Synthesis and antifungal activity of 1H-indole-4,7-diones

Article abstract of DOI:10.1016/j.bmcl.2006.09.076

1H-Indole-4,7-diones were synthesized and tested for in vitro antifungal activity against fungi. The synthesized 1H-indole-4,7-diones generally showed good antifungal activity against Candida krusei, Cryptococcus neoformans, and Aspergillus niger. The results suggest that 1H-indole-4,7-diones would be potent antifungal agents.

Full text of DOI:10.1016/j.bmcl.2006.09.076

Bioorganic & Medicinal Chemistry Letters 17 (2007) 127–131
Synthesis and antifungal activity of 1H-indole-4,7-diones
Chung-Kyu Ryu,* Jung Yoon Lee, Rae-Eun Park, Mi-Young Ma and Ji-Hee Nho
College of Pharmacy, Ewha Womans University, Seodaemun-ku, Seoul 120-750, Republic of Korea
Received 24 July 2006; revised 12 September 2006; accepted 27 September 2006
Available online 29 September 2006
Abstract—1H-Indole-4,7-diones were synthesized and tested for in vitro antifungal activity against fungi. The synthesized 1H-
indole-4,7-diones generally showed good antifungal activity against Candida krusei, Cryptococcus neoformans, and Aspergillus
niger. The results suggest that 1H-indole-4,7-diones would be potent antifungal agents.
ꢀ 2006 Elsevier Ltd. All rights reserved.
O
O
O
O
Heterocyclic quinone compounds represent an
important class of biologically active molecules.1 The
quinones such as 5-n-undecyl-6-hydroxy-4,7-dioxo-
benzothiazole (UHDBT, 1) blockade a mitochondrial
electron transport in Saccharomyces cerevisiae.2 The
UHDBT (1) has been reported as inhibitors of mito-
R3
R2
HO
S
N
S
N
R1
H3C(H2C)10
1
2
3
UHDBT (1)
2 : R , R , R = H, thio,
chondrial cytochrome complex in yeast3 and bacteria.4
amino, alkyl, aryl, ..
5
In our previous report,
4,7-dioxobenzothiazoles 2
O
S
COOR2
O
R1
R2
which could be analogues of UHDBT have demonstrat-
ed potent antifungal activity against pathogenic fungi
(Fig. 1).
H3C
H3C
N
H
N
S
R1
O
O
A variety of heterocyclic quinones with different substit-
uents could exhibit the biological activities through dif-
ferent action and sometimes improve upon the activities.
The presence of thio, amino, halo, and alkyl substituents
of quinones was considerably important factor to affect
their antifungal activity.5 Based on this speculation, we
further extended to synthesize 1H-indole-4,7-dione
derivatives 3 and 4 which would be bioisosteres of qui-
nones 2, and evaluated their antifungal activity.
R1
1
1
3 : R = alkyl or aryl
R2
2
R = alkyl
2
4 : R , R = H, F,..
Figure 1. 1H-Indole-4,7-dione derivatives.
activity. The in vitro antifungal activity of compounds
3 and 4 against pathogenic fungi was determined by
the 2-fold broth dilution method.
There have been many reports on 1H-indole-4,7-diones,
exhibiting cytotoxic activities6–10 against cancer cell
lines, and antibacterial activity.11 However, the inhibito-
ry activity of compounds 3 and 4 on the antifungal
properties has not been reported to the best of our
knowledge. Therefore, the 1H-indole-4,7-diones 3 and
4 with various substituents were designed and synthe-
sized to elucidate their contribution to the antifungal
A method for the synthesis of 1H-indole-4,7-diones 3a–
m (Table 1) is shown in (Scheme 1). 2,3-Dichloro-5,6-
dimethylcyclohexa-2,5-diene-1,4-dione (5) was prepared
by oxidizing 2,3-dimethylbenzene-1,4-diol with HNO3/
HCl according to known method.12 Methyl or ethyl 2-
(2-chloro-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)-
2-cyanoacetate (6a or 6b) was synthesized by nucleophil-
ic substitution of compound 5 with equivalent of methyl
or ethyl cyanoacetate in EtOH in the presence of
NH4OH. When equivalent amounts of compound 6a
and appropriate arylamines were mixed in EtOH and
refluxed for 5 h, compounds 3c–m were formed. In
Keywords: 1H-Indole-4,7-dione; Antimicrobial compounds; Anti-
fungal; Fungi; Substitution effects.
