Microwave-assisted synthesis of diverse pyrrolo[3,4- c ]quinoline-1,3- diones and their antibacterial activities

Article abstract of DOI:10.1021/co500002s

With the aim of developing a general and practical method for library production, a novel and efficient two-phase microwave-assisted cascade reaction between isatins and β-ketoamides in [Bmim]BF₄/toluene was developed for the synthesis of pyrrolo[3,4-c]quinoline-1,3-diones. The features of this methodology are, the use of microwave-assisted rapid synthesis, mild reaction conditions, high yields, operational simplicity, facile product separation, and recyclability. Furthermore, the antibacterial activities of the pyrrolo[3,4-c]quinoline-1,3-dione derivatives produced were evaluated against Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Enterobacter aerogenes) and Gram-positive bacteria (Bacillus cereus and Staphylococcus aureus). These derivatives showed antibacterial activities against Gram-positive strains that were at least equivalent to that against Gram-negative strains. Compound 7{3,5} displayed the most potent antibacterial activity against P. aeruginosa (MIC = 0.5 μg/mL) and greater activity than standard ampicillin (MIC = 1 μg/mL). Compound 7{4,7} exhibited the best inhibitory activity against E. coli and E. aerogenes (MIC = 1 and 0.5 μg/mL), compared with the standard ampicillin (both MICs = 1 μg/mL). The synthesized pyrrolo[3,4-c]quinoline-1,3-diones are expected to be widely used as lead compounds for the development of new antibacterial agents.

Full text of DOI:10.1021/co500002s

Research Article
pubs.acs.org/acscombsci
Microwave-Assisted Synthesis of Diverse Pyrrolo[3,4‑c]quinoline-1,3-
diones and Their Antibacterial Activities
Likai Xia,† Akber Idhayadhulla,† Yong Rok Lee,*,† Sung Hong Kim,‡ and Young-Jung Wee§
†School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea
‡Analysis Research Division, Daegu Center, Korea Basic Science Institute, Daegu 702-701, Republic of Korea
§Department of Food Science and Technology, Yeungnam University, Gyeongsan 712-749, Republic of Korea
S
* Supporting Information
ABSTRACT: With the aim of developing a general and practical method for library production, a novel and efficient two-phase
microwave-assisted cascade reaction between isatins and β-ketoamides in [Bmim]BF4/toluene was developed for the synthesis of
pyrrolo[3,4-c]quinoline-1,3-diones. The features of this methodology are, the use of microwave-assisted rapid synthesis, mild
reaction conditions, high yields, operational simplicity, facile product separation, and recyclability. Furthermore, the antibacterial
activities of the pyrrolo[3,4-c]quinoline-1,3-dione derivatives produced were evaluated against Gram-negative bacteria
(Escherichia coli, Pseudomonas aeruginosa, and Enterobacter aerogenes) and Gram-positive bacteria (Bacillus cereus and
Staphylococcus aureus). These derivatives showed antibacterial activities against Gram-positive strains that were at least
equivalent to that against Gram-negative strains. Compound 7{3,5} displayed the most potent antibacterial activity against
P. aeruginosa (MIC = 0.5 μg/mL) and greater activity than standard ampicillin (MIC = 1 μg/mL). Compound 7{4,7} exhibited
the best inhibitory activity against E. coli and E. aerogenes (MIC = 1 and 0.5 μg/mL), compared with the standard ampicillin
(both MICs = 1 μg/mL). The synthesized pyrrolo[3,4-c]quinoline-1,3-diones are expected to be widely used as lead compounds
for the development of new antibacterial agents.
KEYWORDS: microwave irradiation, isatins, β-ketoamides, pyrrolo[3,4-c]quinoline-1,3-diones, antibacterial activity
biologically active natural products15a,b and are used in dye-
INTRODUCTION
■
sensitized solar cells.15c−f For an example, arcyriarubin A (3)
Quinolines have attracted the attentions of chemists and
biologists because they are key building blocks for the synthesis
and related compounds, exhibit potent antimicrobial16 and
antiviral activities,17 and are strong protein kinase C
of biologically active natural products bearing quinoline
inhibitors.18 The pyrroledione derivative 4 has been reported
skeletons.1 In addition, they are widely used in numerous
to have antibacterial activity against resistant strains of
commercial products, such as, pharmaceuticals, fragrances, and
dyes.2 Molecules bearing quinoline skeletons have wide ranging
Mycobacterium smegmatis and some other Gram positive
bacteria.19 The natural pyrrolo[3,4-c]quinoline-1,3-diones
pharmaceutical activities, for example, they have been reported
to have, antituberculosis,3 antimalarial,4 anti-inflammatory,5
bearing a quinoline and a pyrroledione ring exhibit a broad
anticancer,6 antibiotic,7 antihypertensive,8 platelet derived
spectrum of biologically and pharmacologically important
properties, such as, inhibitory activities against caspase-320
growth factor receptor tyrosine kinase (PDGF-RTK) inhib-
and hepatitis C virus (HCV) polymerase,21 to act selectively as
agonists, antagonists, or inverse agonists of γ-aminobutyric acid
(GABA) brain receptor,22 and to have antitumor activities.23
However, the antibacterial activities of pyrrolo[3,4-c]quinoline-
1,3-dione derivatives have not been evaluated to date.
itory,9 and antihuman immunodeficiency virus (HIV) activ-
ities.10 In particular, mefloquine (1) is still being used as an
antimalarial, despite its side-effects (Figure 1).11 Furthermore, a
number of mefloquine analogues have been reported to possess
antibacterial and antituberculosis activities.12 Synthetic quino-
line 2 has antibacterial and antifungal activities.13 Pyrrolediones
are also common structural motifs and one of the most
important classes of bioactive heterocycles.14 Molecules
containing a pyrroledione ring are present in a number of
Received: January 10, 2014
Revised: April 7, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/co500002s | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
in vitro antibacterial activities against Gram-negative bacteria
[Escherichia coli (E. coli, KCTC-1924 (Korean Collection for
Type Cultures)], Pseudomonas aeruginosa (P. aeruginosa,
KCTC-2004), Enterobacter aerogenes (E. aerogenes, KCTC-
2190)] and Gram-positive bacteria [Staphylococcus aureus (S.
aureus, KCTC-1916) and Bacillus cereus (B. cereus, KCTC-
1012)].
