Substituted indoloquinolines as new antifungal agents.

Article abstract of DOI:10.1016/S0968-0896(01)00401-1

Cryptolepine (2) possesses desirable properties to serve as a lead in developing new antifungal agents. Using SAR techniques, several analogues of cryptolepine were designed to increase potency and to broaden the antifungal spectrum over several opportuni

Full text of DOI:10.1016/S0968-0896(01)00401-1

Bioorganic & Medicinal Chemistry 10 (2002) 1337–1346
Substituted Indoloquinolines as New Antifungal Agents
Seth Y. Ablordeppey,a,* Pingchen Fan,a Shouming Li,a Alice M. Clarkb
and Charles D. Huffordb
aFlorida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA
bThe National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences,
and Department of Pharmacognosy, The School of Pharmacy, University of Mississippi, University, MS 38677, USA
Received 20 September 2001; accepted 8 November 2001
Abstract—Cryptolepine (2) possesses desirable properties to serve as a lead in developing new antifungal agents. Using SAR tech-
niques, several analogues of cryptolepine were designed to increase potency and to broaden the antifungal spectrum over several
opportunistic microorganisms. A number of 2-substituted indoloquinolines have been synthesized and evaluated in antifungal
screens and several have been shown to increase potency and expand the antifungal spectrum of cryptolepine. Comparison of MICs
of a number of these analogues with standard antifungal agents, shows them to be comparable to Amphotericin B and Ketocona-
zole. # 2002 Elsevier Science Ltd. All rights reserved.
Although the AIDS epidemic appears to have stabilized
in the developed countries, there is continuing interest in
new antifungal agents partially because of the chronic
nature of the disease and the continuing dramatic rise in
AIDS cases in the developing countries.1 In sub-
Saharan Africa, for example, it is estimated that 25.3
million people were living with AIDS by the close of last
year. There are several additional reasons,2 such as,
toxicity and the emergence of fungi resistant to currently
available antifungal agents that has kept the need to
develop new agents at the forefront of current research.
ently, the tetracyclic structure of cryptolepine is not
necessary for its antifungal activity and this has led us to
propose the d-carboline moiety as a pharmacophore for
antifungal activity.14 Cryptolepine has interesting prop-
erties to serve as a lead compound in antifungal drug
development. For example, its zone of inhibition against
Candida albicans, Cryptococcus neoformans Aspergillus
niger are wider than those of Amphotericin B in agar
well assays, it is fairly water soluble (ꢀ1.2 mg/mL), it
has relatively low toxicity15 and a broad spectrum of
activity against opportunistic fungal and bacterial
infections associated with AIDS.16 The purpose of this
study was to investigate the ability of substituents on
the tetracyclic moiety to extend the antifungal spectrum
and increase potency.
The indoloquinoline alkaloid, Cryptolepine (2) and its
analogues have been the subject of several recent pub-
lications.3À6 Although Cryptolepine (isolated from
Cryptolepis sanguinolenta)7 has been shown to have
antibacterial,8 antihypertensive,9 anti-aggregatory,10
anticancer,4,11 and other properties, it was only more
recently that we have documented its antifungal activ-
ity.12 As part of a SAR study, we have shown that, N-5
alkylation of the tetracyclic structure, quindoline, 1, is
essential for antifungal activity13 and o-cycloalkylpentyl
substituents on the N-5 atom has a broad-spectrum
inhibition of several opportunistic infections.14 Appar-
*Corresponding author. Tel.: +1-850-599-3834; fax: +1-850-599-
3934; e-mail: seth.ablordeppey@famu.edu
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00401-1

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S. Y. Ablordeppey et al. / Bioorg. Med. Chem. 10 (2002) 1337–1346
Scheme 1. Holt method of the synthesis of quindolines.
Scheme 2. Nucleophilic substitution of 2-iodoquinoline to other designed analogues.
Chemistry
acids were required and were available from commercial
sources. Thus, 5-substituted anthranilic acid was acyl-
ated with 2-chloroacetyl chloride and utilized in alkyl-
ating aniline to yield the desired intermediate (Scheme
3). In a double intramolecular cyclization reaction with
polyphosphoric acid (PPA), the alkylated intermediate
was converted to 2-substituted-11-indoloquinolone,
which was subsequently converted to 2-substituted
quindoline by chlorination with phosphorous oxychlor-
ide (POCl3) and hydrogenation on Pd/C to remove the
chlorine. The desired product (14) was then obtained by
alkylation in the usual way. Compound 15, was
obtained from 14 by O-demethylation using pyridine
hydrochloride.22
Several synthetic methods leading to the construction of
the tetracyclic indoloquinoline structure, have been
described recently.3,5,17À19 Because the 2-position of
quindoline is para to the N-5 atom and because substitu-
tion on N-5 modulates antifungal potency, we selected the
2-position for exploration. Thus, in this study, methods
were chosen that would enable the introduction of sub-
stituents at the 2-position of the quindoline nucleus.
Although it has a 10-day waiting period to complete,
the Holt method20 provided a first entry into the 2-sub-
stituted compounds (Scheme 1). Thus, stirring a sol-
ution of 5-substituted-isatin and 3-acetylindoxyl, under
basic conditions, 11-carboxy-2-substituted quindoline
was obtained in excellent yields. Decarboxylation in
mineral oil and subsequent N-5 alkylation were
achieved as previously reported. Compounds 3–6 and
13 were synthesized by this method. This approach was,
however, limited by the availability of starting materials
and the failure of isatins with strongly electron-with-
drawing groups to undergo the condensation reaction
under the stated conditions.
A fourth method was previously reported23 and is
shown in Scheme 4. In this method, 3-bromo-6-nitro-
quinoline is aminated, then phenylated using triphe-
nylbismuth diacetate in the presence of metallic copper
to afford 3-anilino-6-nitroquinoline. Subsequent cycli-
zation was effected by palladium(II) acetate in refluxing
trifluoroacetic acid to afford 2-nitroquindoline.
Most of the compounds reported herein were, however,
obtained from 2-iodoquindoline by nucleophilic sub-
stitution with the appropriate substituents. The sulf-
oxides (7 and 9) were obtained from the corresponding
sulfides by oxidation with one equivalent of mCPBA
and the sulfones (8 and 10) by using two equivalents of
mCPBA.
An alternative pathway to the 2-substituted quindolines
involves obtaining 2-iodoquindoline by the Holt
method and converting to the desired target compound
by nucleophilic substitution (Scheme 2). Compounds
11, 16, and 17 and intermediates leading to 7–10 utilized
this approach.
A third pathway to 2-substituted quindolines was much
broader in scope and amenable to other substitutions
and was therefore preferred.21 To obtain 2-substituted
quindolines by this method, 5-substituted anthranilic
Results and Discussion
We have previously shown that alkylation of the tetra-
cyclic 10H-indolo[3.2-b]quinolines confers antifungal

S. Y. Ablordeppey et al. / Bioorg. Med. Chem. 10 (2002) 1337–1346
1339
Scheme 3. Alternative synthesis of 2-substituted quindolines.
