Optimization of 3-(phenylthio)quinolinium compounds against opportunistic fungal pathogens

Article abstract of DOI:10.1016/j.ejmech.2011.02.034

Ring-opened benzothieno[3,2-b]quinolinium salts (3) were designed and synthesized with substitution on the thiophene moiety. In vitro screenings were carried out against fungal pathogens including Cryptococcus neoformans, Candida albicans, Candida glabrat

Full text of DOI:10.1016/j.ejmech.2011.02.034

European Journal of Medicinal Chemistry 46 (2011) 1789e1797
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Optimization of 3-(phenylthio)quinolinium compounds against opportunistic
fungal pathogens
Comfort A. Boateng a, Xue Y. Zhu a, Melissa R. Jacob b, Shabana I. Khan b, Larry A. Walker b,
,
Seth Y. Ablordeppeya
*
a College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
b The National Center for the Development of Natural Products, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Ring-opened benzothieno[3,2-b]quinolinium salts (3) were designed and synthesized with substitution
on the thiophene moiety. In vitro screenings were carried out against fungal pathogens including
Cryptococcus neoformans, Candida albicans, Candida glabrata, Candida krusei and Aspergillus fumigatus. In
Received 16 October 2010
Received in revised form
14 February 2011
Accepted 15 February 2011
Available online 23 February 2011
all, by replacing the N-methyl group (2) with N-
substituted 3-(phenylthio)quinolinium compounds produced remarkable potencies, as high as 300-fold
(cf, cryptolepine (1) ¼ 250 g/mL vs 11p ¼ 0.8 g/mL for C. albicans) over the starting tetracyclic parent.
In addition, all the N- -cyclohexylpentyl analogs produced superior activity against all the microor-
ganisms tested than the N- -phenylpentyl substituted compounds. The potential of these compounds to
induce toxicity in Vero cells was also investigated and the majority of them showed lower or no cyto-
toxicity at 10 g/mL than amphotericin B, the gold standard in antifungal drug development. For
u-phenylpentyl or u-cyclohexylpentyl group to form
m
m
u
Keywords:
Cryptolepine analog
Benzothienoquinoline
Benzo[3,2-b]quinolinium salt
Quaternary aromatic compound
Antifungal agent
Opportunistic infection agent
Ring-opened benzothienoquinoline
u
m
instance, the trifluoromethyl substituted analogs (11n-p) have selectivity indices over 2-fold better than
those of amphotericin B in C. neoformans. Overall, this ring-opened scafford of benzothienoquinolines,
with substitution on the thiophenyl moiety, serves as a new lead for further development.
Published by Elsevier Masson SAS.
1. Introduction
opened analogs of cryptolepine and those of 5-alkylated benzo-
thieno[3,2-b]quinolinium salts (3) [5a]. The results lend support to
We recently reported that sulfur isosteres of cryptolepine (1),
benzothieno[3,2-b]quinolinium salts (2), have the potential to
become useful agents with broad antifungal properties and low
cytotoxicity [1]. Cryptolepine [2], the original indoloquinoline
alkaloid from which these compounds are derived, presumably acts
in part by intercalating into DNA [3] and interfering with top-
oisomerase II [3,4]. We have hypothesized that opening the tetra-
cyclic ring to form ring-opened analogs of cryptolepine might curtail
DNA intercalation and decrease cytotoxicity. This hypothesis was
tested indirectly by the synthesis and biological evaluation of ring B-
the hypothesis as these compounds were found to be more potent
and less toxic than the parentcryptolepine and morepotent than the
benzothienoquinolinium salts from which they were derived [5b].
Consequently, in this paper, we have sought to optimize ring B-
opened analogs of 5-alkylated benzothienoquinolinium salts (3)
by synthesizing and evaluating additional ring-opened analogs
and studying the structure-activity relationships involved in
substituting on ring A in an attempt to increase selective toxicity to
fungal pathogens that are commonly associated with AIDS.
* Corresponding author.
E-mail address: seth.ablordeppey@famu.edu (S.Y. Ablordeppey).
0223-5234/$ e see front matter Published by Elsevier Masson SAS.
doi:10.1016/j.ejmech.2011.02.034

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C.A. Boateng et al. / European Journal of Medicinal Chemistry 46 (2011) 1789e1797
2. Results and discussion
Cryptococcus neoformans,Candida albicans and Aspergillus fumiga-
tus while 11a-p were evaluated against additional pathogens
Candida glabrata and Candida krusei since they were found to be
more potent than 10a-p and preliminary investigations showed
them to have fungicidal properties. The inclusion of C. glabrata and
C. krusei in the evaluations is related to their emerging status as
microbes of health concern for immune-compromised populations.
For example, the results of a recent study indicated that C. glabrata
and C. krusei were the leading causes of candidemia in patients with
hematologic malignancies [10]. It has also been reported that
C. krusei is prevalent in bone marrow transplantation and accounts
for 2e3% of all Candida bloodstream infections [11] and thus, is
considered an emerging health concern.
2.1. Synthesis
The synthesis of the ring-opened analog, 1-alkylated-3-(phe-
nylthio)quinolinium iodide (3), required 3-iodoquinoline (5) as the
starting material. Compound 5 was obtained by employing Finkel-
stein reaction [6] to convert commercially available 3-bromoqui-
noline to the desired iodide. Using a copper-catalyzed carbon-sulfur
bond formationreaction [7], substituted benzenethiols werereacted
with 3-iodoquinoline to form substituted 3-(phenylthio)quinolines
(6) (Scheme 1). The synthesis of 3-(hydroxyphenylthio)-quinoline
(7a-c) was achieved by demethylation of 3-(methoxy phenylthio)
quinoline (6j-l) using pyridine hydrochloride.
An alternate route to the preparation of 1-alkylated-3-(phenyl-
thio)quinolinium iodide (Scheme 1) was employed [8] where
appropriately substituted starting materials were unavailable. 3-
Iodoquinoline was converted to S-quinolin-3-yl benzothioate (8) by
reaction with thiobenzoic acid. Using the Cu-catalyzed C-S bond
formation reaction adopted earlier, substituted-iodobenzenes were
reacted with S-quinolin-3-yl benzothioate to obtain cyano-substituted
3-(phenylthio)quinolines (9a-c). Finally, to obtain the final target
compounds, 3-[(substituted) phenylthio]quinolines were alkylated
with appropriate alkyl halides to yield 3-(substituted-phenyl-
sulfanyl)-1-(5-phenylpentyl)- (10a-p) or 3-(substituted-phenyl-
sulfanyl)-1-(5-cyclohexylpentyl)- (11a-p) quinolinium iodides in
good yields as shown in Scheme 2.