RESULTS AND DISCUSSION
■
Chemistry. We first investigated the reaction between isatin
5{1} and 3-oxo-N-phenylbutanamide 6{1} under various
conditions (Table 1). When isatin 5{1} and 3-oxo-N-
phenylbutanamide 6{1} in different solvents were irradiated
at 140 °C for 1 h at 60−600 W, the desired product 7{1,1} was
isolated at yields of 5−40% (entries 1−5). The yield was not
highly increased by the addition of 0.l mL of AcOH (entries 6
and 7). AcOH was used as the solvent and catalyst to obtain the
desired product 7{1,1} in 70% yield (entry 8). Ionic liquids
were then added to these reaction mixtures to increase
microwave absorbance.27 Using 0.1 mL [Bmim]BF4 (1-butyl-
3-methylimidazolium tetrafluoroborate) as an additive in
toluene at 80 °C for 40 min at 60 W, compound 7{1,1} was
produced in 75% yield (entry 9). The sole usage of [Bmim]BF4
or conventional method gave the desired product 7{1,1} in
decreased yields (entries 10−11). It is worthy of notice that the
optimized loading amount of ionic liquid was 0.1 mL and the
reduced additive loading would cause the decrease of yield
(entry 12). The high temperature setting would also lead to
decomposition of the product, therefore decreasing the yield of
7{1,1} (entries 13−16). The further examination of other ionic
liquids showed that [Bmim]BF4 (1-butyl-3-methylimidazolium
tetrafluoroborate) was superior to [Bmim]PF6, [Bmim]Br, and
[Omim]BF4 (entries 17−19). At greater or lesser reaction
times, yields were decreased (entries 20−25). Thus, the best
yield of 7{1,1} (90%) was achieved via the irradiation with 0.1
mL [Bmim]BF4 as an additive in toluene at 100 °C for 40 min
at 60 W (entry 10).
Figure 1. Design concept for new quinoline derivatives bearing
pyrroledione moieties.
Accordingly, we designed a series of pyrrolo[3,4-c]quinoline-
1,3-diones bearing a quinoline and a pyrroledione ring with a
view toward determining their antibacterial activities.
Because of their importances and usefulnesses, several syn-
thetic approaches have been developed to construct pyrrolo-
[3,4-c]quinoline-1,3-dione derivatives,24 and of these, 3-step
reactions based on the Pfitzinger reaction have generally been
used to prepare pyrrolo[3,4-c]quinoline-1,3-diones.24c,d Another
facile procedure was described for the 2-step syntheses of novel
pyrrolo[3,4-c]quinolinediones via the cyclocondensation of
2-amino-5-fluorophenyl glyoxylic acid and β-ketoamides.24e
Very recently, a BF3 Et2O-catalyzed cascade strategy was
developed for the construction of pyrrolo[3,4-c]quinoline-1,3-
diones via isocyanide-based cascade cycloaddition reaction with
methyleneindolinones.24f However, these procedures are
limited by their complexity, the long reaction time and harsh
reaction conditions required, and their low yields. Recently, we
developed a means of synthesizing pyrrolo[3,4-c]quinoline-1,3-
dione derivatives using ethylenediamine diacetate as a
catalyst.25 To minimize reaction time and increase the yields
of pyrrolo[3,4-c]quinoline-1,3-diones, microwave-assisted cas-
cade reactions between isatins and β-ketoamides were
investigated (Scheme 1) because of the success achieved
using microwave-assisted reactions in organic synthesis.26 Here,
we describe the microwave-assisted synthesis of pyrrolo
[3,4-c]quinoline-1,3-dione derivatives 7 and evaluations of their
To explore the generality of this reaction, reactions between
several isatins 5 and β-ketoamides 6 bearing electron-donating
or -withdrawing groups on the benzene ring were conducted
under optimized reaction conditions. The results obtained are
summarized in Table 2. The reaction between isatin 5{1} and
3-oxo-N-(p-tolyl)butanamide 6{2} or N-(4-methoxyphenyl)-3-
oxobutanamide 6{3} gave 7{1,2} and 7{1,3} in 86 and 85%
Scheme 1. Microwave-Assisted Green Synthesis of Pyrrolo[3,4-c]quinoline-1,3-diones 7
B
dx.doi.org/10.1021/co500002s | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Importantly, the design of our current library was based on
the basic skeleton of pyrrolo[3,4-c]quinoline-1,3-diones, which
were adapted from medicinally important scaffolds.20−23 The
calculated cLogP (2.97−5.77) values of our library well match
those of reported bioactive molecules of the same class.20−24
Catalyst recyclability is one of the most desirable features and
makes it useful for commercial applications. Thus, we examined
the recyclability of the two phase [Bmim]BF4/toluene catalyst
system used for the synthesis of 7{1,1} (Figure 2). After
completing reactions under optimized conditions, reaction
mixtures were diluted with water and extracted with ethyl acetate
(2 × 10 mL). Combined organic extracts were washed with water,
dried over anhydrous Na2SO4, and concentrated in vacuo, and
resulting residues were purified by column chromatography or by
recrystallization (from hot toluene) to afford pure products. The
[Bmim]BF4 was recovered by evaporating the aqueous layer in
vacuo. The recovered [Bmim]BF4 was further dried at 80 °C under
reduced pressure for use in subsequent cycles. The catalyst system
was found to be highly effective even after six recovery cycles
without any significant yield reduction.
Biological Evaluation. Antibacterial activity results re-
vealed that most of the synthesized compounds inhibited the
growth of the microorganisms tested. The synthesized
compounds 7 were tested at 100 μg/mL for in vitro
antibacterial activity against Gram-negative bacteria [Escherichia
coli (KCTC-1924), Pseudomonas aeruginosa (KCTC-2004),
Enterobacter aerogenes (KCTC-2190)], and Gram-positive
bacteria [Bacillus cereus (KCTC-1012) and Staphylococcus
aureus (KCTC-1916)]. Primary screening was carried out
Table 1. Optimization of the Reaction Conditions for the
Synthesis of 7{1,1}
a
MWI
(W)
temp
(°C)
time
(min)
yield
b
entry solvent
additive
(%)
1
toluene
MeCN
EtOH
DMF
600
600
300
100
60
140
140
140
140
140
140
140
140
80
60
60
60
60
60
60
60
60
40
40
300
90
40
40
40
40
40
40
40
5
5
15
20
40
25
30
35
70
75
71
54
57
90
89
87
82
40
85
32
30
70
85
89
88
85
2
3
4
5
H2O
6
toluene AcOH
540
270
120
60
7
EtOH
AcOH
AcOH
8
9
toluene [Bmim]BF4
[Bmim]BF4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
60
80
c
[Bmim]BF4
100
80
d
toluene [Bmim]BF4
toluene [Bmim]BF4
toluene [Bmim]BF4
toluene [Bmim]BF4
toluene [Bmim]BF4
toluene [Bmim]PF6
toluene [Bmim]Br
toluene [Omim]BF4
toluene [Bmim]BF4
toluene [Bmim]BF4
toluene [Bmim]BF4
toluene [Bmim]BF4
toluene [Bmim]BF4
toluene [Bmim]BF4
300
60
100
120
140
170
100
100
100
100
100
100
100
100
100
60
120
300
75
100
540
60
using the agar disc-diffusion method and Muller-Hinton agar
̈
medium.28
Results for the preliminary antibacterial compounds (100
μg/disc) tested and for standards (100 μg/disc) are shown in
Table 3. All compounds showed potent antibacterial activities.