Scheme 4. Synthesis of 2-nitroquindoline.
properties to the structure.13,14 In addition, o-cyclo-
hexylpentyl and o-phenylpentyl moieties were identified
as optimal N-5 substituents. Although antifungal activ-
ity increased substantially, it was hypothesized that
higher activities might result from modifying the elec-
tron density around the N-5 atom through substitution
on the quindoline moiety. Position 2 was selected for
exploration because it was directly para to the N-5 atom
whose substitution led to increase in anticryptococcal
activity.13 In addition, position 2 was easily accessible
synthetically and substituents at this position can influ-
ence the electron density around the N-5 atom through
resonance effect.
To test this hypothesis, we investigated the effect of elec-
tron withdrawing groups at position 2 and the results are
reported in Table 1. While the previously reported N-5
alkylated compounds13,14 showed activity primarily
against C. neoformans, the 2-substituted electron-with-
drawing analogues of cryptolepine showed activity
against both C. neoformans and C. albicans, two impor-
tant opportunistic fungi associated with AIDS. In parti-
cular, all the 2-halogenated analogues (3–6) showed
higher potencies than Cryptolepine. In addition, 2-
chlorocryptolepine (4) was even more potent against
Aspergillus flavus (MIC=0.2 mg/mL). Interestingly, while
the two analogues, 2-cyano (11) and 2-nitro (12), with
Table 1. The effect of electron withdrawing substituents on antifungal activity
Compd
Structure
R
Minimum inhibition concentration (MIC, mg/mL)
C. neoformans
C. albicans
A. flavus
2
3
4
5b
6
H12.5–15.6
F
Cl
Br
250
7.8
2.0
15.6
5.5
3.9
3.9
50
35a
40a
35a
0.2a
20
0.2
ꢁ1.9
I
7.8
7
8
9
10
11
12
CH3SO
CH3SO2
PhSO
PhSO2
CN
NO2
50
>50
>50
>50
20a
0.3
0.39
Amphotericin B
0.39
aIC50 values.
bWhile this manuscript was in review, we became aware of the article by Wright et al.24 on the antisplasmodial action of 2-bromocryptolepine.

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S. Y. Ablordeppey et al. / Bioorg. Med. Chem. 10 (2002) 1337–1346
strong resonance electron withdrawing capacity were
quite active, the sulfoxides (7 and 9) and sulfones (8 and
10) possessing equally strong resonance electron with-
drawing capacity, were much less active against both
fungi. These observations do not appear to support the
notion that there exists a correlation between electron-
withdrawing effect (at position 2) and antifungal potency.
broadens the antifungal spectrum of cryptolepine. With
this limited data, it is tempting to suggest that the
increased potency of the compounds are due to steric
factors at the 2-position, since electron-withdrawing and
electron-donating as well as substituents with hydro-
phobic and hydrophilic properties appear to increase
potency. However, the fact that compounds 7–10 (sulf-
oxide and sulfone analogues) have reduced activity
makes the steric hypothesis less tenable.
In Table 2, we report the effect of electron donating
groups on antifungal activity. In general, the analogues
with electron-donating groups are more active than
cryptolepine and are potent against both C. neoformans
and C. albicans. Based on a comparison of compounds
13, 16, and 17 (with hydrophobic substituents), with
analogues, 12 and 15 (possessing hydrophilic sub-
stituents) it is suggested that hydrophobicity per se does
not appear to play a major role in the increase in anti-
fungal activity. The thiomethoxy analogue, 16, was fur-
ther tested against A. flavus and was found to be active
(MIC=7.8 mg/mL). Clearly, substitution at the 2-pos-
ition not only increases potency, but also extends or
In Table 3, an attempt is made to combine 2-substitu-
tion with N-5 alkylation in order to optimize potency.
Compound 19 is the o-cyclohexylpentyl analogue of
1813 and shows increased potency against C. albicans. It
was also of interest to incorporate our finding that N-10
alkylation, which introduces a permanent quaternary
pyridinium nitrogen at N-5, retains or improves
potency. Thus, compound 20, an N-10 methylated ana-
logue of 18, has an extended antifungal spectrum to
include both C. neoformans and C. albicans. However,
N-10 methylation of 2-bromocryptolepine (5) to obtain
Table 2. The effect of electron donating substituents on antifungal activity
Compd
Structure
R2
Minimum inhibition concentration (MIC, mg/mL)
C. neoformans
C. albicans
A. flavus
2
H12.5–15.6
CH3
OCH3
OH15.6
CH3S
PhS
250
31.2
13
14
15
16
17
15.6
ꢁ1.9
ꢁ1.9
3.9
3.12
6.25
0.39
1.56
50
0.39
7.8
Amphotericin B
Table 3. Effect of multi-substitution on antifungal activity
Compd
Structurex
R5
Minimum inhibition concentration (MIC, mg/mL)
R2
R10
C. neoformans
C. albicans
A. flavus
2
HCH
HPh(CH
H
HPh(CH
Br
Br
Br
Br
OCH3
H12.5–15.6
H
H
CH3
CH3
H62.5
CH3
H
250
125
3
18a
19
20
21
22
23
24
25
26
27
28
2)5—
ꢁ1.9
ꢁ1.9
125
C6H11(CH2)5
2)5—
CH3—
Ph(CH2)5—
Ph(CH2)5—
C6H11(CH2)5
Ph(CH2)5—
CH3
ꢁ1.9
6.25
3.12
6.25
3.12
ꢁ1.9
62.5
ꢁ1.9
125
3.12
3.12
ꢁ1.9
ꢁ1.9
H
CH3
CH3
CH3O
CH3O
CN
6.25
Ph(CH2)5—
C6H11(CH2)5
Amphotericin B
12.5
H12.5
12.5
0.39
0.39
aPreviously reported in ref 13.

S. Y. Ablordeppey et al. / Bioorg. Med. Chem. 10 (2002) 1337–1346
1341
21 did not result in further increase in potency and
replacing the N-5 methyl group with the optimum sub-
stituents (22 and 23) has a mixed effect. The brominated
analogue of 19, that is, 24 retained activity (MIC=1.9 mg/
mL for both Cn and Ca). Similar effects were obtained on
the 2-methoxy analogues (25–27). Replacing N-5 methyl
group on 11 with the optimum o-cyclohexylpentyl
group to form 28 also resulted in mixed effect, as there is
an increase in C. neoformans potency but a decrease in
C. albicans activity.
at the types of substituents at the 2-position reveals that
the effect of electron-donating and-withdrawing groups
at the 2-position appears to be complex, as both types of
substituents enhance activity. In addition, hydro-
phobicity does not appear to have any obvious effect on
the SAR of these compounds. Further investigation of
the SAR is warranted and is currently underway in our
laboratories.
Experimental
Finally, because 2-nitrocryptolepine (12) has a high
potency against C. neoformans, we investigated the effect
of placing the nitro group at other synthetically feasible
positions on the quindoline nucleus. Thus, the 7- and 11-
nitro analogues (29 and 30) were synthesized and subse-
quently evaluated against C. neoformans and A. flavus.
Both compounds showed similar high potency (MIC for
Cn=0.25 and for Af=0.39 mg/mL) but were not available
in sufficient quantities for a full spectrum evaluation.
Melting points were determined on a Gallenkamp (UK)
apparatus and are uncorrected. NMR spectra were
obtained on a Bruker 270 MHz NMR Spectrometer at
Florida State University. Elemental analyses were car-
ried out by Atlantic Microlab, Inc., Norcross, GA, USA
and are within 0.4% of theory unless otherwise noted.
Flash chromatography was performed with Davisil
grade 634 silica gel.