*
Corresponding author. Tel.: +82 2 3277 3027; fax: +82 2 3277
3051; e-mail: ckryu@mm.ewha.ac.kr
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.09.076

128
C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 127–131
Table 1. Structures and in vitro antifungal activity for 1H-indole-4,7-diones
O
O
O
O
O
O
O
O
R1
R2
R1
S
S
CH3
H3C
H3C
H3C
H3C
N
N
N
H
CH3
O
O
R1
R1
3a-b
3c-m
4a-i
R2
R2
Compound
R1
R2
MICa (lg/mL)
Candida albicansb
Candida tropicalis
Candida krusei
Cryptococcus
neoformans
Aspergillus niger
3a
3b
CH3
CH3CH2
H
—
—
H
F
>100
>100
3.2
>100
25
3.2
50
1.6
100
6.3
3.2
12.5
50
>100
>100
25
3c
3d
12.5
>100
12.5
6.3
1.6
3.2
H
>100
12.5
50
12.5
25
3e
H
Cl
Br
I
0.8
50
3f
3g
H
3.2
H
25
12.5
>100
50
50
3.2
50
100
>100
>100
6.3
3h
3i
H
CH3
CH3O
CH3
>100
>100
12.5
>100
25
0.8
100
1.6
1.6
50
H
3.2
0.8
3j
3k
CH3
H
>100
>100
50
CF3O
CH3CH2
(CH3)2CH
6.3
50
3.2
3.2
3l
3m
H
H
12.5
>100
100
12.5
>100
25
100
>100
3.2
100
12.5
6.3
3.2
3.2
3.2
50
3.2
50
4a
4b
H
H
H
F
100
>100
12.5
50
4c
4d
H
Cl
Br
H
>100
>100
>100
>100
>100
6.3
12.5
>100
12.5
>100
>100
1.6
25
H
>100
>100
>100
12.5
25
4e
CH3
CH3
F
4f
4g
CH3
F
100
>100
25
50
4h
Cl
H
3.2
25
4i
6a
H
—
OH
—
—
50
50
>100
100
100
6.3
>100
>100
>100
50
>100
>100
6.3
>100
>100
12.5
6.3
25
6b
5-Fluorocytosine
—
12.5
a The MIC value was defined as the lowest concentration of the antifungal agent. MIC values were read after 1 day for Candida species and
Cryptococcus neoformans, and 2 days for Aspergillus niger 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, Candida tropicalis Berkout KCCM 50662, Candida krusei Berkout KCCM 11655,
Cryptococcus neoformans KCCM 50564 and Aspergillus niger KCTC 1231.
O
R1
O
O
O
O
O
O
O
H3C
H3C
Cl
Cl
H3C
H3C
CH3
b
H3C
H3C
a
CN
Cl
N
O
O
6a : R1=Me
6b : R1=Et
5
R1
R2
c
3c-m : R1, R2 = H, F,..
O
O
O
R1
H3C
H3C
N
CH3
O
3a : R1=Me
3b : R1=Et
Scheme 1. Synthesis of 1H-indole-4,7-diones. Reagents and conditions: (a) methyl cyanoacetate or ethyl cyanoacetate/EtOH/NH4OH/rt/10 min; (b)
6a/arylamine/EtOH/reflux/5 h; (c) 6a or 6b/methylamine/EtOH/reflux/5 h.

C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 127–131
129
O
O
R1
R2
S
O
OH
b
a
N
H
S
N
H
N
H
O
R1
7
8
R2
4a-i : R1, R2 = H, F,..
