
50.0
25.0
12.5
25.0
25.0
12.5
25.0
25.0
6.3
3f
6.3
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
6
7
50.0
25.0
6.3
6.3
12.5
6.3
12.5
25.0
25.0
6.3
12.5
12.5
25.0
3.2
1.6
3.2
6.3
6.3
3.2
6.3
25.0
25.0
3.2
Cl
6.3
CH3
CH3O
Cl
50.0
50.0
50.0
12.5
3.2
3.2
6.3
12.5
3.2
6.3
6.3
3.2
6.3
12.5
0.8
12.5
12.5
12.5
6.3
6.3
>100.0
1.6
F
CH3O
OH
H
25.0
3.2
H
6.3
12.5
25.0
50.0
12.5
6.3
25.0
25.0
6.3
CH3
CH3
H
H
H
CH3O
OH
H
H
F
Cl
CH3CH2
—
CH3
CH3CH2
n-Pr
—
50.0
50.0
25.0
6.3
12.5
50.0
50.0
6.3
12.5
25.0
12.5
25.0
>100.0
50.0
6.3
25.0
12.5
6.3
H
H
H
F
Cl
F
12.5
25.0
50.0
12.5
12.5
25.0
12.5
25.0
100.0
25.0
12.5
12.5
100.0
25.0
12.5
25
6.3
3.2
6.3
25.0
100.0
6.3
3.2
3.2
12.5
25.0
50.0
25.0
12.5
3.2
6.3
12.5
6.3
H
CH3CH2S
—
H
H
H
—
—
9a
9b
9c
3.2
3.2
12.5
3.2
25.0
6.3
3.2
Fluconazole
—
—
12.5
6.3
5-FCc
—
a
The MIC value is defined as lowest concentration of the antifungal agent exhibiting no fungal growth. MIC values were read after 1 day for Candida species and C.
neoformans, and 2 days for A. niger, A. flavus in 37 °C. The inoculum sizes contained approximately 1 ꢀ 105 cells/mL. Culture media tested were the modified Sabouraud
dextrose broth (Difco Lab.). The final concentration of antifungal agents was between 0.2 and 100 lg/mL.
b
Fungi tested: Candida albicans Berkout KCCM 50235, C. tropicalis Berkout KCCM 50662, C. krusei Berkout KCCM 11655, Cryptococcus neoformans KCCM 50564, Aspergillus
niger KCTC 1231, and A. flavus KCCM 11899.
c
5-FC: 5-fluorocytosine.
moieties appear to be not an important factor to affect their
antifungal activity. The activity of compounds 9 was comparable
to those of compounds 3–6. Therefore, the 3-arylthio-, 3,4-bis(aryl-
thio)-, and 3-arylamino-substituents could not be essential for the
antifungal activity of compounds 3, 4, and 5.
In conclusion, 3-arylamino-6-hydroxy-1H-carbazole-1,4(9H)-
diones 3 were synthesized by nucleophilic addition of 1H-carba-
zole-1,4(9H)-diones 9 with 1 equiv of appropriate arylamines.
3-Arylthio-6-hydroxy-1H-carbazole-1,4(9H)-diones 4 were syn-
thesized by nucleophilic addition on 1H-carbazole-1,4(9H)-diones
9 with 1 equiv of appropriate arylthiols. 3,4-bis(Arylthio)-6-hydro-
xy-1H-carbazole-1,4(9H)-diones 5 were synthesized by nucleo-
philic addition on 1H-carbazole-1,4(9H)-diones 9 with 2 equiv of
arylthiols.
In addition, [1,10-biphenyl]-2,20-diol (7) and exhibited no or
poor, if any, antifungal activity. In contrast, most of 1H-carba-
zole-1,4(9H)-diones 3–6 and 9 showed more potent antifungal
activity than compound 7. Thus, the quinone moiety in 1H-carba-
zole-1,4(9H)-diones 3–6 and
activity, for example, as nonquinonoid compound 7 lost the
activity.
9
should be essential for the
Among them tested, many of compounds 3–6 and 9 showed po-
tent antifungal activity against pathogenic fungal strain. These 1H-
carbazole-1,4(9H)-diones may thus be a promising lead for the

430
C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 427–430
development of antifungal agents. Moreover, the results should
encourage the synthesis of 1H-carbazole-1,4(9H)-dione analogs
for improving antifungal properties.
HO
HO
O
O
O
O
R1
+
3
H2N
R2
9
N
N
Acknowledgment
R
R
1
-
Ce3+
Ce3+
This study was supported by a Grant of the Korea Healthcare
Technology R&D Project, Ministry for Health, Welfare and Family
Affairs, Republic of Korea (A08-0414-AA1723-08N1-00010A).
10
9
9'
HO
O
O
H
N
R1
R2
References and notes
1. Middleton, R. W.; Parrick, J. In The Chemistry of the Quinonoid Compounds; Patak,
S., Rappoport, Z., Eds.; John Wiley & Sons: London, 1988; p 1019.
2. Roberts, H.; Choo, W. M.; Smith, S. C.; Mrzuki, S.; Linnane, A. W.; Porter, T. H.;
Folkers, K. Arch. Biochem. Biophys. 1978, 191, 306.