N,N-Dimethylformamide was distilled from CaSO4 and
stored over 4 A molecular sieves. Sulpholane was dried
over 4 A molecular sieves. 5-Cyclohexylpentyl bromide
and 5-phenylpentyl bromide were prepared by treat-
ment of the corresponding alcohols with PBr3.13,14 The
remaining alkyl halides were obtained from either
Sigma-Aldrich Chemicals or Fisher Scientific and were
used without further purification.
General procedure for synthesizing 2-substituted
quindolines: method A
2-Fluoro-10H-indolo[3,2-b]quinoline (2-fluoroquindoline).
A mixture of 3-indolyl acetate (3.504 g, 20 mmol), 5-
fluoroisatin (3.305 g, 20 mmol) and KOH(9.60 g) in 130
mL of water was stirred for 10 days under N2 and at
room temperature. The mixture was then diluted with
water. To this mixture was added concd HCl until a
permanent faint yellow precipitate was observed. It was
then filtered and washed with water. The filtrate was
collected, an equal volume of EtOHwas added and the
resulting solution was acidified with concd HCl until a
lot of yellow precipitate was formed (pH3–4). It was
then filtered, washed with water and EtOH, and dried at
120 ꢂC to afford 2-fluoro-10H-indolo[3,2-b]quindoline-
11-carboxylic acid as a yellow solid (3.70 g). A mixture
of 2-fluoro-11-carboxylquindoline (3.0 g) in 100 mL of
mineral oil was stirred at 300 ꢂC. After 30 min, the
mixture was cooled to room temperature, petroleum
ether (100 mL) was added, the mixture was filtered and
the solid was washed with petroleum ether. The result-
ing solid was chromatographed to give the de-
carboxylated compound, which was recrystallized from
benzene to give 2.13 g of crystals: mp 254–256 ꢂC.
Clearly, the SAR of these substituents appears to be
complex at best and we speculate that multiple
mechanisms of fungal inhibition may be involved. This
speculation is supported by the report11 that cryptole-
pine interferes with topoisomerase II and intercalates
with DNA. Whether these events occur in these oppor-
tunistic fungi evaluated in this study is unknown at this
time. Toxicity studies along with the identification of
the mechanism of action of this group of compounds
should follow shortly.
Conclusion
This study confirms our previous report that N-5 alky-
lation with an appropriate group is a requirement for
antifungal activity and o-cycloalkylpentyl substitution
at the 5-position enhances potency and appears to con-
fer an optimum activity.13,14 Substitution at the 2-posi-
tion of the quindoline ring increases potency and
broadens the antifungal spectrum of this group of com-
pounds. However, combining an optimum substituent
at the 5-position with 2-substituents did not result in
further increases in potency. Similarly, N-10 alkylation
of 2-substituted compounds resulted in minimum chan-
ges in the activity of these compounds. A cursory look
General procedure for synthesizing 2-substituted
quindolines: method B
2-Methoxy-10H-indolo[3,2-b]quinoline (2-methoxyquin-
doline). A mixture of 5-methoxy-anthranilic acid (10.0
g, 60 mmol), and chloroacetyl chloride (4.8.0 mL, 60
mmol) in benzene (150 mL) was heated at 100 ꢂC for 5 h

1342
S. Y. Ablordeppey et al. / Bioorg. Med. Chem. 10 (2002) 1337–1346
and then allowed to cool to room temperature. The
solvent was evaporated and the crude residue was taken
up in DMF (30 mL). Aniline (20 mL, 219 mmol) was
added to the residue and then heated at 90 ꢂC for 5 h.
The mixture was allowed to cool to room temperature,
H2O (50 mL) was added and the resulting mixture was
extracted exhaustively with CHCl3. The pooled CHCl3
extracts were washed with H2O (50 mL), dried
(Na2SO4) and the solvent was evaporated to give a
residue, which was recrystallized from EtOAc to give a
solid (7.8 g).
organic layer was washed with brine, dried over Na2SO4
and concentrated by rotary evaporation, to yield a resi-
due. The residue was chromatographed on silica gel,
with EtOAc/hexanes (30–60%), to obtain a yellow solid
(24 mg): mp 344–346 ꢂC. HNMR (DMSO- d6) d 11.73
1
(1H, s), 9.21 (1H, s), 8.63 (1H, s), 8.38 (1H, d, J=8.1
Hz), 8.32 (1H, d, J=1.2 Hz), 8.31 (1H, d, J=1.2 Hz),
7.69 (1H, dt, J=8.1, 1.2 Hz), 7.61 (1H, d, J=8.1 Hz),
7.33 (1H, dt, J=8.1, 1.2 Hz).
General procedure for quindoline alkylation: method D
A mixture of the above product (7.8 g) and polyphos-
phoric acid (PPA, 100g) was heated at 130 ꢂC for 3 h.
After cooling, the mixture was poured onto ice and
neutralized with a saturated solution of NaHCO3 before
filtration of the solid. The solid was washed several
times with H2O and oven-dried at 115 ꢂC for 1 h. A
solution of the crude 2-methoxy-11-quindolone in
POCl3 (150 g) was heated at 125 ꢂC for 2 h, at which
point POCl3 was evaporated and a saturated solution of
NaHCO3 was added. The solution was extracted with
EtOAc (3Â100 mL), dried (Na2SO4) and solvent was
evaporated to yield crude 2-methoxy-11-chloroquindo-
line, (1.4 g). A portion of this material (1.1 g), NaOAc
(4.5 g) and 10% Pd/C (0.5 g) in AcOH(100 mL) was
hydrogenated at 60 psi for 2 h. The solution was filtered
to remove Pd/C, solvent evaporated to a small volume,
basified with ice-cold saturated solution of NaHCO3
and extracted with EtOAc (3Â100 mL). The pooled
solution was washed with H2O (50 mL), dried (Na2SO4)
and solvent was removed under reduced pressure to
yield 2-methoxyquindoline (1g). 1HNMR (CDCl 3) d
8.43 (1H, d, J=8.1Hz), 8.15 (1H, d, J=10.5Hz), 7.90
(1H, s, br), 7.83 (1H, s), 7.50 (1H, dd, J=8.1, 2.5Hz),
7.35 (1H, d, J=10.5Hz), 7.25 (2H, m), 7.10 (1H, d,
J=3.5Hz), 3.90 (3H, s).
A mixture of alkyl halide (0.8 mL), 2-substituted quin-
doline (0.100 g) and sulpholane (2.0 mL) was heated in
a sealed 10 mL round-bottomed flask overnight. After
cooling to room temperature, the mixture was directly
chromatographed on silica gel with 5–20% MeOH/
CH2Cl2 (gradient elution) to give a yellow solid which
was usually recrystallized from an appropriate solvent.
General procedure for quindoline alkylation: method E
A mixture of quindoline or 2-substituted quindoline
(0.100 g), alkyl halide (2.0 mL) and a few drops of DMF
was refluxed in a sealed 10 mL round-bottomed flask
overnight. The mixture was allowed to cool to room
temperature and then precipitated with Et2O–MeOH.
Flash chromatography with 5–20% MeOH/CH2Cl2
(gradient elution) yielded a yellow solid, which was
recrystallized from an appropriate solvent.