Greatest antibacterial activities were displayed by compounds
7{1,3}, 7{3,5}, 7{3,7}, and 7{4,7}; the Gram-negative bac-
terium E. aerogenes appeared to be the most sensitive
microorganism tested. Compound 7{4,7} showed excellent
activity against E. coli (growth inhibition zones = 18 mm);
compounds 7{1,3}, 7{2,3}, 7{2,4}, 7{3,2}, and 7{3,5} showed
moderate activity against E. coli (zone of growth inhibition;
range 14−16 mm) (Figure 3a). Compound 7{3,5} exhibited
excellent activity against P. aeruginosa (growth inhibition zone =
28 mm); compounds 7{1,3} and 7{4,3} exhibited moderate
activity against P. aeruginosa (growth inhibition zone, 22 mm
and 20 mm) (Figure 3b). Compounds 7{1,3}, 7{1,7}, 7{2,5},
7{3,6}, 7{4,6}, and 7{4,7} showed excellent activity against
E. aerogenes (zone of growth inhibition; range 18−23 mm) and
the other compounds also showed good activity against
E. aerogenes (zone of growth inhibition; range 14−16 mm)
(Figure 3c). Compounds 7{1,5}, 7{1,7}, 7{3,7}, 7{4,7}, and
7{4,8} were moderately active against S. aureus (zone of growth
inhibition; range 20−22 mm) (Figure 3d). None of the syn-
thesized compounds were significantly active against B. cereus
(growth inhibition zones ≤ 20 mm) (Figure 3e).
60
15
25
35
45
55
60
60
60
60
a
Reactions were carried out with isatin (1.0 mmol) and 3-oxo-N-
phenylbutanamide (1.0 mmol) in solvent (5.0 mL) in the presence of
b
c
0.1 mL of additives. Isolated yields. Conventional method (oil bath)
d
was used. 0.02 mL of additive was used.
yield, respectively (entries 2−3). Reactions between isatin 5{1}
and N-(4-bromophenyl)-3-oxobutanamide 6{4}, N-(4-chloro-
phenyl)-3-oxobutanamide 6{5}, N-(4-fluorophenyl)-3-oxo-
butanamide 6{6}, N-(4-nitrophenyl)-3-oxobutanamide 6{7},
N-(4-acetylphenyl)-3-oxobutanamide 6{8}, or ethyl 4-(3-
oxobutanamido)benzoate 6{9} bearing an electron-withdraw-
ing group on the benzene ring afforded 7{1,4} - 7{1,9} in 48−75%
yield (entries 4−9). Furthermore, treatment of isatin 5{1} with
sterically hindered N-benzyl-3-oxobutanamide 6{10} or 3-oxo-
N,3-diphenylpropanamide 6{11} gave 7{1,10} and 7{1,11} in
68% and 63% yield, respectively (entries 6 and 7). Similarly,
treatment of 5-methylisatin 5{2} with β-ketoamides 6 produced
7{2,1}−7{2,5}, 7{2,10}, and 7{2,11} in 65−88% yield. With
other 5-bromoisatin 5{3}, 5-chloroisatin 5{4}, and 5,7-
dimethylisatin 5{5}, 7{3,1}−7{5,11} were also produced in
50−88% yield. Reactions of N-aryl-3-oxobutanamides, possess-
ing an electron-donating group on the N-phenyl ring afforded
products at better yields than their counterparts with an
electron-withdrawing group. Steric hindrance also had a great
effect and decreased yields. The structures of synthesized com-
pounds 7 were confirmed by 1H NMR, 13C NMR, HRMS, and
IR analysis.
The minimal inhibitory concentrations (MIC) of the most
active compounds 7{1,2}, 7{1,3}, 7{1,5}, 7{1,7}, 7{2,10},
7{3,5}, 7{3,6}, 7{3,7}, 7{4,3}, 7{4,6}, 7{4,7}, and 7{4,8}
were in accordance with the results obtained during the pre-
liminary screening (Table 4). According to their antibacterial
activities, we concluded that 8-bromo-2-(4-chlorophenyl)-4-methyl-
1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione [7{3,5}] was superior
(MIC: 0.5 μg/mL) to the other pyrrolo[3,4-c]quinoline-1,3-dione
C
dx.doi.org/10.1021/co500002s | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Table 2. Structure, Molecular Formula, cLogP, and Yield of Pyrrolo[3,4-c]quinoline-1,3-dione Derivatives 7
a
b
entry
compound
R1
R2
R3
Me
R4
molecular formula
cLogP
yield (%)
1
7{1,1}
7{1,2}
7{1,3}
7{1,4}
7{1,5}
7{1,6}
7{1,7}
7{1,8}
7{1,9}
7{1,10}
7{1,11}
7{2,1}
7{2,2}
7{2,3}
7{2,4}
7{2,5}
7{2,10}
7{2,11}
7{3,1}
7{3,2}
7{3,3}
7{3,4}
7{3,5}
7{3,6}
7{3,7}
7{3,8}
7{3,9}
7{3,10}
7{3,11}
7{4,1}
7{4,2}
7{4,3}
7{4,4}
7{4,5}
7{4,6}
7{4,7}
7{4,8}
7{4,9}
7{4,10}
7{4,11}
7{5,1}
7{5,2}
7{5,3}
7{5,4}
7{5,5}
7{5,10}
7{5,11}
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Phenyl
C18H12N2O2
3.18
3.67
3.15
4.16
4.01
3.44
3.36
2.97
4.03
4.06
4.78
3.67
4.17
3.65
4.66
4.51
4.56
5.27
4.07
4.56
4.04
5.05
4.90
4.33
4.25
3.85
4.91
4.95
5.66
3.91
4.41
3.89
4.90
4.75
4.18
4.10
3.70
4.76
4.80
5.51
4.17
4.67
4.15
5.15
5.00
5.06
5.77
90
86
85
72
71
74
48
62
75
68
63
88
86
84
65
66
65
66
86
82
87
75
72
78
52
63
76
66
65
86
84
86
76
70
77
50
61
74
68
65
85
80
88
73
72
72
68
2
H
Me
4-Me-phenyl
4-OMe-phenyl
4-Br-phenyl
4-Cl-phenyl
4-F-phenyl
4-NO2-phenyl
4-COMe-phenyl
4-COEt-phenyl
Benzyl
C19H14N2O2
3
H
Me
C19H14N2O3
4
H
Me
C18H11BrN2O2
C18H11CIN2O2
C18H11FN2O2
C18H11N3O4
5
H
Me
6
H
Me
7
H
Me
8
H
Me
C20H14N2O3
9
H
Me
C21H16N2O4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
H
Me
C19H14N2O2
H
Phenyl
Me
Phenyl
C23H14N2O2
Me
Me
Me
Me
Me
Me
Me
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Me
Me
Me
Me
Me
Me
Me
Phenyl
C19H14N2O2
Me
4-Me-phenyl
4-OMe-phenyl
4-Br-phenyl
4-Cl-phenyl
Benzyl
C20H16N2O2
Me
C20H16N2O3
Me
C19H13BrN2O2
C19H13ClN2O2
C20H16N2O2
Me
Me
Phenyl
Me
Phenyl
C24H16N2O2
Phenyl
C18H11BrN2O2
C19H13BrN2O2
C19H13BrN2O3
C18H10Br2N2O2
C18H10BrCIN2O2
C18H10BrFN2O2
C18H10BrN3O4
C20H13BrN2O3
C21H15BrN2O4
C19H13BrN2O2
C23H13BrN2O2
C18H11ClN2O2
C19H13ClN2O2
C19H13ClN2O3
C18H10BrClN2O2
C18H10Cl2N2O2
C18H10ClFN2O2
C18H10ClN3O4
C20H13ClN2O3
C21H15ClN2O4
C19H13ClN2O2
C23H13ClN2O2
C20H16N2O2
Me
4-Me-phenyl
4-OMe-phenyl
4-Br-phenyl
4-Cl-phenyl
4-F-phenyl
4-NO2-phenyl
4-COMe-phenyl
4-COOEt-phenyl
Benzyl
Me
Me
Me
Me
Me
Me
Me
Me
Phenyl
Me
Phenyl
Phenyl
Me
4-Me-phenyl
4-OMe-phenyl
4-Br-phenyl
4-Cl-phenyl
4-F-phenyl
4-NO2-phenyl
4-COMe-phenyl
4-COOEt-phenyl
Benzyl
Me
Me
Me
Me
Me
Me
Me
Me
Phenyl
Me
Phenyl
Phenyl
Me
4-Me-phenyl
4-OMe-phenyl
4-Br-phenyl
4-Cl-phenyl
Benzyl
C21H18N2O2
Me
C21H18N2O3
Me
C20H15BrN2O2
C20H15ClN2O2
C21H18N2O2
Me
Me
Me
Phenyl
Phenyl
C25H18N2O2
a
b
Estimated CLogP by ChemBioOffice 2010. Isolated yields.