Scheme 2. Synthesis of 5,6-bis(arylthio)-1H-indole-4,7-diones. Reagents and conditions: (a) Fremy’s salt (2 equiv) in 0.3 M KH2PO4/EtOH/rt; (b)
arylthiol (2 equiv)/EtOH/reflux/5 h.
similar manner, compounds 3a–b were prepared by
cyclization of compound 6a or 6b with methylamine in
EtOH. Experimental details and data for this procedure
are cited in the References and Notes.13–17
In addition, alkyl 2-(2-chloro-4,5-dimethyl-3,6-dioxocy-
clohexa-1,4-dienyl)-2-cyanoacetates (6a and 6b)
exhibited no or poor, if any, antifungal activity. The
1H-indole-4,7-diones 3a–m and 4a–i showed, in general,
more potent antifungal activity than cyclohexa-2,5-di-
ene-1,4-diones 6a–b. Thus, 1H-indole-4,7-dione moiety
appears to partially contribute to antifungal potency.
A convenient method for the synthesis of 5,6-bis(aryl-
thio)-1H-indole-4,7-diones 4a–i (Table 1) is shown in
(Scheme 2). The preparation of 1H-indole-4,7-dione
(8) by oxidation of 1H-indol-4-ol (7) was carried out
with Fremy’s salt (potassium nitrosodisulfonate) in
59% yield. The compounds 4a–i were synthesized by
nucleophilic substitution of the compound 8 with appro-
priate arylthiols. Most of these substitutions went as
expected and had overall high yields of 72–91%.
In conclusion, alkyl 2-(2-chloro-4,5-dimethyl-3,6-dioxo-
cyclohexa-1,4-dienyl)-2-cyanoacetates 6a and 6b were
synthesized by nucleophilic substitution of 2,3-dichlo-
ro-5,6-dimethylcyclohexa-2,5-diene-1,4-dione (5) with
equivalent of alkyl cyanoacetates in the presence of
NH4OH. 1H-Indole-4,7-dione derivatives 3a–m were
synthesized by cyclization of compound 6a or 6b with
appropriate amines. The 5,6-bis(arylthio)-1H-indole-
4,7-diones 4a–i were synthesized by nucleophilic substi-
tution of 1H-indole-4,7-dione (8) with appropriate aryl-
thiols in overall high yields. Among them tested, many
of 1H-indole-4,7-dione derivatives 3a–m and 4a–i
showed potent antifungal activity against C. krusei, C.
neoformans, and A. niger. These 1H-indole-4,7-diones
may thus be a promising lead for the development of
antifungal agents. Moreover, the results should encour-
age the synthesis of 1H-indole-4,7-diones analogs for
improving antifungal properties.
The synthesized 1H-indole-4,7-diones 3a–m, 4a–i, and
cyclohexa-2,5-diene-1,4-diones 6a–b were tested in vitro
for their growth inhibitory activity against pathogenic
fungi by the standard method.18 The MIC (minimum
inhibitory concentration) values were determined by
comparison with 5-fluorocytosine as a standard agent.18
As indicated in Table 1, most of synthesized 1H-indole-
4,7-diones 3a–m generally showed potent antifungal
activity against Candida krusei, Cryptococcus neofor-
mans, and Aspergillus niger. The antifungal activity
against C. neoformans was prominent. In contrast, com-
pounds 3a–m did not show significant antifungal activity
against C. albicans and C. tropicalis, although com-
pounds 3c, 3e, and 3m exhibited good activity.
Acknowledgment
Many of 5,6-bis(arylthio)-1H-indole-4,7-diones 4a–i
also showed potent antifungal activity against C. krusei,
C. neoformans, and A. niger. Actually, the activity of
compounds 3c, 3e, and 4h was superior or comparable
to those of 5-fluorocytosine against all tested fungi.
The compounds 3c, 3e, and 4h completely inhibited
the growth of all fungal species tested at the MIC level
of 1.6–25 lg/mL.
This work was supported by Seoul R&BD Program
(10688).