2-Fluoro-5-methylquindolinium iodide (3). Method D
was applied to 2-fluoroquindoline, obtained above, to
produce the desired product, 3 which was recrystallized
from MeOHto yield yellow crystals (0.16 g): mp 251–
ꢂ
1
253 C. HNMR (DMSO- d6) d 12.85 (1H, s, br), 9.21
(1H, s), 8.87 (1H, dd, J=8.1, 3.2 Hz), 8.82 (1H, d,
J=8.1 Hz), 8.43 (1H, dd, J=5.4, 2.7 Hz), 8.11 (1H, dt,
J=5.4, 2.7 Hz), 7.95 (1H, t, J=5.4 Hz), 7.87 (1H, d,
J=5.4 Hz), 7.53 (1H, d, J=5.4 Hz), 5.06 (3H, s). Anal.
calcd for C16H12FIN2: C, 50.82; H, 3.20; N, 7.41; found:
C, 50.74; H, 3.19; N, 7.35.
General procedure for synthesizing 2-substituted
quindolines: method C
2-Nitro-10H-indolo[3,2-b]quinoline (2-nitroquindoline). A
mixture of 3-bromo-6-nitroquinoline (2.5 g), concd NH3
(14 mL) and CuSO4 (0.3 g) was heated in a sealed tube
at 145–150 ꢂC for 17 h and allowed to cool to room
temperature. Water (200 mL) was added and resulting
mixture was extracted exhaustively with EtOAc. Solvent
was removed under reduced pressure and the residue
chromatographed over silica gel to yield a yellow solid
(0.6 g): mp 255–257 ꢂC. A mixture of the solid (0.5 g, 2.6
mmol), Ph3Bi(OAc)2 (2.3 g, 3.1 mmol) and Cu (0.3 g) in
CH2Cl2 (14 mL) was stirred under N2 at room tem-
perature for 48 h. The mixture was then quenched with
H2O, basified with NH4OHand extracted with EtOAc
(4Â50 mL). The pooled EtOAc extract was dried
(Na2SO4) and solvent removed under reduced pressure
to yield a residue, which was purified by chromato-
graphy on silica gel to yield deep orange solid. 6-Nitro-
3-anilinoquinoline (0.3 g, 1.13 mmol) and Pd(OAc)2
(0.38 g, 1.13 mmol) in CF3COOH(5 mL) was heated to
90 ꢂC for 30 min. The mixture was cooled to room
temperature and poured into 5% ammonia (50 mL) and
extracted with EtOAc (3Â50 mL). The combined
2-Chloro-5-methylquindolinium iodide (4). Methods A
and D were used: mp 287–289 ꢂC. 1HNMR (DMSO- d6)
d 12.95 (1H, s), 9.22 (1H, s), 8.23 (1H, d, J=5.4 Hz),
8.77 (1H, dd, J=5.4, 1.2 Hz), 7.96 (1H, d, J=8.1 Hz),
7.87 (1H, t, J=5.4 Hz), 7.52 (1H, t, J=5.4 Hz), 5.03
(3H, s). Anal. calcd for C16H12ClIN2: C, 48.70; H, 3.06;
N, 7.10; found: C, 48.53; H, 3.14; N, 7.00.
2-Bromo-5-methylquindolinium iodide (5). Methods A
and D were used: mp 294–297 ꢂC. 1HNMR (DMSO- d6)
d 12.93 (1H, s, br), 9.21 (1H, s), 8.91 (1H, d, J=2.7 Hz),
8.83 (1H, d, J=8.1 Hz), 8.74 (1H, d, J=8.1 Hz), 8.26
(1H, dd, J=5.4, 2.7 Hz), 7.95 (1H, t, J=5.4 Hz), 7.87
(1H, d, J=5.4 Hz), 7.54 (1H, t, J=5.4 Hz), 5.03 (3H, s).
Anal. calcd for C16H12BrIN2: C, 43.77; H, 2.75; N, 6.83;
found: C, 43.89; H, 2.80; N, 6.32.
2-Iodo-5-methylquindolinium iodide (6). Methods A and
ꢂ
1
D were used: mp 312–314 C. HNMR (DMSO- d6): d
9.17 (1H, s), 9.05 (1H, d, J=2.7), 8.79 (1H, d, J=8.1),

S. Y. Ablordeppey et al. / Bioorg. Med. Chem. 10 (2002) 1337–1346
1343
8.55 (1H, d, J=8.1), 8.36 (1H, dd, J=8.1, 2.7), 7.95
(1H, t, J=8.1), 7.83 (1H, d, J=8.1), 7.52 (1H, t,
J=8.1), 5.01 (3H, s). Anal. calcd for C16H12I2N2: C,
39.54; H, 2.49; N, 5.76; found: C, 39.58; H, 2.44; N, 5.69.
(1H, t, J=5.4 Hz). Anal. calcd for C21H14N2O2S: C,
70.37; H3.94; N, 7.82; found: C, 70.20; H, 4.02; N, 7.71.
Using method D, the above sulfone (40 mg), was con-
verted to 10, as an orange solid: mp 250–251 ꢂC. H
1
5-Methyl-2-phenylsulfenylquindolinium Iodide (9). To a
solution of 2-iodoquindoline (0.1 g, 0.29 mmol),
obtained by method A, and CuI (10.0 mg) in HMPA
(2.0 mL) was added NaSPh (0.2 g, 1.5 mmol) and the
resulting mixture was stirred at 130 ꢂC overnight. The
reaction was quenched with water and the mixture was
extracted with ETOAc (3Â25 mL). The combined
extracts was washed with brine, dried over (Na2SO4),
concentrated in vacuo and chromatographed on silica
gel to give the desired sulfide, a yellow solid (70 mg): mp
216–217 C. HNMR (DMSO- d6): d 11.46 (1H, s), 8.33
(1H, d, J=8.1), 8.24 (1H, s), 8.17 (1H, d, J=8.1), 8.15
(1H, d, J=2.7), 7.60 (2H, m), 7.49 (1H, dd, J=8.1, 2.7),
7.35 (6H, m). Anal. calcd for C21H14N2S: C, 77.27; H,
4.32; N, 8.58; found: C, 77.16; H, 4.42; N, 8.54.
NMR (DMSO-d6) d 9.53 (1H, s), 9.40 (1H, d, J=1.2
Hz), 8.93 (1H, d, J=8.1 Hz), 8.84 (1H, d, J=8.1 Hz),
8.46 (1H, dd, J=5.4, 1.2 Hz), 8.12 (2H, dd, J=5.4, 1.2
Hz), 7.99 (1H, t, J=5.4 Hz), 7.88 (1H, d, J=5.4 Hz),
7.70 (3H, m), 7.55 (1H, t, J=5.4 Hz), 5.03 (3H, s). Anal.
.
calcd for C22H17IN2O2S H2O: C, 50.98; H, 3.69; N,
5.40; found: C, 51.04; H, 3.63; N, 5.37.
5-Methyl-2-methylsulfonylquindolinium iodide (8). Same
procedure as 10, mp 244–246 ꢂC. HNMR (DMSO- d6)
1
ꢂ
1
d 13.18 (1H, s), 9.65 (1H, s), 9.28 (1H, d, J=1.2 Hz),
9.03 (1H, d, J=8.1 Hz), 8.78 (1H, d, J=8.1 Hz), 8.55
(1H, dd, J=5.4, 1.2 Hz), 8.02 (1H, t, J=5.4 Hz), 7.89
(1H, d, J=5.4 Hz), 7.58 (1H, t, J=5.4 Hz), 5.10 (3H, s),
3.45 (3H, s). Anal. calcd for C17H15IN2O2S: C, 46.59;
H, 3.45; N, 6.39; found: C, 46.71; H, 3.55; N, 6.33.