derivatives and the standard (ampicillin; MIC: 1 μg/mL)
against P. aeruginosa. In addition, 8-chloro-4-methyl-2-(4-nitro-
phenyl)-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione [7{4,7}]
was greater (MIC = 1 μg/mL) than that of the other
compounds, and equivalent to standard ampicillin against E. coli.
Compound 7{4,7} was also superior (MIC: 0.5 μg/mL) to the
other pyrrolo[3,4-c]quinoline-1,3-dione derivatives and the stand-
ard (ampicillin; MIC = 1 μg/mL) against E. aerogenes. All of the
tested compounds were less active than standard ampicillin against
S. aureus and B. cereus (Figure 4).
D
dx.doi.org/10.1021/co500002s | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Figure 2. Recyclability of the two phase [Bmim]BF4/toluene catalyst system used for the synthesis of 7{1,1}.
SAR Studies. The observed antibacterial activities of the
synthesized compounds demonstrated the following structure−
activity relationships (Figure 5). Interestingly, the quinoline
moiety29 showed significant activity against both Gram-positive
and Gram-negative bacteria. Particularly, compound 7{3,5}
exhibited extraordinary antibacterial activity against P. aerugi-
nosa bacterial pathogens, and compound 7{4,7} exhibited
excellent antibacterial activity against E. coli and E. aerogenes
bacterial pathogens. (i) The compounds 7{4,7} bearing 4′-NO2
and 7{4,8} bearing 4′-COMe showed significant antibacterial
activity against E. coli, with the MIC 1 and 2 μg/mL respec-
tively, which were comparable and similar to the standard
ampicillin (MIC = 1 μg/mL). (ii) Compound 7{3,5} con-
taining 8-Br and 4′-Cl showed remarkable activity (MIC =
0.5 μg/mL) as compared with standard ampicillin (MIC =
1 μg/mL) against P. aeruginosa. (iii) The compound 7{4,7}
containing 8-Cl and 4′-NO2 also exhibited excellent activity
(MIC = 0.5 μg/mL) against E. aerogenes, as compared with the
other compounds and standard ampicillin (MIC = 1 μg/mL).
(iv) The 4′-NO2 substituted compound 7{3,7} and 4′-COMe
substituted compound 7{4,8} were screened against S. aureus,
and exhibited potent inhibitory activities (both MIC =
2 μg/mL) as compared with the other compounds, but lower
activity than the standard ampicillin (MIC = 0.5 μg/mL). (v)
All synthesized compounds were at best only weakly active
against B. cereus (growth inhibition zones ≤ 20 mm), whereas
the standard ampicillin produced a much larger growth
inhibition zone of 32 mm.
work offered some advantages over existing methods for the
preparation of pyrrolo[3,4-c]quinoline-1,3-dione, such as one-
pot, single step process that employed readily available starting
materials, shortened reaction time, improved yields, and
recyclability of the ionic liquids. Furthermore, various
modifications of a quinoline and N-aryl fragment on pyrrolo-
[3,4-c]quinoline-1,3-dione skeletons showed potent antibacte-
rial activities. The most active pyrrolo[3,4-c]quinoline-1,3-
diones with MIC values of 0.5 μg/mL featured halogen or NO2
groups, which markedly inhibited P. aeruginosa and E. aerogenes
strains, respectively. The results suggest that synthesized
pyrrolo[3,4-c]quinoline-1,3-diones can be widely used for
further design of new antibacterial agents as lead compounds.
Further biological evaluation such as mammalian cytotoxicities
and medicinal applications of the pyrrolo[3,4-c]quinoline-1,3-
dione derivatives are currently under investigation in our
laboratory.
EXPERIMENTAL PROCEDURES
■
General Experimental Details. Chemicals were purchased
from Sigma-Aldrich, Fluka, or Tokyo Chemical Industry (TCI),
and used without further purification. Solvents were dried and
distilled prior to be used. All experiments were conducted in a
nitrogen atmosphere. Merck precoated silica gel plate (Art.
5554) containing a fluorescent indicator was used for analytical
TLC, and flash column chromatography was performed using
1
silica gel 9385 (Merck). H NMR and 13C NMR spectra were
Importantly, the sterically hindered phenyl group at C-4
position was not preferred to antibacterial activity. It has been
shown that Cl, F, or NO2 functional groups at C-4′ position
increase efficacy. Particularly, the introduction of 4′-F and
4′-NO2 would significantly enhance the inhibitory activity
against S. auresus strain. The beneficial effects of halogens and
NO2 groups on antibacterial activities have been previously
reported.30 Furthermore, halogens (Br and Cl) at the C-8
position would slightly enhance the inhibitory activities. The
optimized combinations of C-4, C-8, and C-4′, such as 7{3,5},
7{3,6}, 7{4,6}, and 7{4,7}, would markedly increase the
inhibitory activities.
recorded on a Bruker ARX spectrometer (at 300 and 75 MHz,
respectively) in CDCl3. IR spectra were recorded on a Jasco
FTIR (Fourier transform infrared spectroscopy) 5300 spec-
trophotometer. High-resolution mass spectra (HRMS) were
recorded on a JEOL JMS-600 mass spectrometer at the Korean
Basic Science Institute.