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.
4. Musser, S. M.; Stowell, M. H. B.; Lee, H. K.; Rumbley, J.
N.; Chan, S. I. Biochemistry 1997, 36, 894.
5. Ryu, C.-K.; Kang, H.-Y.; Yi, Y.-J.; Shin, K.-H.; Lee,
B.-H. Bioorg. Med. Chem. Lett. 2000, 10, 1589; Ryu,
C.-K.; Choi, K. U.; Shim, J.-Y.; You, H.-J.; Choi, I.
H.; Chae, M. J. Bioorg. Med. Chem. 2003, 11, 4003;
In terms of structure–activity relationship, the 4,7-dihy-
dro-5,6-dimethyl-4,7-dioxo-1H-indole-3-carboxylates 3
showed, in general, a more potent antifungal activity
than the other 5,6-bis(arylthio)-1H-indole-4,7-diones 4.
The 1-aryl-compounds 3 exhibited good activity, indicat-
ing a correlation that may offer insight into the mode of
action of these compounds. The halogen-moieties of sub-
stituents (R1, R2: H, F, Cl, . . .) for the 1-aryl and 5,6-
bis(arylthio) moieties of compounds 3c–m and 4a–i ap-
pear to contribute partially toward biological potency.

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C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 127–131
Ryu, C.-K.; Lee, S. K.; Han, J. Y.; Jung, O. J.; Lee, J.
Y.; Jeong, S. H. Bioorg. Med. Chem. Lett. 2005, 15,
2617.
powder (60%); mp 227–228 ꢁC; 1H NMR d 2.08 (s, 3H,
CH3), 2.12 (s, 3H, CH3), 3.91 (s, 3H, CH3O), 7.00 (q, 1H,
Ph), 7.10 (m, 1H, Ph), 7.30 (m, 1H, Ph), 7.39 (q, 1H, Ph),
7.64 (s, 1H, pyrrole); MS (m/z) 342 (M+); compound 3e:
6. Mohammed, J.; Roger, M. P.; Kaye, J. W.; Ibrahim, M.;
Christian, C.; Natasha, S. W.; Timothy, H. W.; Ian, J. S.;
Adam, V. P. Biochem. Pharmacol. 2003, 66, 1199.
7. Santo, L. L.; do, E.; Galvao, D. S. J. Mol. Struct. 1999,
464, 273.
8. Beall, H. D.; Winski, S. L. Front. Biosci. 2000, 5, 639.
9. Matthew, A. N.; Mohammed, J.; John, N.; Miriam, A. S.;
Susan, B.; Kantilal, B. P.; Steven, A. E.; Gerald, E. A.;
Ian, J. S. J. Med. Chem. 1997, 40, 2335.
10. Mohammed, J.; Matthew, A. N.; Naomi, R.; Stacey, D.
L.; Roger, M. P.; Steven, A. E.; Gerald, E. A.; Ian, J. S.
Anti-cancer Drug Design 1998, 13, 105.
11. Fukuyama, Y.; Iwatsuki, C.; Kodama, M.; Ochi, M.;
Kataoka, K.; Shibata, K. Tetrahedron 1998, 54, 10007.