To a solution of the above sulfide (0.13 g, 0.4 mmol) in
CH2Cl2 (3.0 mL) and MeOH(3.0 mL) was added
mCPBA (90 mg, 0.52 mmol) at 0 ꢂC and the resulting
mixture was stirred for 1.5 h at room temperature. The
mixture was chromatographed directly to give 2-phe-
nylsulfenylquindoline, as a bright yellow solid (80 mg):
2-Cyano-5-methylquindolinium iodide (11). A mixture of
2-iodoquindoline (34 mg, 0.1 mmol), Pd(PPh3)4 (6 mg,
0.005 mmol) and KCN (13 mg, 0.2 mmol) in THF (2
mL) was heated under N2 overnight at 70 ꢂC. The
resulting mixture was poured into ammonia solution
and extracted exhaustively with EtOAc. The pooled
extracts was dried (Na2SO4) and solvent was removed
under reduced pressure to yield a residue, which was
purified by chromatography over silica gel. Recrystalli-
zation was achieved from Toluene to afford a greenish-
yellow solid (19 mg): mp 287–288 ꢂC.
mp 281–282 ꢂC. HNMR (DMSO- d6): d 11.60 (1H, s),
1
8.64 (1H, d, J=1.8), 8.49 (1H, s), 8.35 (1H, d, J=8.1),
8.26 (2H, d, J=8.1), 7.79 (2H, dd, J=5.4, 1.8), 7.71
(1H, dd, J=5.4, 1.8), 7.55 (5H, m), 7.30 (1H, dt, J=5.4,
.
1.8). Anal. calcd for C21H14N2OS 1.1H2O: C, 69.63; H,
4.51; N, 7.73; found: C, 69.79; H, 4.70; N, 7.30.
Using method D, the above sulfoxide (50 mg) was con-
verted to the desired product, 9, as a yellow solid. Mp
Method D was used to coꢂnvert the solid to the desired
1
product, 11: mp 257–258 C. HNMR (DMSO- d6) d
245–246 ꢂC. HNMR (DMSO- d6): d 9.48 (1H, s), 8.97
9.35 (1H, s), 9.23 (1H, d, J=1.8 Hz), 8.95 (1H, d, J=8.1
Hz), 8.84 (1H, d, J=8.1 Hz), 8.46 (1H, dd, J=8.1, 1.8
Hz), 8.01 (1H, dt, J=8.1, 1.8 Hz), 7.91 (1H, d, J=8.1
Hz), 8.57 (1H, J=8.1, 1.8 Hz), 5.06 (3H, s). Anal. calcd
for C17H12IN3: C, 53.01; H, 3.14; N, 10.91; found: C,
53.14; H, 3.18; N, 10.85.
1
(1H, d, J=1.8), 8.70 (2H, d, J=8.1), 8.22 (1H, dd,
J=8.1, 1.8), 7.99 (1H, dt, J=8.1, 1.8), 7.85 (3H, m),
7.36 (4H, m), 5.10 (3H, s). Anal. calcd for
.
C22H17IN2OS 1.1H2O: C, 52.41; H, 3.84; N, 5.52;
found: C, 52.35; H, 3.62; N, 5.52.
5-Methyl-2-methylsulfenylquindolinium iodide (7). Same
procedure as for compound 9: mp 245–246 ꢂC. 1H
NMR (DMSO-d6): d 13.14 (1H, s), 9.46 (1H, s), 8.95
(1H, d, J=8.1), 8.93 (2H, s), 8.84 (1H, d, J=8.1), 8.36
(1H, dd, J=8.1, 1.8), 7.99 (1H, t, J=5.4), 7.87 (1H, d,
J=5.4), 7.55 (1H, dt, J=5.4, 1.8), 5.10 (3H, s), 2.95
(3H, s). Anal. calcd for C17H15IN2OS: C, 48.35; H, 3.58;
N, 6.63; found: C, 48.42; H, 3.53; N, 6.58.
2,5-Dimethylquindolinium iodide (13). Method A was
used with 5-methylisatin as starting material to obtain
2-methylquindoline, which was methylated with iodo-
methane (method D): mp 283–286 ꢂC. 1HNMR
(DMSO-d6) d 12.73 (1H, s, br), 9.15 (1H, s), 8.78 (1H, d,
J=8.1 Hz), 8.56 (1H, d, J=8.1 Hz), 8.42 (1H, s), 8.01
(1H, d, J=5.4 Hz), 7.92 (1H, t, J=5.4 Hz), 7.83 (1H, d,
J=5.4 Hz), 7.51 (1H, t, J=5.4 Hz), 5.01 (3H, s), 2.63
(3H, s). Anal. calcd for C17H15IN2O: C, 54.56; H, 4.04;
N, 7.49; found: C, 54.51; H, 3.96; N, 7.41.
5-Methyl-2-phenylsulfonylquindolinium Iodide (10). To a
solution of 2-methylthio-quindoline (0.13 g, 0.4 mmol)
in CH2Cl2 (4.0 mL) and MeOH(4.0 mL) was added
mCPBA (0.17 g, 1.0 mmol) and the resulting mixture
was stirred at room temperature for 1 h. After the mix-
ture was basified with NH4OHand chromatographed to
give the desired sulfone, as a bright yellow solid (72 mg):
2-Methoxy-5-methylquindolininium iodide (14). Using
method D, 2-methoxyquindoline (15 mg) was converted
to 14: mp 286–288 ꢂC. HNMR (DMSO- d6) d 12.70
1
(1H, s, br), 9.09 (1H, s), 8.74 (1H, d, J=8.1 Hz), 8.67
(1H, d, J=8.1 Hz), 7.95 (1H, d, J=2.7 Hz), 7.90 (1H, t,
J=5.4 Hz), 7.78 (2H, m), 7.50 (1H, t, J=5.4 Hz), 5.02
(3H, s), 4.03 (3H, s). Anal. calcd for C17H15IN2O: C,
52.33; H, 3.87; N, 7.18; found: C, 52.27; H, 3.82; N,
7.10.
mp 275–278 ꢂC. HNMR (DMSO- d6) d 11.72 (1H, s),
1
8.95 (1H, d, J=1.8 Hz), 8.6 (1H, s), 8.38 (1H, d, J=8.1
Hz), 8.32 (2H, d, J=8.1 Hz), 8.05 (2H, dd, J=5.4, 1.8
Hz), 7.95 (1H, dd, J=5.4, 1.8 Hz), 7.63 (5H, m), 7.32

1344
S. Y. Ablordeppey et al. / Bioorg. Med. Chem. 10 (2002) 1337–1346
2-Hydroxy-5-methylquindolinium iodide (15). A mixture
of 2-methoxyquindoline (15 mg) and pyridine hydro-
chloride (1 g) was heated under N2 at 175 ꢂC for 2 h and
then neutralized by NaHCO3 solution. The solution was
then extracted with CHCl3 (4Â50 mL), dried (Na2SO4)
and solvent was removed by evaporation, under
reduced pressure, to give the product (6 mg). Subse-
quently, additional product (35 mg) was obtained, then
methylated to form a yellow solid, 15, (50 mg) using
method D: mp 312–314 ꢂC. 1HNMR (DMSO- d6) d 9.03
(1H, s), 8.72 (1H, d, J=8.1 Hz), 8.61 (1H, d, J=8.1
Hz), 7.88 (1H, t, J=4.1 Hz), 7.79 (1H, d, J=4.1 Hz),
7.70 (1H, s), 7.68 (1H, d, J=4.1 Hz), 7.74 (1H, t, J=4.1
Hz), 4.98 (3H, s). Anal. calcd for C17H15IN2O: C, 52.33;
H, 3.87; N, 7.18; found: C, 52.27; H, 3.82; N, 7.10.