2.3. In-vitro evaluation
The results of the in vitro antifungal screening of substituted-3-
(phenylthio)quinolinium iodides with the
-cyclohexylpentyl moieties are presented in Tables 1 and 2
respectively. When both IC50 and MIC values are between 1 and
10 g/mL, the compounds are considered active, moderately active
between 10 and 15 g/mL and weak above 15 and up to 20 g/mL.
Compounds with activities above 20 g/mL are considered inactive
while activities below 1 g/mL are considered very potent. Most of
u-phenylpentyl and
u
m
m
m
m
m
the compounds in the first group (Table 1) show potent activities
against C. neoformans (Cn) and C. albicans (Ca) but are generally
inactive against A. fumigatus. On the other hand, compounds in
Table 2 are generally very potent not only against the three fungi
but extend to C. krusei and C. glabrata, two emerging opportunistic
pathogens. Both of these pathogens are more recent and are of
significant concern in especially cancer patients. In addition to their
enhanced potency, compounds 11a-p in general are fungicidal at
low concentrations against all the pathogens evaluated except for
A. fumigatus.
Substituents on phenyl ring A were selected using the Craig plot
in order to explore the complete electronic and lipophilic space
surrounding the phenylthio- moiety.
2.2. Biological evaluation
Previous studies in our laboratories have revealed that substi-
tution on the ring of cryptolepine and 5-methyl benzothieno[3,2-b]
quinolinium salt (2) enhanced potency and broadened anti-
opportunistic activity profile [5,9]. This result was validated in
murine models of cryptococcosis and candidiasis [5]. Further
optimization, by opening the benzo[b]thiophene ring, has led to the
identification of 1-substituted-3-(phenylthio)quinolinium iodide
(3) as a potential anti-opportunistic agent [5]. It was of interest to
explore a library of substituents on the benzenethiol moiety of 1-
substituted-3-(phenylthio)quinolinium iodide since substitution
here would have the most impact on the sulfur linking the rings.
Thus, compounds 10a-p were synthesized and evaluated against
Compound 10a, the unsubstituted N-alkylated-3-phenyl-
thioquinolinium salt, was previously reported [5] and support the
initial hypothesis that ring-opening at the benzo[b]thiophene
moiety and substitution of an
u-phenyl- or u-cyclohexyl-pentyl
group enhances activity against fungal pathogens. The effect of
various substituents with varying electronic and lipophilic proper-
ties was evaluated by introducing substituents on the thiophenyl
moeity with an
u-phenylpentyl group on the quinoline nitrogen.
Compounds 10b-d with fluoro substituents at ortho-, meta- and
para- positions have only moderate to weak activity against two of
the three pathogens excluding C. albicans. Activity against C. albicans
Scheme 1. Synthetic Procedure for 3-(substituted-phenylthio)quinoline. Reagents and Conditions: (a) CuI, CH3NHCH2CH2NHCH3, NaI, Dioxane, reflux under N2, 110 ꢀC, 48 h; (b)
Substituted-benzenethiol, CuI, HOCH2CH2OH, K2CO3, i-PrOH, reflux under N2, 110 ꢀC, 48 h; (c) Py.HCl, 200e220 ꢀC, 6 h; (d) Thiobenzoic acid, CuI, 1,10-phenanthroline, i-Pr2EtN,
Toluene, reflux under N2, 110 ꢀC 24 h (e) Substituted-benzene halide, CuI, HOCH2CH2OH, K2CO3, DMA, reflux under N2, 110 ꢀC, 48 h.

C.A. Boateng et al. / European Journal of Medicinal Chemistry 46 (2011) 1789e1797
1791
Scheme 2. Synthetic Procedure for 3-(substituted-phenylsulfanyl)-1-(5-alkyl)quinolinium iodide. Reagents and Conditions: (a) and (b) C6H5(CH2)4CH2-I or C6H11(CH2)4CH2-I,
Tetramethylene sulfone, 110 ꢀC, 12e16 h.
was much subdued compared tothe other fungi under investigation.
The electron-donating and weakly polar methoxy group did not fare
any better. However, the effect of the larger, more lipophilic and
electron-withdrawing bromo atom substituted at the o-, m- and p-
positions (compounds 10h-j) showed comparable activity to the
unsubstituted compound. Interestingly, activity against A. fumigatus
was much more significant than for any other substituted analog in
the series. Compounds 10k-m, the trifluoromethyl substituted
analogs had similar activities as the bromo analogs except that they
were essentially inactive against A. fumigatus. Finally, the electron-
donating and lipophilic methyl group was evaluated. These had no
significant activity against both C. albicans and A. fumigatus but
retain comparable activity as the unsubstituted analog against
C. neoformans. Overall, cytotoxicity in Vero cells was considered
acceptable (TC50 ꢁ 10
mg/mL) for all analogs except for 10d, the o-
methoxy, 10o, the m-methyl and 10p, the p-methyl analogs.
Table 1
Antifungal activities of 3-(substituted-phenylsulfanyl)-1-(5-phenylpentyl)quinoli-
nium iodide.