12. Van Allan, J. A.; Priest, W. J.; Marshall, A. S.; Reynolds,
G. A. J. Org. Chem. 1968, 33, 1100.
1
dark purple powder (43%); mp 212 ꢁC (dec); H NMR d
2.08 (s, 3H, CH3), 2.12 (s, 3H, CH3), 3.91 (s, 3H, CH3O),
6.95 (q, 1H, Ph), 7.26 (m, 1H, Ph), 7.32 (m, 1H, Ph), 7.59
(s, 2H, Ph), 7.65 (s, 1H, pyrrole); MS (m/z) 358 (M+);
1
compound 3f: purple powder (38%); mp 237–238 ꢁC; H
NMR d 2.08 (s, 3H, CH3), 2.12 (s, 3H, CH3), 3.91 (s, 3H,
CH3O), 6.89 (q, 1H, Ph), 7.26 (m, 1H, Ph), 7.46 (m, 2H,
Ph), 7.59 (s, 1H, pyrrole), 7.79 (q, 1H, Ph); MS (m/z) 402
(M+); compound 3g: purple powder (58%); mp 229–
1
230 ꢁC; H NMR d 2.07 (s, 3H, CH3), 2.11 (s, 3H, CH3),
3.91 (s, 3H, CH3O), 6.75 (q, 1H, Ph), 7.26 (m, 1H, Ph),
7.57 (s, 1H, pyrrole), 7.64 (m, 2H, Ph), 7.96 (m, 1H, Ph);
MS (m/z) 450 (M+); compound 3h: dark violet powder
(65%); mp 220–221 ꢁC; 1H NMR d 2.05 (s, 3H, CH3), 2.11
(s, 3H, CH3), 2.34 (s, 3H, CH3), 3.90 (s, 3H, CH3O), 6.90
(d, 1H, Ph), 7.12 (m, 2H, Ph), 7.43 (t, 1H, Ph), 7.65 (s, 1H,
pyrrole); MS (m/z) 323 (M+); compound 3i: dark violet
13. Experimental: All melting points were measured with
Buchi melting point B-545 and are uncorrected. H NMR
¨
1
1
spectra were recorded on Varian Unity INOVA 400 MHz
FT-NMR spectrometer using DMSO-d6 or CDCl3 with
TMS. Mass spectra were taken with Jeol JMS AX505
WA. 2,3-Dimethylbenzene-1,4-diol and other reagents
were purchased from Aldrich Chemical Co. The 2,3-dichlo-
ro-5,6-dimethylcyclohexa-2,5-diene-1,4-dione (5) was pre-
pared by oxidizing 2,3-dimethylbenzene-1,4-diol with
HNO3/HCl variation according to known method.12
powder (83%); mp 214 ꢁC (dec); H NMR d 2.06 (s, 3H,
CH3), 2.12 (s, 3H, CH3), 3.82 (s, 3H, CH3O), 3.89 (s, 3H,
CH3O), 6.91 (dd, 1H, Ph), 6.96 (d, 1H, Ph), 7.14 (d, 1H,
Ph), 7.59 (s, 1H, pyrrole); MS (m/z) 354 (M+); compound
1
3j: dark violet powder (91%); mp 232–233 ꢁC; H NMR d
2.03 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.24 (s, 6H, CH3),
3.87 (s, 3H, CH3O), 6.78 (s, 1H Ph), 7.37 (s, 2H, Ph), 7.52
(s, 1H, pyrrole); MS (m/z) 352 (M+); compound 3k: dark
1
14. Synthesis of alkyl 2-(2-chloro-4,5-dimethyl-3,6-dioxocyclo-
hexa-1,4-dienyl)-2-cyanoacetates (6a and 6b): To a solu-
tion of compound 5 (1.295 g, 2.66 mmol) and methyl
cyanoacetate or ethyl cyanoacetate (2.66 mmol) in 100 mL
EtOH, NH4OH solution (2 mL) was added dropwise. The
mixture was stirred at rt for 10 min, d-HCl was then
added. The mixture was then extracted several times with
CH2Cl2, and the organic layer was washed with water,
dried with anhydrous MgSO4, and concentrated. The
product 6a or 6b was separated by silica gel column
chromatography with n-hexane/EtOAc. Methyl 2-(2-chlo-
ro-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)-2-cyanoac-
violet powder (55%); mp 183–184 ꢁC; H NMR d 2.10(s,
3H, CH3), 2.12 (s, 3H, CH3), 3.91 (s, 3H, CH3O), 7.04 (d,
1H, Ph), 7.2 5 (m, 2H, Ph), 7.54 (d, 1H, Ph), 7.65 (s, 1H,
pyrrole); MS (m/z) 408 (M+); compound 3l: dark violet
powder (70%); mp 209–210 ꢁC; 1H NMR d 1.22 (t, 3H,
CH3), 2.07 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.64 (q, 2H,
CH2), 3.88 (s, 3H, CH3O), 6.92 (q, 1H, Ph), 7.14 (m, 1H,
Ph), 7.26 (m, 1H, Ph), 7.46 (m, 2H, Ph), 7.56 (s, 1H,
pyrrole); MS (m/z) 352 (M+); compound 3m: dark violet
1
powder (73%); mp 203–204 ꢁC; H NMR d 1.23 (d, 6H,
CH3), 2.07 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.32 (sept, 1H,
CH), 3.86 (s, 3H, CH3O), 6.93 (m, 1H, Ph), 7.22 (m, 1H,
Ph), 7.26 (m, 1H, Ph), 7.48 (m, 2H, Ph), 7.56 (s, 1H,
pyrrole): MS (m/z) 366 (M+).