Hz), 7.16 (5H, m), 5.55 (2H, t, J=5.4 Hz), 4.22 (3H, s),
2.67 (2H, t, J=4.1 Hz), 2.28 (2H, m), 1.80 (4H, m).
Anal. calcd for C27H27BrN2.1.5H2O) C, 64.31; H, 5.40;
N, 5.55; found: C, 64.36; H, 5.44; N, 5.54.
2-Bromo-5-(5-phenylpentyl)quindolinium bromide (22).
Method D was used with 2-bromoquindoline as start-
ing material: mp 254–255 ꢂC. HNMR (DMSO- d6) d
1
13.16 (1H, s, br), 9.27 (1H, s), 8.94 (1H, d, J=2.7 Hz),
8.73 (1H, d, J=8.1 Hz), 8.52 (1H, d, J=8.1 Hz), 8.25
(1H, dd, J=5.4, 2.7 Hz), 7.97 (1H, t, J=5.4 Hz), 7.90
(1H, d, J=5.4 Hz), 7.58 (1H, t, J=5.4 Hz), 7.20 (5H, m),
5.50 (2H, t, J=5.4 Hz), 2.57 (2H, t, J=4.1 Hz), 2.13 (2H,
br), 1.65 (4H, br). Anal. calcd for C26H24Br2N2: C,
59.56; H, 4.61; N, 5.34; found: C, 59.66; H, 4.67; N, 5.42.
2-Methylthio-5-methylquindolinium iodide (16). Method
D was used with 2-methylthio-quindoline as starting
2-Bromo - 10- methyl - 5 - ( - 5 - phenylpentyl)quindolinium
iodide (23). Method F was used with 2-bromoquindo-
line as starting material: mp 217–220 ꢂC. 1HNMR
(DMSO-d6) d 9.46 (1H, s), 9.01 (1H, d, J=2.7 Hz), 8.76
(1H, d, J=10.8 Hz), 8.57 (1H, d, J=10.8 Hz), 8.28 (1H,
dd, J=10.8, 2.7 Hz), 8.08 (1H, d, J=2.7 Hz), 8.06 (1H,
s), 7.63 (1H, m), 7.19 (5H, m), 5.52 (2H, t, J=8.1 Hz),
4.16 (3H, s), 2.58 (2H, t, J=5.4 Hz), 2.11 (2H, br), 1.67
ꢂ
1
material: mp 274–277 C. HNMR (DMSO- d6) d 12.81
(1H, s, br), 9.13 (1H, s), 8.76 (1H, d, J=8.1), 8.65 (1H,
d, J=8.1), 8.30 (1H, s), 8.01 (1H, d, J=5.4), 7.91 (1H, t,
J=5.4), 7.85 (1H, d, J=5.4), 7.51 (1H, t, J=5.4), 5.01
(3H, s), 2.70 (3H, s). Anal. calcd for C17H15IN2S: C,
50.26; H, 3.72; N, 6.89; found: C, 50.07; H, 3.71; N,
6.77.
.
(4H, br). Anal. calcd for C27H26Br1N2 1.0 MeOH: C,
55.97; H, 4.70; N, 4.84; found: C, 56.05; H, 4.60; N, 4.77.
2-Phenylthio-5-methylquindolinium iodide (17). Method
D was used with 2-phenylthio-quindoline as starting
2-Bromo - 5 - (5 - cyclohexylpentyl)quindolinium bromide
(24). Method D was used with 2-bromoquindoline as
starting material: mp 256–258 ꢂC. 1HNMR (DMSO- d6)
d 9.25 (1H, s), 8.91 (1H, s), 8.72 (1H, d, J=8.1 Hz), 8.51
(1H, d, J=8.1 Hz), 8.25 (1H, d, J=5.4 Hz), 7.98 (1H, d,
J=5.4 Hz), 7.91 (1H, t, J=5.4 Hz), 7.56 (1H, t, J=5.4
Hz), 6.42 (1H, s), 5.48 (2H, t, J=4.1 Hz), 2.08 (4H, m),
1.63 (8H, m), 1.35 (1H, m), 1.15 (4H, m), 0.82 (2H, m).
Anal. calcd for C26H30Br2N2: C, 58.88; H, 5.70; N, 5.28;
found: C, 61.69; H, 6.08; N, 5.55.
ꢂ
1
material: mp 253–256 C. HNMR (DMSO- d6) d 12.86
(1H, s, br), 9.20 (1H, s), 8.79 (1H, d, J=8.1 Hz), 8.72
(1H, d, J=8.1 Hz), 8.43 (1H, d, 1.8), 7.90 (4H, m), 7.51
(6H, m), 5.01 (3H, s). Anal. calcd for C22H17IN2S: C,
56.42; H, 3.66; N, 5.98; found: C, 56.36; H, 3.69; N,
5.93.
5-(5-Phenylpentyl)quindolinium bromide (18). Method D
was used to obtain the desired product: mp 218–219 ꢂC.
1HNMR (DMSO- d6) d 12.95 (1H, s, br), 9.33 (1H, s),
8.76 (1H, d, J=5.4 Hz), 8.61 (1H, d, J=5.4 Hz), 8.52
(1H, d, J=5.4 Hz), 8.18 (1H, t, J=5.4 Hz), 7.95 (3H,
m), 7.56 (1H, t, J=5.4 Hz), 7.20 (5H, m), 5.51 (2H, t,
J=5.4 Hz), 2.58 (2H, s, br), 2.15 (2H, s, br), 1.70 (4H, s,
br). Anal. calcd for C26H25BrN2: C, 70.11; H, 5.66; N,
6.29; found: C, 69.71; H, 5.74; N, 6.23.
2-Methoxy-5-(5-phenylpentyl)quindolinium bromide (25).
Method D was used with 2-methoxyquindoline as
starting material: mp 233–234 ꢂC. 1HNMR (DMSO- d6)
d 12.86 (1H, s), 9.15 (1H, s), 8.67 (1H, d, J=8.1 Hz),
8.46 (1H, d, J=8.1 Hz), 8.02 (1H, d, J=2.71 Hz), 7.92
(1H, t, J=5.4 Hz), 7.89 (1H, d, J=5.4 Hz), 7.80 (1H,
dd, J=5.4, 2.7 Hz), 7.53 (1H, t, J=5.4 Hz), 7.20 (5H,
m), 5.48 (2H, t, J=5.4 Hz), 4.02 (3H, s), 2.57 (2H, t,
J=4.1 Hz), 2.11 (2H, br), 1.65 (4H, br). Anal. calcd for
C27H27BrN2O: C, 68.21; H, 5.72; N, 5.89; found: C,
68.11; H, 5.78; N, 5.94.