3. Di Rigo, J.-P.; Bruel, C.; Graham, L. A.; Sonimski, P.; Trumpower, B. L. J. Biol.
Chem. 1996, 271, 15341.
N
R
3
In similar manner, the 3-arylthio products 4 and 6 were formed by an addition of
arylthiols to 90. Most of these reactions went as expected. Actually, the additions
in compounds 9 gave mainly 3-substituted products 3, 4, and 6 along with traces
of 2-substituted compounds as by-product. The products 3, 4, and 6 were
separated by silicagel columnchromatography. Purity ofproducts 3, 4, and 6 was
determined both by to TLC and GC. The results showed that a single compound
was contained in each product. TLC was performed on precoated silica gel (60G
254, Merck) using CHCl3 for solvent. The compounds were detected under UV
light (254 nm). The purity of products was also verified by GC (Hewlett Packard
5890A, HP-5 capillary column at 260 °C, N2, 17 mL/mim as carrier gas, FID).
16. Experimental: All melting points were measured with Büchi melting point B-
545 and were uncorrected. 1H NMR spectra or 13C NMR spectra were recorded
on Varian Unity INOVA 400 MHz FT-NMR spectrometer with TMS. Mass
spectra were taken with Jeol JMS AX505 WA. 9-Ethyl-6-hydroxy-3-(4-methoxy-
phenylamino)-9H-carbazole-1,4-dione (3a): mp 176–178 °C; 1H NMR (DMSO-
d6) d 1.32 (t, J = 7.2, 3H, CH2CH3), 3.78 (s, 3H, OCH3), 4.63 (q, J = 7.2, 2H,
CH2CH3), 6.99 (m, 1H), 7.02 (d, J = 9.2, 2H), 7.33 (d, J = 9.2, 2H), 7.45 (d, 1H),
7.62 (d, 1H), 9.13 (s, 1H), 9.58 (s, 1H); 13C NMR (DMSO-d6) d 178.6, 173.1,
157.3, 154.1, 151.6, 140.5, 138.5, 135.7, 132.2, 124.8, 118.5, 114.2, 113.1, 110.3,
107.9, 103.3, 56.9, 43.9, 15.4; MS (m/z) 362 (M+). 9-Ethyl-6-hydroxy-3-(4-
methoxy-phenylthio)-9H-carbazole-1,4-dione (4a): mp 273–274 °C; 1H NMR
(CDCl3) d 1.42 (t, J = 7.2, 3H, CH2CH3), 3.87 (s, 3H, OCH3), 4.57 (q, J = 7.2, 2H,
CH2CH3), 5.54 (s, 1H), 5.65 (s, 1H), 7.01 (m, 2H), 7.04 (m, 1H), 7.33 (m, 1H), 7.45
(d, 2H), 7.72 (d, 1H); 13C NMR (CDCl3) d 176.5, 173.1, 157.6, 157.1, 152.9, 139.8,
137.7, 134.4, 131.7, 127.9, 124.2, 123.3, 116.2, 114.9, 109.2, 104.1, 56.1, 43.8,
16.0; MS (m/z) 379 (M+). 9-Ethyl-6-hydroxy-2,3-bis-(4-methoxy-phenylthio)-9H-
carbazole-1,4-dione (5a): mp 166–168 °C; 1H NMR (CDCl3) d 1.45 (t, J = 7.2, 3H,
CH2CH3), 3.71 (s, 6H, OCH3), 4.72 (q, J = 7.2, 2H, CH2CH3), 6.65 (m, 4H), 6.98 (m,
4H), 7.09 (m, 1H), 7.25 (d, J = 8.0, 1H), 7.33 (d, J = 8.0, 1H), 7.82 (s, 1H); MS (m/z)
517 (M+). 9-Ethyl-3-ethythio-6-hydroxy-9H-carbazole-1,4-dione (6): mp 275–
277 °C; 1H NMR (DMSO-d6) d 1.43 (t, J = 7.4, 3H, CH2CH3), 1.42 (t, J = 7.1, 3H,
CH2CH3), 2.88 (q, J = 7.4, 2H, CH2CH3), 4.61 (q, J = 7.1, 2H, CH2CH3), 6.22 (s, 1H),
6.98 (t, 1H), 7.41 (d, 1H), 7.53 (d, 1H), 9.42 (s, 1H); MS (m/z) 301 (M+).
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15. 3-Substituted-1H-carbazole-1,4(9H)-diones 3, 4, and
6
9
were formed by
with 1 equiv of
regioselective nucleophilic addition of compounds
appropriate arylamines 10 or thiols in the presence of CeCl3. As results of
catalytic action of Ce3+ ions, the addition in compounds 9 gave mainly 3-
substituted products 3, 4, and 6. The regioselectivity should be originated from
the selective increment of the electrophilicity of 3-position in compounds 9 by
the formation of Ce(III) chelate between carbonyl oxygen at 1-position and
nitrogen at 9-position. The catalysis by Ce3+ ions is understood from the
intermediate 90. The 3-arylamino products 3 were formed by a Michael-type
addition of arylamines 10 to 90. These additions were similar to the regioselective
reaction of arylamines 10 on 5,8-quinolinedione or 5,8-quinazolinedione the
presence of Ce(III).14