1
etate (6a): brown oil (31%); H NMR (CDCl3) d 2.01 (s,
3H, CH3), 2.04 (s, 3H, CH3), 3.76 (s, 3H, OCH3), 5.25 (s,
1H, CH). MS (m/z) 267 (M+).
17. General procedure for synthesis of 5,6-bis(arylthio)-
1H-indole-4,7-diones 4a–i: To a solution of 1H-indol-4-ol
(7) (0.2 g, 1.5 mmol) in 15 EtOH/KH2PO4 was added a
solution of potassium nitrosodisulfonate (1.5 g,
5.60 mmol) in the KH2PO4 buffer (0.3 M, 200 mL). The
mixture was stirred at rt for 5 h and was extracted twice
with CHCl3. The extract was evaporated and purified by
column chromatography with CHCl3. 1H-Indole-4,7-dione
(8) was obtained: dark orange powder (23%); mp 174–
175 ꢁC; 1H NMR (DMSO-d6), d 5.75 (s, 1H, NH), 6.53 (d,
1H, J = 7.1, pyrrole), 6.63 (s, 2H, quinone), 7.25 (s, 1H,
J = 7.1, pyrrole); MS (m/z) 147 (M+). A solution of
compound 8 (0.147 g, 1 mmol) in 20 mL of 95% EtOH was
added to a solution of the arylthiol (2.1 mmol) in 10 mL of
95% EtOH and then refluxed for 5 h. After the reaction
mixture was kept overnight, the precipitate was collected
by the filtration. The crude product was purified by silica
gel column chromatography with CHCl3 or crystallized
from 95% EtOH. Crystallization from aq. EtOH afforded
5,6-bis(arylthio)-1H-indole-4,7-diones 4a–i. Compound
4a: red needle (71%); mp 235–236 ꢁC; 1H NMR
(DMSO-d6), d 6.52 (d, 1H, pyrrole), 7.22 (s, 1H, pyrrole),
7.24–7.36 (m, 10H, Ph), 12.70 (s, 1H, NH); MS (m/z) 363
(M+); compound 4b: red needle (45%); mp 217–218 ꢁC; 1H
NMR d 6.51 (d, 1H, pyrrole), 7.23 (d, 1H, pyrrole), 7.17
(q, 4H, Ph), 7.45 (m, 4H, Ph), 12.64 (s, 1H, NH); MS (m/z)
15. General procedure for synthesis of 4,7-dihydro-5,6-dimeth-
yl-4,7-dioxo-1H-indole-3-carboxylates (3a and 3b): Equiv-
alent weight of methylamine was added to the solution of
compounds 6a or 6b 300 mg in 100 mL 95% EtOH and
heated under reflux for 1 h. The products 3a and 3b were
purified by silica gel column chromatography and crys-
tallized from 95% EtOH (Table 1). Compound 3a: dark
violet powder (55%); mp 233–234 ꢁC; 1H NMR (CDCl3) d
2.01 (s, 3H, CH3), 2.03 (s, 3H, CH3), 3.82 (s, 3H, CH3O),
3.91 (s, 3H, CH3), 5.61 (s, 1H, pyrrole); MS (m/z) 263
(M+); compound 3b: dark violet powder (42%); mp 113–
1
115 ꢁC; H NMR d 1.26 (t, 3H, CH3), 2.00 (s, 3H, CH3),
2.03 (s, 3H, CH3), 3.79 (s, 3H, CH3), 4.36 (q, 2H, CH2),
5.61 (s, 1H, pyrrole); MS (m/z) 276 (M+).