General Procedure for the Synthesis of Pyrrolo[3,4-
c]quinoline-1,3-dione Derivatives 7. A mixture of isatins 5
(1.0 mmol) and β-ketoamides (1.0 mmol) in [Bmim]BF4/
toluene (0.1 mL/5.0 mL) in a vessel was loaded into a
microwave. The vessel was sealed and irradiated with stirring at
a ceiling temperature of 100 °C at 60 W for 40 min, and cooled
in an air stream. The reaction mixture was then washed with
diethyl ether (3 × 10 mL), and combined ether extracts were
concentrated in vacuo. The resulting product was directly
charged onto a silica gel column and eluted with a mixture of
hexane:AcOEt (7:1) to afford pure pyrrolo[3,4-c]quinoline-1,3-
diones.
CONCLUSION
■
A series of pyrrolo[3,4-c]quinoline-1,3-dione derivatives 7 were
synthesized by microwave-assisted cascade reaction between
isatins and β-ketoamides and screened for antibacterial activity
against Gram-positive and Gram-negative bacteria. The current
E
dx.doi.org/10.1021/co500002s | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Figure 3. Zones of inhibition against (a) E. coli, (b) P. aeruginosa, (c) E. aerogenes, (d) S. aureus, and (e) B. cereus.
Recycling of [Bmim]BF4. The reaction mixture was diluted
with water and extracted with ethyl acetate (2 × 10 mL), and
combined organic extracts were washed with water, dried over
anhydrous Na2SO4, and concentrated in vacuo. The resulting
reaction product was purified by column chromatography or by
recrystallization (from hot toluene), and the [Bmim]BF4 was
recovered by evaporating the aqueous layer in vacuo. The ionic
liquid thus obtained was further dried at 80 °C under reduced
pressure for use in subsequent runs.
Biology: In Vitro Antibacterial Activity. The synthesized
pyrrolo[3,4-c]quinoline-1,3-dione derivatives 7 were evaluated
for their in vitro antibacterial activities against E. coli (KCTC-
1924), P.aeruginosa (KCTC-2004), E.aerogenes (KCTC-2190),
B.cereus (KCTC-1012), and S. aureus (KCTC-1916) [all obtained
Figure 4. MIC values of selected compounds against E. coli,
P. aeruginosa, E. aerogenes, S. aureus, and B. cereus.
F
dx.doi.org/10.1021/co500002s | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Table 3. Antibacterial Activities of Compounds 7
Table 4. Minimal Inhibitory Concentrations (MIC, μg/mL)
of Selected Compounds
a
diameter of growth inhibition zone (mm)
a
minimal inhibitory concentration (MIC, μg/mL)
Gram-positive
bacteria
Gram-negative bacteria
Gram-positive
bacteria
Gram-negative bacteria
compound
E. coli P. aeruginosa E. aerogenes S. aureus B. cereus
compound
E. coli P. aeruginosa E. aerogenes S. aureus B. cereus
7{1,1}
7{1,2}
7{1,3}
7{1,4}
7{1,5}
7{1,6}
7{1,7}
7{1,8}
7{1,9}
7{1,10}
7{1,11}
7{2,1}
7{2,2}
7{2,3}
7{2,4}
7{2,5}
7{2,10}
7{2,11}
7{3,1}
7{3,2}
7{3,3}
7{3,4}
7{3,5}
7{3,6}
7{3,7}
7{3,8}
7{3,9}
7{3,10}
7{3,11}
7{4,1}
7{4,2}
7{4,3}
7{4,4}
7{4,5}
7{4,6}
7{4,7}
7{4,8}
7{4,9}
7{4,10}
7{4,11}
7{5,1}
7{5,2}
7{5,3}
7{5,4}
7{5,5}
7{5,10}
7{5,11}
ampicillin
DMSO
10
13
14
10
13
9
10
10
22
10
11
18
10
8
13
−
8
12
18
12
20
15
20
12
18
−
13
12
−
16
10
12
18
−
−
13
10
11
−
−
8
7{1,2}
7{1,3}
7{1,5}
7{1,7}
7{2,10}
7{3,5}
7{3,6}
7{3,7}
7{4,3}
7{4,6}
7{4,7}
7{4,8}
ampicillin
16
4
ND
4
ND
1
64
16
4
64
ND
ND
64
23
11
14
13
18
11
10
12
16
11
12
12
15
18
10
−
4
64
64
16
16
1
64
16
8
4
64
4
16
4
ND
ND
ND
32
8
0.5
−
−
−
−
10
8
64
64
64
64
1
64
32
4
1
32
2
10
8
32
64
1
12
10
11
13
15
15
10
13
12
12
15
12
13
16
10
10
8
16
64
4
ND
64
10
10
10
12
10
10
12
13
10
12
8
32
64
32
1
−
−
−
8
0.5
32
2
8
1
2
64
1
0.5
16
a
ND: Not determined.
12
10
10
−
8
−
−
11
12
13
12
19
16
15
15
8
17
11
15
13
15
23
18
10
10
12
10
15
18
15
13
13
20
22
10
−
15
10
−
11
13
10
12
10
35
−
12
10
8
8
28
10
15
10
13
10
11
10
10
20
8
-
14
−
−
12
10
11
−
8
Figure 5. Structure activity relationships of compounds 7.
10
11
10
12
12
13
12
16
9
and the diameters of bacteria inhibition zones were measured
and recorded.
16
−
Determination of Minimal Inhibitory Concentration (MIC).
Pyrrolo[3,4-c]quinoline-1,3(2H)-diones 7 and standard ampicillin
were dissolved in dimethyl sulfoxide (DMSO) at a concentration
of 64 μg/mL. A 2-fold dilution series was then prepared (64, 32, ...,
0.5 μg/mL). Microorganism suspensions at 106 CFU/mL (colony
forming unit/mL) were inoculated into corresponding wells.
Plates were incubated at 37 °C at 24 h. Minimum inhibitory
concentrations (MIC) were defined as the lowest drug
concentration at which there was no visible growth.
14
11
12
12
18
21
15
10
15
15
−
12
11
−
12
10
8
8
12
14
10
13
12
10
10
10
8
8
8
18
15
15
12
11
8
20
16
−
11
8
ASSOCIATED CONTENT
−
−
10
10
−
12
8
■
S
12
8
* Supporting Information
Experimental procedures, H NMR, 13C NMR, and HRMS
1
10
12
11
12
13
28
−
10
9
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
8
AUTHOR INFORMATION
Corresponding Author
*E-mail: yrlee@yu.ac.kr. Phone: +82-53-810-2529. Fax: +82-
53-810-4631.
10
18
−
■
18
32
−
a
The minus (−) represents inactive (growth inhibition zone <8 mm).
Funding
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2012R1A1A4A01009620).
from the Korean Collection for Type Cultures (KCTC)] by
agar-disc diffusion method.24 All compounds were tested at a
concentration of 100 μg/mL in DMSO. Samples were carefully
placed on agar culture plates that had previously been
inoculated with a microorganism. Ampicillin was used as the
standard. The plates were then incubated for 24 h at 37 °C,
Notes
The authors declare no competing financial interest.
G
dx.doi.org/10.1021/co500002s | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
molecular modeling and biological evaluation of 2-aminomethyl-5-
(quinolin-2-yl)-1,3,4-oxadiazole-2(3H)-thione quinolone derivatives as
novel anticancer agent. Eur. J. Med. Chem. 2013, 60, 23−28.