Next, the
u
-phenylpentyl group was replaced with the more
hydrophobic
u-cyclohexylpentyl group (Table 2) in line with
previous observations that the latter enhanced activity even more
[12]. Comparing the two unsubstituted analogs, the former (10a)
and the latter (11a) showed the latter to be the more potent against
all pathogens tested except for A. fumigatus where the reverse is the
case. This observation was further probed using two meta-
substituted analogs (11b and 11c) and one ortho-substituted analog
(11d) with similar results. Compounds 11e-g, methyl-substituted
analogs with electron donating and lipophilic characteristics
provided a nice contrast with compounds 11h-j, the cyano-
substituted analogs with electron-withdrawing and hydrophilic
characteristics. The results appear to suggest that the methyl
substituents have marginally better activity against all pathogens
although they also seem to have higher cytotoxicity. Comparing the
electron-donating and hydrophilic hydroxy substituents (11k-m)
with the electron-donating but lipophilic methyl substituents (11e-
g), it would appear that lipophilicity rather than hydrophilicity was
preferred for increased antifungal activity. Compounds 11n-p with
trifluoromethyl substituents at the o-, m- and p-positions respec-
tively, also allowed for a head to head comparison of the effect of
Compda 10 Rl
R
IC50/MIC/MFC (
Cn Ca
PP 1.5/5.0/>20 5.5/10/>20 NT/1.3/>20
m
g/mL)
TC50
g/mL)
(
m
Af
a
H
NT
NC
NC
NC
b
c
d
o-F
m-F
p-F
PP 9.5/20/>20 >20
PP 7.0/10/>20 >20
PP 15/20/>20
9.0/20/>20
5.0/20/>20
9.0/20/>20
>20
e
o-OMe PP 15/>20/>20 >20
8.0/>20/>20 4.3
3.5/5.0/>20 >10
f
g
m-OMe PP 10/20/>20
p-OMe PP 15/20/<20
>20
>20
4.5/20/>20
1.0/2.5/>20 10
2.5/10/>20 >10
8.5/20/>20 3.5/10/>20 NC
10
h
o-Br
PP 3.0/5.0/20
PP 2.0/5.0/10
PP 2.0/10/10
PP 2.2/5.0/10
PP 2.1/5.0/10
PP 2.7/5.0/10
PP 4.0/5.0/20
10/20/>20
10/20/>20
i
j
m-Br
p-Br
k
l
m
n
o-CF3
m-CF3
p-CF3
o-CH3
12/>20/>20 6.9/>20/>20 NC
14/>20/>20 17/>20/>20 NC
11/20/>20
>20
15/>20/>20 10
>20 NC
the
u
-phenylpentyl- (10k-m) and
u
-cyclohexylpentyl-(11n-p)
-cyclo-
o
m-CH3 PP 1.4/2.5/20
>20
>20
20/>20/>20 8.8
16/>20/>20 4.2
substituents. Consistent with previous observations, the
u
p
p-CH3
PP 1.2/2.5/5.0
0.7/1.3/5.0
hexylpentyl group demonstrated superior potency against all five
pathogens, including C. glabrata and C. krusei. Among the three
cyclohexylpentyl substituted analogs however, the p-substituted
trifluoromethyl analog 11p showed the highest potencies similar in
magnitude to those of amphotericin B. With no cytotoxicities
AmB
0.3/1.3/1.3
0.7/1.3/5.0
6.5b
Abbreviations: Cn ¼ Cryptococcus neoformans, Ca ¼ Candida albicans, Af ¼ Aspergillus
fumigatus, AmB ¼ Amphotericin B. R ¼ PP ¼ 5-Phenylpentyl-.
a
All compounds were subjected to CHN analysis and each passed within 0.4% of
the theoretical value. NT ¼ Not Tested. IC50 ¼ The concentration that affords 50%
inhibition of growth; MIC ¼ Minimum inhibitory concentration, is the lowest test
observed at 10 mg/mL, the N-cyclohexylpentyl 3-phenylthio-qui-
concentration that allows no detectable growth. MFC
¼
Minimum Fungicidal
nolinium scaffold now constitutes a new anti-opportunistic infec-
tion pharmacophore warranting further development including in
vivo efficacy evaluation. These investigations are currently on-
going.
Concentration, is the lowest test concentration that kills the microorganism.
TC50 ¼ The concentration that is toxic to 50% of cells.
b
TC50 value previously reported.9 NC ¼ No cytotoxicity observed on Vero cells at
10 mg/mL.

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C.A. Boateng et al. / European Journal of Medicinal Chemistry 46 (2011) 1789e1797
Table 2
Antifungal activities of 3-(substituted-phenylsulfanyl)-1-(5- cyclohexylpentyl)quinolinium iodide.
Compda Rl11
R
IC50/MIC/MFC (
m
g/mL)
Ca
TC50
(
m
g/mL)
S.I.
Cn
Cn
Cg
Ck
Af
aH
bm-F
c m-OMe
d o-Br
CP
CP
CP
CP
CP
CP
CP
CP
CP
CP
CP
CP
CP
CP
CP
CP
0.5/1.3/2.5
0.5/0.6/2.5
0.4/0.6/2.5
0.3/0.6/1.3
0.3/0.6/1.3
0.2/0.3/0.4
0.2/0.3/1.3
1.1/1.3/10
0.7/1.3/5.0
0.5/1.3/5.0
1.0/1.3/1.3
1.3/2.5/5.0
0.7/1.3/2.5
0.3/0.6/1.3
0.4/0.6/0.6
0.3/0.6/0.6
0.7/1.3/5.0
2.7/5.0/10
2.7/5.0/10
2.7/5.0/10
1.4/2.5/2.5
1.7/5.0/10
1.4/2.5/5.0
1.3/2.5/5.0
3.3/10/10
6.7/20/20
6.2/10/20
4.7/10/20
3.5/10/20
3.9/10/20
1.1/2.5/2.5
1.3/2.5/5.0
0.8/2.5/2.5
0.3/1.3/1.3
15/20/20
12/20/20
16/20/>20
3.2/5.0/10
13/20/20
5.5/10/10
5.5/10/10
12/20/20
13/20/20
6.3/10/20
12/20/>20
>20
0.7/1.3/2.5
0.3/0.6/1.3
0.6/1.3/1.3
0.3/0.6/1.3
0.6/1.3/1.3
0.4/0.6/1.3
0.5/0.6/1.3
0.7/2.5/5.0
1.4/5.0/10
2.3/5.0/10
4.4/10/10
5.1/10/20
1.5/5.0/5.0
1.1/1.3/1.3
1.2/2.5/2.5
1.3/2.5/5.0
0.9/2.5/2.5
8.6/10/>20
5.3/10/20
5.5/10/20
4.6
6.6
4.5
9.7
4.0
3.7
2.8
10
NC
NC
9.3
NC
NC
NC
NC
NC
6.5b
9.2
13
11
32
13
19
14
9.1
>14
>20
9.3
>7.7
>14
>33
>25
>33
14
2.0/2.5/20
4.8/10/>20
3.5/5.0/5.0
2.7/5.0/5.0
5.0/19/20
19/20/>20
19/20/>20
3.9/10/>20
10/20/>20
7.9/20/>20
1.8/5.0/5.0
2.2/2.5/>20
1.7/2.5/>20
0.7/1.3/5.0
e o-CH3
f m-CH3
g p-CH3
h o-CN
i m-CN
j p-CN
k o-OH
l m-OH
m p-OH
n o-CF3
o m-CF3
p p-CF3
AmB
>20
3.0/5.0/10
4.6/10/10
4.7/10/10
0.6/1.3/2.5
Abbreviations: Cn ¼ Cryptococcus neoformans, Ca ¼ Candida albicans, Cg ¼ Candida glabrata, Ck ¼ Candida krusei, Af ¼ Aspergillus fumigatus, AmB ¼ Amphotericin B. R ¼ CP ¼ 5-
Cyclohexylpentyl-.
a
All compounds were subjected to CHN analysis and each passed within 0.4% of the theoretical value. IC50 ¼ The concentration that affords 50% inhibition of growth;
MIC ¼ Minimum inhibitory concentration, is the lowest test concentration that allows no detectable growth. MFC ¼ Minimum Fungicidal Concentration, is the lowest test
concentration that kills the microorganism. TC50 ¼ The concentration that is toxic to 50% of cells.
b
TC50 value previously reported NC ¼ No cytotoxicity on Vero cells at 10
m
g/mL. Selectivity Index (S.I.) ¼ TC50(Vero cells)/IC50 (Cn).