10-Methyl-5-(5-phenylpentyl)quindolinium bromide (20).
Method F. A mixture of quindoline (0.15 g), 5-phe-
nylpentylbromide## (1.0 mL) and sulpholane (2.0 mL)
was heated to 95 ꢂC for 24 h. After cooling to room
temperature, the mixture was chromatographed with 5–
20% methanol in CH2Cl2 (gradient elution) to yield a
yellow solid (60 mg) which was converted to the free
base with ammonia solution. The solution was extracted
with CH2Cl2 (4Â25 mL), pooled and dried (Na2SO4).
The solvent was removed and the residue (45 mg) was
taken up in acetone (50 mL). Iodomethane (2 mL) was
added and the mixture was refluxed for 24 h. After
cooling to room temperature, the solvent was removed
and the residue was purified by chromatography over
silica gel (5–20% MeOHin CH 2Cl2) to give (15 mg): mp
5,10-Dimethyl - 2 - methoxyquindolinium iodide (26).
Method D was used with excess iodomethane and 2-
methoxyquindoline as starting materials: mp 262–
264 ꢂC. 1HNMR (CD 3COD) d 9.18 (1H, s), 8.75 (1H, d,
J=8.1 Hz), 8.60 (1H, d, J=8.1 Hz), 8.56 (1H, s), 7.87
(3H, m), 7.61 (1H, d, J=4.1 Hz), 5.12 (3H, s), 4.18 (3H,
s), 4.07 (3H, s). Anal. calcd for C18H17IN2O: C, 49.55;
H, 3.93; N, 6.42; found: C, 49.65; H, 4.13; N, 6.02.
2-Methoxy - 10- methyl - 5 - (5 - phenylpentyl)quindolinium
iodide (27). Method F was used with 2-methoxyquindo-
line as starting material: mp 237–238 ꢂC. 1HNMR
(DMSO-d6) d 9.37 (1H, s), 8.82 (1H, d, J=8.1 Hz), 8.51
203–204 ꢂC. HNMR (DMSO- d6) d 9.38 (1H, s), 8.65
1
(1H, d, J=5.4 Hz), 8.52 (2H, t, J=5.4 Hz), 8.21 (1H, dt,
J=5.4, 1.8 Hz), 7.98 (3H, m), 7.63 (1H, dt, J=5.4, 1.8

S. Y. Ablordeppey et al. / Bioorg. Med. Chem. 10 (2002) 1337–1346
1345
(1H, d, J=8.1 Hz), 8.02 (2H, d, J=2.7 Hz), 7.89 (2H, d,
J=2.7 Hz), 7.58 (1H, m), 7.19 (5H, m), 5.01 (2H, t,
J=5.4 Hz), 4.13 (3H, s), 4.02 (3H, s), 2.57 (2H, s, br),
2.12 (2H, s, br), 1.65 (4H, s, br). Anal. calcd for
C28H29BrN2O 1.5 MeOH: C, 62.57; H, 5.44; N, 5.21;
found: C, 62.66; H, 5.47; N, 5.18.
bation at 37 ꢂC. Amphotericin B was included as posi-
tive control in each assay.
.
Acknowledgements
We gratefully acknowledge research support from the
National Institutes of Health, National Institute of
Allergy and Infectious Diseases, through AREA grant
number R15 Al37976-01 and MBRS grant # GM 08111
to SYA, Research Centers at Minority Institutions
(RCMI) grant number G12 RR 03020 to Florida A&M
University and RO1-AI 27094 to AMC. We also
appreciate the generous contributions of Dr. Tom Ged-
ric of Florida State University Chemistry Department
who obtained the NMR spectra of compounds in this
paper.
2-Cyano - 5 - (5 - cyclohexylpentyl)quindolinium bromide
(28). Method D was used wꢂith 2-cyanoquindoline as
starting material: mp 245–248 C. 1HNMR (DMSO- d6)
d 9.40 (1H, s), 9.28 (1H, S), 8.98 (1H, d, J=8.1 Hz),
8.57 (1H, d, J=8.1 Hz), 8.47 (1H, dd, J=8.1, 1.8 Hz),
8.03 (1H, t, J=8.1 Hz), 7.95 (1H, d, J=8.1 Hz), 7.62
(1H, J=8.1 Hz), 5.02 (2H, t, J=5.4 Hz), 2.10 (4H, m),
1.63 (6H, m), 1.37 (1H, m), 1.05 (6H, m), 0.84 (2H, m).
Anal. calcd for C27H30IN2: C, 68.06; H, 6.35; N, 8.82;
found: C, 68.01; H, 6.42; N, 8.72.
7-Nitro-5-methylquindolinium iodide (29). To a solution
of quindoline (300 mg) in AcOH(10 mL) was added
fuming HNO3 (10 mL) at 0 ꢂC and the resulting mixture
was stirred at room temperature overnight. Cold H2O
(20 mL) and NH4OHwere added until the solution
became basic (pH ꢀ11) and extracted with EtOAc. The
combined extracts was washed with brine, dried
(Na2SO4) and evaporated under reduced pressure. The
residue was chromatographed with 40% EtOAc in hex-
ane, using gradient elution, to give 11-nitroquindoline
(50 mg) and 7-nitroquindoline (260 mg).
References and Notes
1. (a) Piot, P.; Bartos, M.; Ghys, P. D.; Walker, N.; Schwart-
lander, B. Nature 2001, 410, 968. (b) De Cock, K. M.; Weiss,
H . A.Trop. Med. Int. Health 2000, 5, A3.
2. Ablordeppey, S. Y.; Fan, P.; Ablordeppey, J. H.; Marden-
borough, L. Curr. Med. Chem. 1999, 6, 1151.
3. (a) Arzel, E.; Rocca, P.; Grellier, P.; Labaeid, M.; Frappier,
F.; Gueritte, F.; Gaspard, C.; Marsais, F.; Godard, A.; Que-
guiner, G. J. Med. Chem. 2001, 44, 949. (b) Radl, S.; Kon-
vicka, P.; Vachal, P. J. Heterocycl. Chem. 2000, 37, 855.
4. Dassonneville, L.; Lansiaux, A.; Wattelet, A.; Wattez, N.;
Mahieu, C.; Van Miert, S.; Pieters, L.; Bailly, C. Eur. J.
Pharmacol. 2000, 409, 9.
5. (a) Bierer, D. E.; Fort, D. M.; Mendez, C. D.; Luo, J.;
Imbach, P. A.; Dubenko, L. G.; Jolad, S. D.; Gerber, R. E.;
Litvak, J.; Lu, Q.; Zhang, P.; Reed, M. J.; Waldeck, N.; Bru-
ening, R. C.; Noamesi, B. K.; Hector, R. F.; Carlson, T. J.;
King, S. R. J. Med. Chem. 1998, 41, 894. (b) Bierer, D. E.;
Dubenko, L. G.; Zhang, P.; Lu, Q.; Imbach, P. A.; Garofalo,
A. W.; Phuan, P.-W.; Fort, D. M.; Litvak, J.; Gerber, R. E.;
Sloan, B.; Luo, J.; Cooper, R.; Reaven, G. M. J. Med. Chem.
1998, 41, 2754.