(7) Mahamoud, A.; Chevalier, J.; Davin-Regli, A.; Barbe, J.; Pages, J.-
M. Quinoline derivatives as promising inhibitors of antibiotic efflux
pump in multidrug resistant Enterobacter aerogenes isolates. Curr. Drug
Targets 2006, 7, 843−847.
(8) Muruganantham, N.; Sivakumar, R.; Anbalagan, N.; Gunasekaran,
V.; Leonard, J. T. Synthesis, anticonvulsant and antihypertensive
activities of 8-substituted quinoline derivatives. Biol. Pharm. Bull. 2004,
27, 1683−1687.
ABBREVIATIONS
■
PDGF-RTK, platelet derived growth factor receptor tyrosine
kinase; HIV, human immunodeficiency virus; HCV, hepatitis C
virus; GABA, γ-aminobutyric acid; DMF, N,N-dimethylform-
amide; KCTC, Korean Collection for Type Cultures; E. coli,
Escherichia coli; P. aeruginosa, Pseudomonas aeruginosa; E.
aerogenes, Enterobacter aerogenes; B. cereus, Bacillus cereus; S.
aureus, Staphylococcus aureus; CFU, colony forming unit;
[Bmim]BF4, 1-butyl-3-methylimidazolium tetrafluoroborate;
DMSO, dimethyl sulfoxide; MIC, minimal inhibitory concen-
trations; SAR, structure−activity relationship; FTIR, Fourier
transform infrared spectroscopy; HRMS, high-resolution mass
spectra; TLC, thin layer chromatography
(9) Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada, A. P.;
Zilberstein, A. A new series of PDGF receptor tyrosine kinase
inhibitors: 3-Substituted quinoline derivatives. J. Med. Chem. 1994, 37,
2129−2137.
(10) (a) Wilson, W. D.; Zhao, M.; Patterson, S. E.; Wydra, R. L.;
Janda, L.; Strekowski, L.; Schinazi, R. F. Design of RNA interactive
anti-HIV-1 agents: Unfused aromatic intercalators. Med. Chem. Res.
1992, 2, 102−110. (b) Strekowski, L.; Mokrosz, J. L.; Honkan, V. A.;
Czarny, A.; Cegla, M. T.; Wydra, R. L.; Patterson, S. E.; Schinazi, R. F.
Synthesis and quantitative structure−activity relationship analysis of 2-
(aryl or heteroaryl)quinolin-4-amines, A new class of anti-HIV-1
agents. J. Med. Chem. 1991, 34, 1739−1746.
REFERENCES
■
(1) (a) Russ, T. H.; Pramanik, A.; Khansari, M. E.; Wong, B. M.;
Hossain, M. A. A quinoline based bis-urea receptor for anions: A
selective receptor for hydrogen sulfate. Nat. Prod. Commun. 2012, 7,
301−304. (b) Cai, X.-H.; Li, Y.; Su, J.; Liu, Y.-P.; Li, X.-N.; Luo, X.-D.
Novel indole and quinoline alkaloids from Melodinus yunnanensis. Nat.
Prod. Bioprospect. 2011, 1, 25−28. (c) Isaac-Marquez, A. P.;
McChesney, J. D.; Nanayakara, N. P. D.; Satoskar, A. R.; Lezama-
Davila, C. M. Leishmanicidal activity of racemic 8-[(4-amino-1-
methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]-
quinoline. Nat. Prod. Commun. 2010, 5, 387−390. (d) Michael, J. P.
Quinoline, quinazoline, and acridone alkaloids. Nat. Prod. Rep. 2008,
25, 166−187. (e) Michael, J. P. Quinoline, quinazoline, and acridone
alkaloids. Nat. Prod. Rep. 2007, 24, 223−246. (f) Michael, J. P.
Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2005,
22, 627−646. (g) Michael, J. P. Quinoline, quinazoline and acridone
alkaloids. Nat. Prod. Rep. 2004, 21, 650−668. (h) Michael, J. P.
Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2003,
20, 476−493. (i) Michael, J. P. Quinoline, quinazoline and acridone
alkaloids. Nat. Prod. Rep. 2002, 19, 742−760. (j) Michael, J. P.
Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2001,
18, 543−559.
(2) (a) Gorka, A. P.; de Dios, A.; Roepe, P. D. Quinoline drug−heme
interactions and implications for antimalarial cytostatic versus cytocidal
activities. J. Med. Chem. 2013, 56, 5231−5246. (b) Michael, J. P.
Quinoline, quinazoline, and acridone alkaloids. Nat. Prod. Rep. 2008,
25, 166−187. (c) Michael, J. P. Quinoline, quinazoline, and acridone
alkaloids. Nat. Prod. Rep. 2007, 24, 223−246. (d) Padwa, A.; Brodney,
M. A.; Liu, B.; Satake, K.; Wu, T. A Cycloaddition Approach toward
the Synthesis of Substituted Indolines and Tetrahydroquinolines. J.
Org. Chem. 1999, 64, 3595−3607. (e) Atkins, R. J.; Breen, G. F.;
Crawford, L. P.; Grinter, T. J.; Harris, M. A.; Hayes, J. F.; Moores, C.
J.; Saunders, R. N.; Share, A. C.; Walsgrove, T. C.; Wicks, C. Synthetic
Routes to Quinoline Derivatives: Novel Syntheses of 3-Butyryl-8-
methoxy-4-[(2-methylphenyl)amino]quinoline and 3-Butyryl-8-(2-hy-
droxyethoxy)-4-[(2-methylphenyl)amino]quinoline. Org. Process Res.
Dev. 1997, 1, 185−197.
(11) Kunin, C. M.; Ellis, W. Y. Antimicrobial activities of mefloquine
and a series of related compounds. Antimicrob. Agents Chemother.
2000, 44, 848−852.
(12) (a) Jayaprakash, S.; Iso, Y.; Wan, B.; Franzblau, S. G.;
Kozikowski, A. P. Design, synthesis, and SAR studies of mefloquine-
based ligands as potential antituberculosis agents. ChemMedChem.
2006, 1, 593−597. (b) Mao, J.; Yuan, H.; Wang, Y.; Wan, B.; Pieroni,
M.; Huang, Q.; Van Breemen, R. B.; Kozikowski, A. P.; Franzblau, S.
G. From serendipity to rational antituberculosis drug discovery of
mefloquine-isoxazole carboxylic acid esters. J. Med. Chem. 2009, 52,
6966−6978. (c) Murai, Z.; Baran, B.; Tolna, J.; Szily, E.; Gazdag, G.
Neuropsychiatric symptoms caused by mefloquine (report of several
cases). Orv. Hetil. 2005, 146, 133−136. (d) Bermudez, L. E.;
Kolonoski, P.; Seitz, L. E.; Petrofsky, M.; Reynolds, R.; Wu, M.;
Young, L. S. SRI-286, A thiosemicarbazole, in combination with
mefloquine and moxifloxacin for treatment of murine Mycobacterium
avium complex disease. Antimicrob. Agents Chemother. 2004, 48, 3556−
3558.