3. Conclusion
Microlab, Inc., Norcross, GA, and were within 0.4% of the theory
unless otherwise noted.
By opening the benzo[b]thiophene ring and replacing the N-
methyl group with N- -phenylpentyl or -cyclohexylpentyl groupto
form substituted 3-(phenylthio)quinolinium compounds, we have
obtained potencies as high as 300-fold (cf, cryptolepine ¼ 250 g/mL
vs 11p ¼ 0.8 g/mL for C. albicans) over the starting tetracyclic parent.
u
u
4.2. Procedure for the synthesis of 3-iodoquinoline, 5
m
The method of Klapars was used [6]. A mixture of 3-bromoqui-
noline (9.8 g, 47.3 mmol), CuI (0.45 g, 2.4 mmol), NaI (14.2 g,
94.5 mmol), N, N-dimethylethylenediamine (0.5 mL) and dioxane
(47.3 mL) was stirred and heated to 110 ꢀC and allowed to reflux
under N2 for 48 h. The reaction was monitored by TLC till the
conversion reached 100%. The resulting mixture was allowed to cool
to rt, diluted with 30% aqueous NH3 (20 mL), then diluted with
distilled H2O and extracted with EtOAc (3 ꢂ 30 mL). The organic
layer was washed with brine (100 mL), dried over anhydrous Na2SO4
and concentrated by rotary evaporation at reduced pressure to yield
the pure product in quantitative yield as a pale yellow solid. Yield
m
Several of these analogs (11a-p) have also demonstrated significantly
higher activity against C. krusei than the other pathogens tested. In
addition, unlike their tetracyclic counterparts, these ring-opened
analogs demonstrated fungicidal activity as well. The potential of
these compounds to induce toxicity in Vero cells was also investi-
gated. Except for the unsubstituted, methyl-substituted (11e-f) and o-
OMe(11c) substitutedanalogsinthecyclohexylpentylseries, allofthe
compounds showed better cytotoxicity profile in Vero cells than
amphotericin B and in fact most of them showed no cytotoxicity
at10
mg/mL. In particular, the trifluoromethyl substituted analogs
12 g, 100%. 1HNMR (CDCl3):
1H), 8.08e8.04 (m, 1H), 7.76e7.69 (m, 2H), 7.59e7.53 (m, 1H).
d
9.03 (d, 1H, J ¼ 2.4 Hz), 8.54e8.53 (m,
(11n-p) have selectivity indices over 2-fold better than those of
amphotericin B in C. neoformans.
4. Experimental section
4.3. General procedure for the synthesis of 3-[(substituted)
phenylthio]quinoline, 6a-p
4.1. Chemistry
The method of Kwong was used [7]. A mixture of Cu (I) iodide
(20 mg, 0.10 mmol), K2CO3 (540 mg, 3.92 mmol), 3-iodoquinoline
(500 mg, 1.96 mmol), substituted benzenethiol (0.21 mL,
1.96 mmol), ethylene glycol (0.22 mL, 3.92 mmol) and 2-propanol
(2 mL) was heated at 80 ꢀC and allowed to reflux under N2 for 30 h.
After cooling to rt, the mixture was diluted with distilled H2O
(20 mL) and then extracted with EtOAc (3 ꢂ 15 mL). The pooled
organic layer was washed with brine (50 mL), dried over anhydrous
Na2SO4 and concentrated by rotary evaporation at reduced pres-
sure to provide a crude product. The crude product was purified by
column chromatography on silica gel using hexane: EtOAc (9.8: 0.2)
All reagents were purchased from SigmaeAldrich, Fisher
Scientific or Alfa Aesar and were used without further purification.
Flash chromatography was performed with Davisil grade 634 silica
gel. Analytical thin layer chromatography (TLC) was carried out on
Merck TLC plates coated with silica gel 60 F254 (0.25 mm layer
thickness); visualization was carried out using a UV lamp (254 nm).
Melting points were determined on an Electrothermal MEL-TEMPÒ
3.0 device and are uncorrected. Nuclear Magnetic Resonance
(1HNMR) spectra were obtained on a Varian 300 MHz Mercury
NMR Spectrometer. Elemental analyses were carried out by Atlantic

C.A. Boateng et al. / European Journal of Medicinal Chemistry 46 (2011) 1789e1797
1793
to afford 3-[(substituted)phenylthio]quinoline. A typical reaction
yield was found to be 90e95%.
4.3.14. 3-(3-bromophenylthio)quinoline, 6n
Yield 90%; 1HNMR (CDCl3):
d
8.83 (s, 1H), 8.17 (d, 1H, J ¼ 1.8 Hz),
8.12e8.09 (m, 1H), 7.77e7.70 (m, 2H), 7.60e7.54 (m, 1H), 7.47 (t, 1H,
J ¼ 1.8 Hz), 7.41e7.37 (m, 1H), 7.27e7.23 (m, 1H), 7.19e7.14 (m, 1H).
4.3.1. 3-(2-fluorophenylthio)quinoline, 6a
Yield 94%; 1HNMR (CDCl3):
(m, 2H), 7.70e7.64 (m, 2H), 7.54e7.48 (m, 1H), 7.36e7.26 (m, 2H),
7.14e7.05 (m, 2H).
d
8.15 (d, 1H, J ¼ 1.8 Hz), 8.09e8.05
4.3.15. 3-(4-bromophenylthio)quinoline, 6o
Yield 92%; 1HNMR (CDCl3):
2H), 7.75e7.69 (m, 2H), 7.59e7.53 (m, 1H), 7.46e7.42 (m, 2H),
7.26e7.21 (m, 2H).
d
8.81 (d, 1H, J ¼ 2.4 Hz), 8.10 (m,
4.3.2. 3-(3-fluorophenylthio)quinoline, 6b
Yield 90%; 1HNMR (CDCl3):
J ¼ 1.8 Hz), 8.12e8.09 (m, 1H), 7.78e7.71 (m, 2H), 7.61e7.55 (m, 1H),
7.31e7.24 (m, 1H), 7.11e7.08 (m, 1H), 7.03e6.92 (m, 2H).
d
8.84 (d, 1H, J ¼ 2.1 Hz), 8.19 (d, 1H,
4.3.16. 3-(phenylthio)quinoline, 6p
Yield 92%; 1HNMR (CDCl3):
d 8.81 (s, 1H), 8.08e8.06 (m, 2H),
7.71e7.25 (m, 8H).