16. General procedure for synthesis of 4,7-dihydro-5,6-dimeth-
yl-4,7-dioxo-1-aryl-1H-indole-3-carboxylates (3c–m): Equi-
valent weight of arylamine was added to the solution of
compound 6a 300 mg in 100 mL 95% EtOH and heated
under reflux for 1 h. The products 3c–m were purified by
silica gel column chromatography and crystallized from
95% EtOH. Compound 3c: dark violet powder (55%); mp
253–254 ꢁC; 1H NMR(CDCl3) d 2.07 (s, 3H, CH3), 2.12 (s,
3H, CH3), 3.89 (s, 3H, CH3O), 7.00 (d, 1H, Ph), 7.18 (td,
1H, Ph), 7.35 (td, 1H, Ph), 7.59 (m, 2H, Ph), 7.66 (s, 1H,
pyrrole); MS (m/z) 324 (M+); compound 3d: dark violet

C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 127–131
131
399 (M+); compound 4c: black powder (60%); mp 215–
216 ꢁC; 1H NMR d 6.53 (d, 1H, pyrrole), 7.26 (s, 1H,
pyrrole), 7.35–7.48 (m, 8H, Ph), 12.82 (s, 1H, NH); MS
(m/z) 431 (M+); compound 4d: dark brown powder (61%);
196 ꢁC; 1H NMR d 6.55 (d, 1H, pyrrole), 7.26 (d, 1H,
pyrrole), 7.35 (m, 4H, Ph), 7.65 (m, 2H, Ph), 12.64 (s, 1H,
NH); MS (m/z) 435 (M+); compound 4h: red powder
1
(42%); mp 188–189 ꢁC; H NMR d 6.56 (d, 1H, pyrrole),
1
mp 215–217 ꢁC; H NMR d 6.53 (d, 1H, pyrrole), 7.26 (s,
7.27 (d, 1H, pyrrole), 7.33 (m, 6H, Ph), 7.52 (d, 2H, Ph),
12.62(s, 1H, NH); MS (m/z) 431 (M+); compound 4i: dark
brown powder (50%); mp 241.0–241.5 ꢁC; 1H NMR d 6.45
(d, 1H, pyrrole), 6.71 (m, 4H, Ph), 7.21 (m, 4H, Ph), 7.22
(d, 1H, pyrrole), 9.66 (s, 2H, OH), 12.69 (s, 1H, NH); MS
(m/z) 395 (M+).
1H, pyrrole), 7.35 (q, 4H, Ph), 7.49 (d, 4H, Ph), 12.61 (s,
1H, NH); MS (m/z) 519 (M+); compound 4e: red powder
(58%); mp 195–197 ꢁC; 1H NMR d 2.26 (s, 3H, CH3) 6.51
(d, 1H, pyrrole), 7.25 (d, 1H, pyrrole), 7.05 (m, 2H, Ph),
7.17 (m, 6H, Ph); MS (m/z) 392 (M+); compound 4f: red
1
powder (66%); mp 211–212 ꢁC; H NMR d 2.21 (s, 12H,
18. Mcginnis, M. R.; Rindali, M. G. In Antibiotics in
Laboratory Medicine, 4th ed.; Lorian, V., Ed.;
Williams and Wilkins: Baltimore, 1996; pp. 176–
211.
CH3), 6.48 (d, 1H, pyrrole), 7.07 (d, 4H, Ph), 7.15 (d, 2H,
Ph), 7.21 (d, 1H, pyrrole), 12.71 (s, 1H, NH); MS (m/z) 419
(M+); compound 4g: dark red crystal (71%); mp 195–