A mixture of 7-nitroquindoline (260 mg), methyl iodide
(2 mL) in sulpholane (2 mL) was heated at 55.0 ꢂC
overnight. The mixture was cooled to room temperature
and diluted with EtOAc and the solid formed was
washed with EtOAc and MeOH, and dried to give 29, as
ꢂ
1
a yellow solid (82 mg, 21%) mp 263–266 C. HNMR
(DMSO-d6) d 9.57 (1H, s), 9.48 (1H, s), 8.85 (1H, d,
J=5.4 Hz), 8.71 (1H, d, J=5.4 Hz), 8.65 (1H, d, J=5.4
Hz), 8.24 (1H, t, J=5.4 Hz), 8.02 (2H, m), 5.13 (3H, s).
Anal. calcd for C16H12IN3O2: C, 47.43; H, 2.99; N,
10.37; found: C, 47.24; H, 2.89; N, 10.24.
6. Paulo, A.; Gomes, E. T.; Steele, J.; Warhurst, D. C.;
Houghton, P. J. Planta Med. 2000, 66, 30.
11-Nitro-5-methylquindolinium iodide (30). Compound
30 was obtained by method D using the 11-nitro
7. (a) Ablordeppey, S. Y.; Hufford, C. D.; Borne, R. F.;
Dwuma-Badu, D. Planta Med. 1990, 56, 416. (b) Dwuma-
Badu, D.; Ayim, J. S.; Fiagbe, N. I.; Knapp, J. E.; Schiff, P. L.,
Jr.; Slatkin, D. J. J. Pharm. Sci. 1978, 67, 433. (c) Cimanga,
K.; De Bruyne, T.; Lasure, A.; Van Poel, B.; Pieters, L.;
Claeys, M.; Vanden Berghe, D.; Kambu, K.; Tona, L.; Vlie-
tinck, A. J. Planta Med. 1996, 62, 22.
8. (a) Boakye-Yiadom, K.; Heman-Ackah, S. M. J. Pharm. Sci.
1979, 68, 1510. (b) Paulo, A.; Pimentel, M.; Viegas, S.; Pires, I.;
Duarte, A.; Cabrita, J.; Gomes, E. T. J. Ethnopharmacol.
1994, 44, 73. (c) Sawer, I. K.; Berry, M. I.; Brown, M. W.;
Ford, J. L. J. Appl. Bacteriol. 1995, 79, 314. (d) Paulo, A.;
Duarte, A.; Gomes, E. T. J. Ethnopharmacol. 1994, 44, 127.
9. (a) Noamesi, B. K.; Bamgbose, S. O. Planta Med. 1980, 39,
51. Noamesi, B. K.; Bamgbose, S. O. Planta Med. 1982, 44,
241. (b) Oyekan, A. O. Eur. J. Pharmacol. 1995, 285, 1.
10. (a) Oyekan, A. O.; Ablordeppey, S. Y. Gen. Pharmacol.
1993, 24, 1285. (b) Oyekan, A. O.; Ablordeppey, S. Y. Gen.
Pharmacol. 1993, 24, 461. (c) Oyekan, A. O.; Ablordeppey,
S. Y. Med. Chem. Res. 1996, 6, 602.
obtained above as starting material: mp 261–264 ꢂC. H
1
NMR (DMSO-d6) d 13.45 (1H, s, br), 9.36 (2H, m), 8.89
(2H, m), 8.75 (1H, d, J=5.4 Hz), 8.26 (1H, t, J=5.4
Hz), 8.07 (1H, t, J=5.4 Hz), 7.72 (1H, t, J=5.4 Hz),
5.10 (3H, s). Anal. calcd for C16H12IN3O2: C, 47.43; H,
2.99; N, 10.37; found: C, 47.20; H, 3.07; N, 10.13.
Evaluation of antifungal activity
Quantitative assay. Minimum inhibitory concentration
(MIC),13 of promising compounds were determined
using a 2-fold serial broth dilution assay in Sabouraud-
dextrose broth (SDB) for C. neoformans and A. flavus or
yeast nitrogen broth for C. albicans. A solution of the
compound in DMSO was added to SDB and the
inoculum for the MIC determination was prepared as
previously described.13,14 The MIC value was taken as
the lowest of the concentration that inhibited the
growth of the test organisms after 24 and 48 h of incu-
11. (a) Dassonneville, L.; Bonjean, K.; De Pauw-Gillet, M.-
C.; Colson, P.; Houssier, C.; Quetin-Leclercq, J.; Angenot, L.;

1346
S. Y. Ablordeppey et al. / Bioorg. Med. Chem. 10 (2002) 1337–1346
Bailly, C. Biochemistry 1999, 38, 7719. (b) Bailly, C.; Laine,
W.; Baldeyrou, B.; De Pauw-Gillet, M.-C.; Colson, P.; Hous-
sier, C.; Cimanga, K.; Van Miert, S.; Vlietinck, A. J.; Pieters,
L. Anti-Cancer Drug Des. 2000, 15, 191.
12. Singh, M.; Singh, M. P.; Ablordeppey, S. Y. Drug Dev.
Ind. Pharm. 1996, 22, 379.
18. Yang, S.-W.; Abdel-Kader, M.; Malone, S.; Werkhoven,
M. C. M.; Wisse, J. H.; Bursuker, I.; Neddermann, K.; Fair-
child, C.; Raventos-Suarez, C.; Menendez, A. T.; Lane, K.;
Kingston, D. G. I. J. Nat. Prod. 1999, 62, 976.
19. Chen, J.; Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay,
G. J.; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 2000,
8, 2461.
20. Holt, S. J.; Petrow, V. J. Chem. Soc. 1947, 607.
21. Yamato, M.; Takeuchi, Y.; Chang, M.; Hashigaki, K.;
Tsuruo, T.; Tashiro, T.; Tsukagoshi, S. Chem. Pharm. Bull.
1990, 38, 3048.
13. Ablordeppey, S. Y.; Fan, P.; Clark, A. M.; Nimrod, A.
Bioorg. Med. Chem. 1999, 7, 343.
14. Mardenborough, L. G.; Fan, P. C.; Ablordeppey, S. Y.;
Nimrod, A.; Clark, A. M. Med. Chem. Res. 1999, 9, 118.
15. Ansa-Asamoah, R.; Asante-Frempong. In First Interna-
tional Conference on Cryptoleine; Boakye-Yiadom, K., Bamg-
bose, S. O. A., Eds., UST: Kumasi, Ghana, 1983; p 52.
16. Clark, A. M.; Hufford, C. D.; Liu, S.; Ablordeppey, S.
Pharm. Res. 1989, 6, 512.
22. Yamato, M.; Takeuchi, Y.; Chang, M.; Hashigaki, K.
Chem. Pharm. Bull. 1992, 40, 528.
23. Fan, P.; Ablordeppey, S. Y. J. Heterocycl. Chem. 1997,
34, 1789.
17. (a) Gorlitzer, K.; Weber, J. Arch. Pharm. (Weinheim)
1981, 314, 852. (b) Cooper, M. M.; Lovell, J. M.; Joule, J. A.
Tetrahedron Lett. 1996, 37, 4283.
24. Wright, C. W.; Addae-Kyereme, J.; Breen, A. G.; Brown,
J. E.; Cox, M. F.; Croft, S. L.; Gokcek, Y.; Kendrick, H.;
Phillips, R. M.; Pollet, P. L. J. Med. Chem. 2001, 44, 3187.