4.3.3. 3-(4-fluorophenylthio)quinoline, 6c
Yield 95%; 1HNMR (CDCl3):
d 8.77 (s,1H), 8.08e8.05 (m,1H), 7.97
4.4. General procedure for the synthesis of 3-(hydroxyphenylthio)
quinoline 7a-c
(d, 1H, J ¼ 2.4 Hz), 7.71e7.66 (m, 2H), 7.57e7.51 (m, 1H), 7.47e7.42
(m, 2H), 7.09e7.04 (m, 2H).
A mixture of 3-(methoxyphenylthio)quinoline (6j-l) (100 mg,
0.37 mmol) and pyridine hydrochloride (864 mg, 7.49 mmol) was
stirred for 6 h at 220 ꢀC. The resulting mixture was diluted with
distilled H2O and extracted with EtOAc (3 ꢂ 15 mL). The pooled
organic layer was washed with brine (50 mL), dried over anhydrous
Na2SO4 and concentrated by rotary evaporation at reduced pres-
sure. The crude product was subjected to column chromatography
on silica gel (hexane/EtOAc, 7: 3) to afford 3-(hydroxyphenylthio)
quinoline as a solid. Yield 50e60%.
4.3.4. 3-(2-trifluoromethylphenylthio)quinoline, 6d
Yield 94%; 1HNMR (CDCl3):
d
8.82 (d, 1H, J ¼ 2.1 Hz), 8.18 (s, 1H),
8.09 (d, 1H, J ¼ 8.1 Hz), 7.77e7.71 (m, 3H), 7.60e7.55 (m, 1H),
7.39e7.34 (m, 2H), 7.26e7.23 (m, 1H).
4.3.5. 3-(3-trifluoromethylphenylthio)quinoline, 6e
Yield 95%; 1HNMR (CDCl3):
8.13 (d, 1H, J ¼ 8.1 Hz), 7.78e7.72 (m, 2H), 7.62e7.39 (m, 5H).
d
8.85 (s, 1H), 8.21 (d, 1H, J ¼ 1.8 Hz),
4.3.6. 3-(4-trifluoromethylphenylthio)quinoline, 6f
Yield 97%; 1HNMR (CDCl3):
d
8.87 (d, 1H, J ¼ 1.8 Hz), 8.28 (d, 1H,
4.4.1. 3-(2-hydroxyphenylthio)quinoline, 7a
Yield 51%; 1HNMR (DMSO-d6):
d 8.72(s, 1H), 8.04 (d, 1H,
J ¼ 2.1 Hz), 8.12 (d, 1H, J ¼ 8.4 Hz), 7.78 (t, 2H, J ¼ 8.4 Hz), 7.60 (t, 1H,
J ¼ 8.7 Hz), 7.70e7.40 (m, 6H), 7.10 (d, 1H, J ¼ 7.8 Hz), 7.62e7.00 (t,
J ¼ 6.9 Hz), 7.52 (d, 2H, J ¼ 8.7 Hz), 7.36e7.28 (m, 2H).
1H, J ¼ 15 Hz), 6.54 (s, 1H).
4.3.7. 3-(2-methylphenylthio)quinoline, 6g
Yield 91%; 1HNMR (CDCl3):
d 8.74 (s, 1H), 8.07e8.04 (m,1H), 7.83
4.4.2. 3-(3-hydroxyphenylthio)quinoline, 7b
Yield 60%; 1HNMR (DMSO-d6):
d 9.57 (s, 1H), 8.75 (d, 1H,
(d, 1H, J ¼ 2.1 Hz), 7.66e7.61 (m, 2H), 7.51e7.45 (m, 1H), 7.35e7.12
J ¼ 2.1 Hz), 8.37 (d, 1H, J ¼ 2.1 Hz), 8.02e7.73 (m, 2H), 7.78e7.73 (m,
(m, 4H), 2.40 (s, 3H).
1H), 7.64e7.59 (m, 1H), 7.19e7.14 (m, 1H), 6.80e6.68 (m, 3H).
4.3.8. 3-(3-methylphenylthio)quinoline, 6h
Yield 96%; 1HNMR (CDCl3):
d
8.81 (d, 1H, J ¼ 2.1 Hz), 8.05 (t, 2H,
4.4.3. 3-(4-hydroxyphenylthio)quinoline, 7c
Yield 57%; 1HNMR (DMSO-d6):
d 9.84 (s, 1H), 8.66 (d, 1H,
J ¼ 2.4 Hz), 7.71e7.65 (m, 2H), 7.55e7.50 (m, 1H), 7.25e7.20 (m, 3H),
J ¼ 2.4 Hz), 7.98e7.94 (m, 1H), 7.84e7.81 (m, 1H), 7.78e7.73 (m, 1H),
7.71e7.65 (m, 1H), 7.58e7.53 (m, 1H), 7.41e7.36 (m, 2H), 6.88e6.83
(m, 2H).
7.12e7.09 (m, 1H), 2.39 (s, 3H).
4.3.9. 3-(4-methylphenylthio)quinoline, 6i
Yield 92%; 1HNMR (CDCl3):
(m, 1H), 7.95 (d, 1H, J ¼ 3.0 Hz), 7.67e7.62 (m, 2H), 7.52e7.49 (m,
1H), 7.35e7.32 (m, 2H), 7.17 (d, 2H, J ¼ 8.1 Hz), 2.39 (s, 3H).
d
8.78 (d, 1H, J ¼ 2.4 Hz), 8.06e8.03
4.5. General procedure for the synthesis of S-quinolin-3-yl
benzothioate 8
The method of Sawada was used [8]. A mixture of 3-iodoqui-
noline (5.4 g, 21.2 mmol), thiobenzoic acid (4.5 g, 32.60 mmol), CuI
(400 mg, 2.1 mmol), 1,10-phenanthroline (780 mg, 4.3 mmol), N, N-
diisopropylethylamine (10 mL, 43.00 mmol) in toluene (3 mL) was
refluxed under N2 for 24 h. After cooling to room temperature, the
mixture was directly purified without performing liquideliquid
separation through column chromatography on silica gel (hexane/
EtOAc, 9.6: 0.4) to afford S-quinolin-3-yl benzothioate. Yield 5.17 g,
4.3.10. 3-(2-methoxyphenylthio)quinoline, 6j
Yield 91%; 1HNMR (CDCl3,):
d
8.80 (d, 1H, J ¼ 2.1 Hz), 8.09e8.04
(m, 2H), 7.72e7.66 (m, 2H), 7.56e7.50 (m, 1H), 7.35e7.20 (m, 2H),
6.96e6.91 (m, 2H), 3.86 (s, 3H).