(13) Thomas, K. D.; Adhikari, A. V.; Shetty, N. S. Design, synthesis
and antimicrobial activities of some new quinoline derivatives carrying
1,2,3-triazole moiety. Eur. J. Med. Chem. 2010, 45, 3803−3810.
(14) (a) Kato, Y.; Nagao, Y. Effect of polyvinylpyrrolidone on sperm
function and early embryonic development following intracytoplasmic
sperm injection in human assisted reproduction. Reprod. Med. Biol.
2012, 11, 165−176. (b) Jouyban, A.; Fakhree, M. A. A.; Shayanfar, A.
Review of pharmaceutical applications of N-methyl-2-pyrrolidone. J.
Pharm. Pharm. Sci. 2010, 13, 524−535. (c) Gibbison, R. Diverse
applications of N-alkyl pyrrolidones. Spec. Chem. Mag. 2002, 22, 15−
16. (d) Shorvon, S. Pyrrolidone derivatives. Lancet 2001, 358, 1885−
1892. (e) Decker, M.; Arneric, S. P. In Neuronal Nicotinic Receptors:
Pharmacology and Therapeutic Opportunities; Arneric, S. P., Brioni, J.
D., Eds.; Wiley-Liss: New York, 1999; pp 395−411. (f) Holladay, M.
W.; Dart, M. J.; Lynch, J. K. Neuronal nicotinic acetylcholine receptors
as targets for drug discovery. J. Med. Chem. 1997, 40, 4169−4194.
(15) (a) Dewick, P. M. Medicinal Natural Products: A Biosynthetic
Approach, 3rd ed.; John Wiley & Sons: Chichester, U.K., 2009;
Chapter 6 and references therein. (b) Daly, J. W.; Garraffo, H. M.;
Spande, T. F. In The Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Pergamon Press: Amsterdam, 1990; pp 1−161.
(c) Ikai, T.; Azam, A. K. M. F.; Kuzuba, M.; Kuwabara, T.; Maeda, K.;
Takahashi, K.; Kanoh, S. Synthesis of seleno[3,4-c]pyrrole-4,6-dione-
based polymers for polymer solar cells. Synth. Met. 2012, 162, 1707−
1712. (d) Wu, Z.-L.; Li, A.-Y.; Fan, B.-H.; Xue, F.; Adachi, C.; Ouyang,
J.-Y. Phenanthrene-functionalized 3,6-dithiophen-2-yl-2,5-
dihydropyrrolo[3,4-c]pyrrole-1,4-diones as donor molecules for
solution-processed organic photovoltaic cells. Sol. Energy Mater. Sol.
(3) Lilienkampf, A.; Mao, J.; Wan, B.; Wang, Y.; Franzblau, S. G.;
Kozikowski, A. P. Structure-Activity Relationships for a Series of
Quinoline-Based Compounds Active against Replicating and Non-
replicating Mycobacterium tuberculosis. J. Med. Chem. 2009, 52, 2109−
2118.
(4) Nasveld, P.; Kitchener, S. Treatment of Acute Vivax Malaria with
Tafenoquine. Trans. R. Soc. Trop. Med. Hyg. 2005, 99, 2−5.
(5) Leatham, P. A.; Bird, H. A.; Wright, V.; Seymour, D.; Gordon, A.
A double blind study of antrafenine, naproxen and placebo in
osteoarthrosis. Eur. J. Rheumatol. Inflamm. 1983, 6, 209−211.
(6) (a) Insuasty, B.; Montoya, A.; Becerra, D.; Quiroga, J.; Abonia,
́
R.; Robledo, S.; Velez, I. D.; Upegui, Y.; Nogueras, M.; Cobo, J.
Synthesis of novel analogs of 2-pyrazoline obtained from [(7-
chloroquinolin-4-yl)amino]chalcones and hydrazine as potential
antitumor and antimalarial agents. Eur. J. Med. Chem. 2013, 67,
252−262. (b) Sun, J.; Zhu, H.; Yang, Z.-M.; Zhu, H.-L. Synthesis,
H
dx.doi.org/10.1021/co500002s | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Cells 2011, 95, 2516−2523. (e) Zou, Y.; Najari, A.; Berrouard, P.;
Kobak, V. V.; Il’yin, A. P.; Trifilenkov, A. S.; Busel, A. A. New scaffolds
for combinatorial synthesis. II. 6-Sulfamoylquinolinecarboxylic acids. J.
Comb. Chem. 2003, 5, 645−652. (f) Li, J.; Su, S.; Huang, M.; Song, B.;
Li, C.; Jia, X. Unexpected isocyanide-based cascade cycloaddition
reaction with methyleneindolinone. Chem. Commun. 2013, 49, 10694−
10696.
́
Beaupre, S.; Aïch, B. R.; Tao, Y.; Leclerc, M. A thieno[3,4-c]pyrrole-
4,6-dione-based copolymer for efficient solar cells. J. Am. Chem. Soc.
2010, 132, 5330−5331. (f) Piliego, C.; Holcombe, T. W.; Douglas, J.
́
D.; Woo, C. H.; Beaujuge, P. M.; Frechet, J. M. J. Synthetic control of
structural order in N-alkylthieno[3,4-c]pyrrole-4,6-dione-based poly-
mers for efficient solar cells. J. Am. Chem. Soc. 2010, 132, 7595−7597.
(16) (a) Mahboobi, S.; Eichhorn, E.; Popp, A.; Sellmer, A.; Elz, S.;
(25) Xia, L.; Lee, Y. R. Efficient one-step synthesis of pyrrolo[3,4-
c]quinoline-1,3-dione derivatives by organocatalytic cascade reactions
of isatins and β-ketoamides. Org. Biomol. Chem. 2013, 11, 5254−5263.
(26) For reviews of microwave applications in organic chemistry, see:
(a) Irfan, M.; Glasnov, T. N.; Kappe, C. O. Heterogeneous catalytic
hydrogenation reactions in continuous-flow reactors. ChemSusChem
2011, 4, 300−316. (b) Kappe, C. O.; Van der Eycken, E. Click
chemistry under non-classical reaction conditions. Chem. Soc. Rev.
2010, 39, 1280−1290. (c) Kappe, C. O. Microwave dielectric heating
in synthetic organic chemistry. Chem. Soc. Rev. 2008, 37, 1127−1139.
(d) Wathey, B.; Tierney, J.; Lidstrom, P.; Westman, J. The impact of
microwave-assisted organic chemistry on drug discovery. Drug
Discovery Today 2002, 7, 373−380. (e) Lew, A.; Krutzik, P. O.;
Hart, M. E.; Chamberlin, A. R. Increasing rates of reaction: microwave-
assisted organic synthesis for combinatorial chemistry. J. Comb. Chem.
2002, 4, 95−105. (f) Larhed, M.; Moberg, C.; Hallberg, A. Microwave-
accelerated homogeneous catalysis in organic chemistry. Acc. Chem.
Res. 2002, 35, 717−727. (g) Lidstrom, P.; Tierney, J.; Wathey, B.;
Westman, J. Microwave assisted organic synthesis: A review.
