498
C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 497–499
R1
nucleophilic substitution and cyclization of compounds 7a–d with
R2
1 equiv of active methylenes such as methyl acetoacetate, ethyl
acetoacetate, nitromethane or acetylactone in EtOH. Most of these
additions went as expected and had overall high yields.
OH
O
O
Cl-
H3C
H3C
H3C
H3C
Cl
Cl
H3C
H3C
N+
a
b
path A
In similar manner, benzo[f]pyrido[1,2-a]indole-6,11-diones
4a–o were prepared in two steps from commercially available 2,3-
dichloro-1,4-naphthoquinone (8) according to the reported
method13,14 with minor modification. 1,4-Dioxo-(1,4-dihydro-
naphthalen-2-yl)-4-methyl-pyridinium chlorides 9a–d were
synthesizedby nucleophilic substitution of compound8 with appro-
priate pyridines. Consequently, benzo[f]pyrido[1,2-a]indole-6,11-
diones 4a–o were synthesized by nucleophilic substitution and
cyclization of compounds 9a–d with 1 equiv of appropriate active
methylenes in EtOH. Most of these additions went as expected and
had overall high yields of 39–95%.
The synthesized pyrido[1,2-a]indole-1,4-diones 3a–o and
benzo[f]pyrido[1,2-a]indole-6,11-diones 4a–o, 7a–b, and 9a–b
were tested in vitro for their growth inhibitory activity against
pathogenic fungi using the standard twofold broth dilution meth-
od.15 The MIC (minimum inhibitory concentration) values were
determined by a comparison with fluconazole and 5-fluorocytosine
as standard agents.15
Cl
OH
O
O
7a-d
5
6
d
c
path B
R1
O
O
R2
H3C
H3C
N
R3
3a-o
R1
R2
O
O
Cl-
N+
Cl
Cl
b
d
Cl
As indicated in Table 1, most of synthesized pyrido[1,2-a]
indole-1,4-diones 3a–o, and benzo[f]pyrido[1,2-a]indole-6,
11-diones 4a–o generally showed potent antifungal activity
against all pathogenic fungal strain tested. Actually, the activity
of compounds 3a, 3l, 3o, and 4b was superior or comparable to
those of 5-fluorocytosine against all tested fungi. The compounds
3a, 3l, 3o, and 4b completely inhibited the growth of all fungal
O
O
8
9a-d
c
R1
O
species tested at the MIC level of 1.6–12.5 lg/mL. The activity
of many tested compounds was superior or comparable to those
R2
N
of 5-fluorocytosine against some strain of fungi.
R3
In contrast, pyridinium derivatives 7a–b, and 9a–b did not
show significant antifungal activity against all pathogenic fungal
strain tested, although many of the compound 7a–b also showed
potent antifungal activity.
In terms of structure–activity relationship, the pyrido[1,2-a]
indole-1,4-diones 3a–o and benzo[f]pyrido[1,2-a]indole-6,11-
diones 4a–o showed, in general, more potent antifungal activity
than the other pyridinium derivatives 7a–b, and 9a–b. The pyr-
ido[1,2-a]indole-1,4-dione skeleton of compounds 3 and 4 exhib-
ited good activity, indicating a correlation that may offer insight
into the mode of action of these compounds.
O
4a-o
Scheme 1. Pyrido[1,2-a]indole-1,4-diones and benzo[f]pyrido[1,2-a]indole-6,11-
diones. Reagents and conditions: (a) HNO3/HCl/90 °C/10 min (b) pyridine deriv./
EtOH/Reflux/4 h (c) active methylene deriv. (1 equiv)/EtOH/Reflux/8 h (d) pyridine
deriv./active methylene deriv. (1 equiv)/EtOH/Reflux/16 h.
A convenient method for synthesis of pyrido[1,2-a]indole-1,
4-diones 3a–o and benzo[f]pyrido[1,2-a]indole-6,11-diones 4a–o
is shown in Scheme 1 and Table 1. As shown in Scheme 1, com-
pounds 3a–o could be synthesized by either one-pot (path B) or
two step synthesis (path A) from 2,3-dichloro-5,6-dimethylcyclo-
hexa-2,5-diene-1,4-dione (6) and appropriate pyridine derivatives
and active methylenes. Although one-pot synthesis of compounds
3a–o seems to be much more attractive, the two step synthesis is
much easier than one-pot synthesis as a result of the difficulty in
both the substitution reaction. Herein, we report efficient two-step
synthesis of compounds 3a–o via cyclization of 4,5-dimethyl-3,
6-dioxo-cyclohex-1-enyl-4-methyl-pyridinium chlorides 7a–d
with active methylenes.
The substituents (R1, R2, R3: H, X, Me, ..) for the compounds 3, 4,
7, and 9 may not contribute partially toward biological potency.
Thus, the substituents (R1, R2, R3: H, X, Me, ..) appear to be not
an important factor to affect their antifungal activity.
In addition, 2,3-dimethylbenzene-1,4-diol (5) exhibited no or
poor, if any, antifungal activity. In contrast, most of synthesized
pyrido[1,2-a]indole-1,4-diones 3 and benzo[f]pyrido[1,2-a]indole-
6,11-diones 4 showed more potent antifungal activity than com-
pound 5. Thus, the quinone moiety in compounds 3–4 should be
essential for the antifungal activity, for example, as nonquinonoid
compound 6 lost the activity.
Compounds 3 were prepared in two steps from 2,3-dichloro-
5,6-dimethylcyclohexa-2,5-diene-1,4-dione (6)11 according to the
reported method12 with minor modification. The compound 6
was prepared by oxidizing commercially available 2,3-dimethyl-
benzene-1,4-diol (5) with HNO3/HCl variation. 4,5-Dimethyl-3,6-
dioxo-cyclohex-1-enyl-4-methyl-pyridinium chlorides 7a–d were
synthesized by nucleophilic substitution of compound 5 with
appropriate pyridines and subsequent oxidation. When compound
6 with 3 equiv amount of appropriate pyridines in EtOH were
refluxed for 4 h, compounds 7a–d were formed. Most of these
additions went as expected and had overall high yields. Conse-
quently, pyrido[1,2-a]indole-1,4-diones 3a–o was synthesized by
In conclusion, synthesized pyrido[1,2-a]indole-1,4-diones 3a–o
and benzo[f]pyrido[1,2-a]indole-6,11-diones 4a–o were synthe-
sized by cyclization of compounds 6 and 8 with appropriate pyridine
derivatives and active methylene in EtOH. Most of these reactions
went as expected and had overall high yields. Among them tested,
many of compounds 3, 4, 7, and 9 showed potent antifungal activity
against pathogenic fungal strain tested. These pyrido[1,2-a]indole-
1,4-diones and benzo[f]pyrido[1,2-a]indole-6,11-diones may thus
be a promising lead for the development of antifungal agents. More-
over, the results should encourage the synthesis of pyrido[1,2-a]in-
dole-1,4-dione and benzo[f]pyrido[1,2-a]indole-6,11-dione analogs
for improving antifungal properties.
Ryu, Chung-Kyu