4.3.11. 3-(3-methoxyphenylthio)quinoline, 6k
Yield 92%; 1HNMR (CDCl3):
(m, 2H), 7.74e7.67 (m, 2H), 7.57e7.52 (m, 1H), 7.27e7.21 (m, 1H),
6.97e6.91 (m, 2H), 6.85e6.81 (m, 1H), 3.76 (s, 3H).
d
8.83 (d, 1H, J ¼ 2.4 Hz), 8.09e8.04
90%; 1HNMR (CDCl3):
d 8.89 (1H, s), 8.38 (1H, brs), 8.16 (1H, d,
J ¼ 8.4 Hz), 8.05 (2H, m), 7.85 (1H, d, J ¼ 8.4 Hz), 7.80 (1H, m), 7.63
4.3.12. 3-(4-methoxyphenylthio)quinoline, 6l
(2H, m), 7.52 (2H, m).
Yield 94%; 1HNMR (CDCl3):
d
8.73 (d, 1H, J ¼ 2.4 Hz), 8.05e8.01
(m, 1H), 7.80 (d, 1H, J ¼ 2.1 Hz), 7.65e7.59 (m, 2H), 7.50e7.43 (m,
4.6. General procedure for the synthesis of substituted-(quinolin-3-
ylsulfanyl)-benzonitrile 9a-c
3H), 6.93e6.90 (m, 2H), 3.81 (s, 3H).
4.3.13. 3-(2-bromophenylthio)quinoline, 6m
The method of Deng was used [13]. A mixture of S-quinolin-3-yl
benzothioate (250 mg, 0.94 mmol), 2-iodobenzonitrile (280 mg,
1.22 mmol), ethylene glycol (0.11 mL, 1.88 mmol), Cu (I) iodide
(89 mg, 0.47 mmol), K2CO3 (360 mg, 2.59 mmol) in N, N-
Yield 95%; 1HNMR (CDCl3):
d
8.86 (d, 1H, J ¼ 2.1 Hz), 8.22 (d, 1H,
J ¼ 2.4 Hz), 8.14e8.10 (m, 1H), 7.79e7.72 (m, 2H), 7.63e7.55 (m, 2H),
7.21e7.07 (m, 2H), 7.04e7.00 (m, 1H).

1794
C.A. Boateng et al. / European Journal of Medicinal Chemistry 46 (2011) 1789e1797
dimethylacetamide (4 mL) was heated at 110 ꢀC for 48 h under N2.
The resulting mixture was diluted with EtOAc (3 ꢂ 20 mL), washed
with brine (50 mL). The organic layer was dried over Na2SO4, and
filtered. The filtrate was concentrated in vacuo and followed by
column chromatography on silica gel to afford substituted-(qui-
nolinylthio)benzonitrile. Yield 222 mg, 80e90%.
(m, 2H), 1.43e1.37 (m, 2H). Anal. Calcd for C26H25FINS: C 58.98; H
4.76; N 2.65. Found: C 58.80; H 4.76; N 2.66.
4.7.5. 3-(2-methoxyphenylsulfanyl)-1-(5-phenylpentyl)
quinolinium iodide, 10e
Yield 186 mg, 92%; Mp 121e124 ꢀC; 1HNMR (CD3OD):
d 9.3 (d,
1H, J ¼ 2.1 Hz), 8.7 (d,1H, J ¼ 1.5 Hz), 8.45 (d,1H, J ¼ 9 Hz), 8.25e8.14
(m, 2H), 7.99e7.94 (m, 1H), 7.62e7.52 (m, 2H), 7.23e7.06 (m, 7H),
5.02 (t, 2H, J ¼ 6.9 Hz), 3.78 (s, 3H), 2.6 (t, 2H, J ¼ 7.2 Hz), 2.09e2.00
(m, 2H), 1.71e1.63 (m, 2H), 1.43e1.37 (m, 2H).Anal. Calcd for
C27H28OINS: C 59.89; H 5.21; N 2.59. Found: C 59.84; H 5.17; N 2.63.
4.6.1. 2-(quinolin-3-ylsulfanyl)-benzonitrile, 9a
Yield 90%; 1HNMR (CDCl3):
d
8.86 (d, 1H, J ¼ 1.8 Hz), 8.32 (d, 1H,
J ¼ 2.4 Hz), 8.13 (d, 1H, J ¼ 8.4 Hz), 7.81e7.23 (m, 7H).
4.6.2. 3-(quinolin-3-ylsulfanyl)-benzonitrile, 9b
Yield 84%; 1HNMR (CDCl3):
(m, 1H), 8.15e8.11 (m, 1H), 7.80e7.36 (m, 7H).
d
8.85 (d, 1H, J ¼ 2.4 Hz), 8.27e8.26
4.7.6. 3-(3-methoxyphenylsulfanyl)-1-(5-phenylpentyl)
quinolinium iodide, 10f
Yield 166 mg, 82%; Mp 158e159 ꢀC; 1HNMR (CD3OD):
d 9.34 (d,
4.6.3. 4-(quinolin-3-ylsulfanyl)-benzonitrile, 9c
1H, J ¼ 1.5 Hz), 8.89 (s, 1H), 8.45 (d, 1H, J ¼ 9 Hz), 8.28e8.17 (m, 2H),
8.02e7.96 (m, 1H), 7.44e7.21 (m, 1H), 7.22e7.04 (m, 8H), 5.02 (t, 2H,
J ¼ 7.2 Hz), 3.80 (s, 3H), 2.59 (t, 2H, J ¼ 7.2 Hz), 2.10e2.04 (m, 2H),
1.70e1.65 (m, 2H), 1.42e1.39 (m, 2H). Anal. Calcd for C27H28OINS: C
59.89; H 5.21; N 2.59. Found: C 59.82; H 5.28; N 2.64.
Yield 87%; 1HNMR (CDCl3):
d
8.88 (d, 1H, J ¼ 2.4 Hz), 8.35e8.34
(m, 1H), 8.16e8.13 (m, 1H), 7.82e7.49 (m, 5H), 7.25e7.22 (m, 2H).