Tetrahedron 2001, 57, 9225−9283.
(27) (a) Wasserscheid, P.; Welton, T.; Eds. Ionic Liquids in Synthesis,
2nd ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
Germany, 2008. (b) Kappe, C. O., Stadler, A., Eds. Microwaves in
Organic and Medicinal Chemistry; Wiley-VCH: Weinheim, Germany,
2005. (c) Olofsson, K.; Hallberg, A.; Larhed, M. Microwaves in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, Germany, 2002.
(d) Xia, L.; Lee, Y. R. Efficient one-pot synthesis of multi-substituted
dihydrofurans by ruthenium(II)-catalyzed [3 + 2] cycloaddition of
cyclic or acyclic diazodicarbonyl compounds with olefins. Adv. Synth.
Catal. 2013, 355, 2361−2374.
(28) (a) Bauer, A. W.; Kirby, W. M.; Sherris, J. C.; Turck, M.
Antibiotic susceptibility testing by a standardized single disk method.
Am. J. Clin. Pathol. 1966, 45, 493−496. (b) Idhayadhulla, A.; Xia, L.;
Lee, Y. R.; Kim, S. H.; Wee, Y.-J.; Lee, C.-S. Synthesis of novel and
diverse mollugin analogues and their antibacterial and antioxidant
activities. Bioorg. Chem. 2013, 52, 77−82.
(29) Kidwai, M.; Bhushan, K. R.; Sapra, P.; Saxena, R. K.; Gupta, R.
Alumina-supported synthesis of antibacterial quinolines using micro-
waves. Bioorg. Med. Chem. 2000, 8, 69−72.
(30) Sharma, P.; Rane, N.; Gurram, V. K. Synthesis and QSAR
studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential
antimicrobial agents. Bioorg. Med. Chem. Lett. 2004, 14, 4185−4190.
Mollmann, U. 3-Bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrrole-
̈
dione derivatives as new lead compounds for antibacterially active
substances. Eur. J. Med. Chem. 2006, 41, 176−191. (b) Sancelme, M.;
Fabre, S.; Prudhomme, M. Antimicrobial activities of indolocarbazole
and bis-indole protein kinase C inhibitors. J. Antibiot. 1994, 47, 792−
798.
(17) (a) Slater, M. J.; Cockerill, G. S.; Robinson, J. E. Preparation of
antiviral heterocyclylindole derivatives. Int. Patent WO9507910A1,
1995. (b) Kim, Y.-S.; Sagara, J.; Kawai, A. Studies on the antiviral
activity of protein kinase inhibitors against the replication of vesicular
stomatitis virus. Biol. Pharm. Bull. 1995, 18, 895−899. (c) Slater, M. J.;
Cockerill, G. S.; Littler, E.; Yeates, C. L. Indole derivatives with
antiviral activity. Int. Patent WO9318766A1, 1993. (d) Slater, M. J.;
Cockerill, G. S.; Littler, E. Antiviral bis(indolyl)pyrrolidones. Int.
Patent WO9318765A1, 1993.
(18) Davis, P. D.; Hill, C. H.; Lawton, G.; Nixon, J. S.; Wilkinson, S.
E.; Hurst, S. A.; Keech, E.; Turner, S. E. Inhibitors of protein kinase C.
1. 2,3-Bisarylmaleimides. J. Med. Chem. 1992, 35, 177−184.
(19) Mahboobi, S.; Eichhorn, E.; Winkler, M.; Sellmer, A.;
Mollmann, U. Antibacterial activity of a novel series of 3-bromo-4-
̈
(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrroledione derivatives: An ex-
tended structure-activity relationship study. Eur. J. Med. Chem. 2008,
43, 633−656.
(20) (a) Sharma, S.; Ravichandran, V.; Jain, P. K.; Mourya, V. K.;
Agrawal, R. K. Prediction of caspase-3 inhibitory activity of 1,3-dioxo-
4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c] quinolines: QSAR study. J.
Enzyme Inhib. Med. Chem. 2008, 23, 424−431. (b) Okun, I.;
Malarchuk, S.; Dubrovskaya, E.; Khvat, A.; Tkachenko, S.; Kysil, V.;
Kravchenko, D.; Ivachtchenko, A. Screening for caspase-3 inhibitors:
Effect of a reducing agent on identified hit chemotypes. J. Biomol.
Screening 2006, 11, 694−703. (c) Kravchenko, D. V.; Kysil, V. M.;
Tkachenko, S. E.; Maliarchouk, S.; Okun, I. M.; Ivachtchenko, A. V.
Pyrrolo[3,4-c]quinoline-1,3-diones as potent caspase-3 inhibitors.
Synthesis and SAR of 2-substituted 4-methyl-8-(morpholine-4-
sulfonyl)-pyrrolo[3,4-c]quinoline-1,3-diones. Eur. J. Med. Chem.
2005, 40, 1377−1383.
(21) Summa, V.; Pace, P.; Di, F. M. E.; Martin, H. J. I.; Nizi, E.
Preparation of imidazole derivatives as inhibitors of hepatitis C virus
polymerases. U.K. Patent GB2450771A, 2009.
(22) Thomas, J. W.; Tallman, J. F. Characterization of photoaffinity
labeling of benzodiazepine binding sites. J. Biol. Chem. 1981, 256,
9838−9842.
(23) Thale, Z.; Johnson, T.; Tenney, K.; Wenzel, P. J.; Lobkovsky, E.;
Clardy, J.; Media, J.; Pietraszkiewicz, H.; Valeriote, F. A.; Crews, P.
Structures and cytotoxic properties of sponge-derived bisannulated
acridines. J. Org. Chem. 2002, 67, 9384−9391.
(24) (a) Makki, M. S. T.; Bakhotmah, D. A.; Abdel-Rahman, R. M.
Highly efficient synthesis of novel fluorine bearing quinoline-4-
carboxylic acid and the related compounds as amylolytic agents. Int. J.
Org. Chem. 2012, 2, 49−55. (b) Kravchenko, D. V.; Kysil, V. M.;
Tkachenko, S. E.; Maliarchouk, S.; Okun, I. M.; Ivachtchenko, A. V.
New variant of the Pfitzinger reaction. Synthesis and chemical
transformations of substituted 2-aminomethyl-quinoline-3,4-dicarbox-
ylic acids. Heterocycl. Commun. 2006, 12, 15−18. (c) Kravchenko, D.
V.; Kysil, V. M.; Tkachenko, S. E.; Maliarchouk, S.; Okun, I. M.;
Ivachtchenko, A. V. Synthesis and caspase-3 inhibitory activity of 8-
sulfonyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines. Farmaco
2005, 60, 804−809. (d) Mortoni, A.; Martinelli, M.; Piarulli, U.;
Regalia, N.; Gagliardi, S. Microwave-assisted solvent-free synthesis of a
quinoline-3,4-dicarboximide library on inorganic solid supports.
Tetrahedron Lett. 2004, 45, 6623−6627. (e) Ivachtchenko, A. V.;
I
dx.doi.org/10.1021/co500002s | ACS Comb. Sci. XXXX, XXX, XXX−XXX