4.7. General procedure for the synthesis of 3-(substituted-
phenylsulfanyl)-1-(5-phenylpentyl) quinolinium iodide, 10a-p
4.7.7. 3-(4-methoxyphenylsulfanyl)-1-(5-phenylpentyl)
3-(Substituted-phenylthio)quinoline (100 mg, 0.39 mmol) was
added to 1-(5-iodopentyl)benzene (130 mg, 0.470 mmol) in tetra-
methylene sulfone (0.5 mL). The mixture was heated at 110 ꢀC for
12e16 h in a sealed pressure tube. After cooling to rt, EtOAc (15 mL)
was added to precipitate the solid. The precipitate was collected,
washed with additional EtOAc and dried to a powdery product, 3-
(substituted-phenylsulfanyl)-1-(5-phenylpentyl)quinolinium iodide.
quinolinium iodide, 10g
Yield 180 mg, 89%; Mp 164e166 ꢀC; 1HNMR (CD3OD):
d 9.24 (d,
1H, J ¼ 2.1 Hz), 8.65 (d, 1H, J ¼ 1.8 Hz), 8.41 (d, 1H, J ¼ 9 Hz),
8.21e8.12 (m, 2H), 7.98e7.92 (m, 1H), 7.63e7.60 (m, 2H), 7.20e7.17
(m, 2H), 7.14e7.08 (m, 5H), 4.99 (t, 2H, J ¼ 7.2 Hz), 3.85 (s, 3H), 2.59
(t, 2H, J ¼ 7.5 Hz), 2.08e2.00 (m, 2H), 1.70e1.65 (m, 2H), 1.40e1.35
(m, 2H). Anal. Calcd for C27H28OINS: C 59.89; H 5.21; N 2.59. Found:
C 59.60; H 5.22; N 2.62.
4.7.1. 3-(phenylsulfanyl)-1-(5-phenylpentyl)quinolinium iodide,
10a
4.7.8. 3-(2-bromophenylsulfanyl)-1-(5-phenylpentyl)quinolinium
Yield 162 mg, 75%; Mp 166e167 ꢀC; 1HNMR (DMSO-d6): 9.69 (1H,
s), 9.17 (1H, s), 9.57 (1H, d, J ¼ 9.0Hz), 8.39(1H, d, J ¼ 8.0 Hz), 8.23 (1H,
t, J ¼ 7.5 Hz), 8.02(1H, t, J¼ 7.5Hz), 7.50 (5H, m), 7.24 (2H, t, J ¼7.0 Hz),
7.15 (3H, m), 5.02 (2H, t, J ¼ 7.4 Hz), 2.54 (2H, t, J ¼ 7.4 Hz), 1.98 (2H,
m), 1.60 (2H, m), 1.39 (2H, m). Anal. Calcd for C26H26INS$0.2H2O: C
60.63; H 5.09; N 2.72. Found: C 60.60; H 5.02; N 2.73.
iodide, 10h
Yield 102 mg, 55%; Mp 110e112 ꢀC; 1HNMR (CD3OD):
d 9.43(d,1H,
J ¼ 2.1 Hz), 8.98 (s, 1H), 8.5 (d, 1H, J ¼ 9 Hz), 8.33e8.22 (m, 2H),
8.05e8.00 (m, 1H), 7.81e7.77 (m, 1H), 7.59e7.56 (m, 1H), 7.48e7.35
(m, 2H), 7.22e7.07 (m, 5H), 5.05 (t, 2H, J ¼ 7.2 Hz), 2.6 (t, 2H,
J ¼ 7.5 Hz), 2.11e2.06 (m, 2H), 1.72e1.66 (m, 2H), 1.43e1.37 (m, 2H).
Anal. CalcdforC26H25BrINS:C52.90;H4.27;N2.37. Found:C52.96;H
4.32; N 2.42.
4.7.2. 3-(2-fluorophenylsulfanyl)-1-(5-phenylpentyl)quinolinium
iodide, 10b
Yield 109 mg, 53%; Mp 134e136 ꢀC; 1HNMR (CD3OD):
d
9.47 (d,
4.7.9. 3-(3-bromophenylsulfanyl)-1-(5-phenylpentyl)quinolinium
1H, J ¼ 2.1 Hz), 8.93 (d, 1H, J ¼ 0.9 Hz), 8.47 (d, 1H, J ¼ 9 Hz),
8.30e8.19 (m, 2H), 8.03e7.97 (m, 1H), 7.71e7.65 (m, 1H), 7.59e7.56
(m, 1H), 7.36e7.29 (m, 2H), 7.23e7.17 (m, 2H), 7.14e7.09 (m, 3H),
5.04 (t, 2H, J ¼ 7.5 Hz) 2.60 (t, 2H, J ¼ 7.2 Hz), 2.10e2.05 (m, 2H),
1.74e1.64 (m, 2H), 1.46e1.38 (m, 2H). Anal. Calcd for C26H25FINS: C
58.98; H 4.76; N 2.65. Found: C 58.75; H 4.72; N 2.66.
iodide, 10i
Yield 115 mg, 62%; Mp 156e157 ꢀC; 1HNMR (CD3OD):
d 9.45 (d,
1H, J ¼ 1.8 Hz), 9.04 (d, 1H, J ¼ 1.5 Hz) 8.47 (d, 1H, J ¼ 9.3 Hz),
8.33e8.21 (m, 2H), 8.05e7.99 (m, 1H), 7.79e7.78 (m, 1H), 7.65e7.61
(m, 1H), 7.57e7.54 (m, 1H) 7.42e7.36 (m, 1H), 7.22e7.07 (m, 5H),
5.03 (t, 2H, J ¼ 7.5 Hz), 2.6 (t, 2H, J ¼ 7.5 Hz), 2.12e2.05 (m, 2H),
1.72e1.67 (m, 2H), 1.38e1.43(m, 2H). Anal. Calcd for C26H25BrINS: C
52.90; H 4.27; N 2.37. Found: C 52.61; H 4.22; N 2.33.
4.7.3. 3-(3-fluorophenylsulfanyl)-1-(5-phenylpentyl)quinolinium
iodide, 10c
Yield 120 mg, 58%; Mp 148e149 ꢀC; 1HNMR (CD3OD):
d
9.43 (d,
4.7.10. 3-(4-bromophenylsulfanyl)-1-(5-phenylpentyl)quinolinium
1H, J ¼ 2.1 Hz), 9.0 (s, 1H), 8.45 (d, 1H, J ¼ 9 Hz), 8.29e8.173 (m, 2H),
8.0e7.95 (m, 1H), 7.50e7.42 (m, 1H), 7.36e7.30 (m, 2H), 7.21e7.04
(m, 6H), 4.99 (t, 2H, J ¼ 7.5 Hz), 2.56 (t, 2H, J ¼ 7.2 Hz), 2.07e1.99 (q,
2H, J ¼ 7.2 Hz) 1.7e1.6 (m, 2H), 1.40e1.34 (q, 2H, J ¼ 7.8 Hz). Anal.
Calcd for C26H25FINS: C 58.98; H 4 0.76; N 2.65. Found: C 59.08; H
4.80; N 2.61.
iodide, 10j
Yield 130 mg, 70%; Mp 178e179 ꢀC; 1HNMR (CD3OD):
d 9.4 (d,
1H, J ¼ 2.1 Hz), 8.97 (s, 1H), 8.46 (d, 1H, J ¼ 8.4 Hz), 8.31e8.19 (m,
2H), 8.0 (t, 1H, J ¼ 7.5 Hz), 7.67e7.63 (m, 2H), 7.65 (d, 2H, J ¼ 9.0 Hz),
7.51 (d, 2H, J ¼ 9.0 Hz), 7.14e7.08 (m, 3H), 5.02 (t, 2H, J ¼ 7.2 Hz), 2.6
(t, 2H, J ¼ 7.8 Hz), 2.10e2.00 (m, 2H), 1.71e1.66 (m, 2H), 1.42e1.36
(m, 2H). Anal. Calcd for C26H25BrINS: C 52.90; H 4.27; N 2.37. Found:
C 52.76; H 4.28; N 2.49.
4.7.4. 3-(4-fluorophenylsulfanyl)-1-(5-phenylpentyl)quinolinium,
iodide 10d
Yield 168 mg, 81%; Mp 175e176 ꢀC; 1HNMR (CD3OD):
d
8.82 (s,
4.7.11. 3-(2-Trifluoromethyl-phenylsulfanyl)-1-(5-phenylpentyl)
quinolinium iodide, 10k
1H), 8.45 (d, 1H, J ¼ 9 Hz), 8.27e8.16 (m, 2H), 8.01e7.95 (m, 1H),
7.73e7.68 (m, 2H), 7.36 (d, 1H, J ¼ 2.1 Hz), 7.30e7.08 (m, 7H), 5.02 (t,
2H, J ¼ 7.8 Hz), 2.60 (t, 2H, J ¼ 7.2 Hz), 2.10e2.00 (m, 2H), 1.72e1.66
Yield 60 mg, 32%; Mp 143e144 ꢀC; 1HNMR (CD3OD):
d
9.44 (d,1H,
J ¼ 1.8 Hz), 8.93 (s, 1H), 8.48 (d, 1H, J ¼ 9 Hz), 8.31e8.21 (m, 2H),

C.A. Boateng et al. / European Journal of Medicinal Chemistry 46 (2011) 1789e1797
1795
8.04e7.92 (m, 2H), 7.66e7.69 (m, 3H), 7.17e7.22 (m, 2H), 7.08e7.14
4.8.2. 3-(3-fluorophenylsulfanyl)-1-(5-cyclohexylpentyl)
(m, 3H), 5.04 (t, 2H, J ¼ 7.2 Hz), 2.60 (t, 2H, J ¼ 7.2 Hz) 2.15e2.05 (m,
2H), 1.74e1.64 (m, 2H), 1.46e1.38 (m, 2H). Anal. Calcd for
C27H25F3INS: C 55.96; H 4.35; N 2.42. Found: C 55.88; H 4.34; N 2.40.
quinolinium iodide, 11b
Yield 132 mg, 58%; Mp 141e142 ꢀC; 1HNMR (DMSO-d6):
d
9.48
(d, 1H, J ¼ 1.8 Hz), 9.06e8.95 (m, 1H), 8.52e8.48 (m, 1H), 8.32e8.19
(m, 2H), 8.04e7.97 (m, 1H), 7.73e7.21 (m, 4H), 5.05 (t, 2H,
J ¼ 7.5 Hz), 2.14e2.06 (m, 2H),1.71e1.67 (m, 5H),1.37e1.18 (m,10H),
0.92e0.85 (m, 2H). Anal. Calcd for C26H31FINS: C 58.32; H 5.83; N
2.62. Found: C 58.23; H 5.80; N 2.55.
4.7.12. 3-(3-Trifluoromethyl-phenylsulfanyl)-1-(5-phenylpentyl)
quinolinium iodide, 10l
Yield 79.40 mg, 56%; Mp 151e152 ꢀC; 1HNMR (CD3OD):
d 9.51 (d,
1H, J ¼ 1.8 Hz), 9.08 (s, 1H), 8.52 (d, 1H, J ¼ 9 Hz), 8.33e8.22 (m, 2H),
8.02 (t, 1H, J ¼ 8.1 Hz), 7.93 (s, 1H), 7.77e7.75 (m, 2H), 7.66 (t, 1H,
J ¼ 7.2 Hz), 7.22e7.08 (m, 5H), 5.04 (t, 2H, J ¼ 7.5 Hz), 2.60 (t, 2H,
J ¼ 7.5 Hz), 2.11e2.06 (m, 2H), 1.72e1.67 (m, 2H), 1.48e1.40 (m, 2H).
Anal. Calcd for C27H25F3INS: C 55.96; H 4.35; N 2.42. Found: C
55.92; H 4.31; N 2.44.
4.8.3. 3-(2-bromophenysulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11c
Yield 100 mg, 59%; Mp 157e158 ꢀC; 1HNMR (CD3OD):
d 9.46 (d,
1H, J ¼ 2.1 Hz), 8.99 (s,1H), 8.54 (d,1H, J ¼ 8.7 Hz), 8.32e8.22 (m, 2H),
8.01(t,1H, J¼ 7.5Hz), 7.80e7.77(m,1H), 7.65e7.62(m,1H), 7.49e7.36
(m, 2H), 5.02 (t, 2H, J ¼ 7.5 Hz), 2.09e2.05 (m, 2H),1.70e1.66 (m, 5H),
1.38e1.12 (m,10H), 0.91e0.84 (m, 2H). Anal. Calcd for C26H31BrINS: C
52.36; H 5.24; N 2.35. Found: C 52.18; H 5.24; N 2.27.
4.7.13. 3-(4-Trifluoromethyl-phenylsulfanyl)-1-(5-phenylpentyl)
quinolinium iodide, 10m
Yield 29 mg, 26%; Mp 131e132 ꢀC; 1HNMR (CD3OD):
d 9.54 (d,
1H, J ¼ 1.8 Hz), 9.19 (s, 1H), 8.51 (d, 1H, J ¼ 9 Hz), 8.37e8.25 (m, 2H),
8.04 (t, 1H, J ¼ 7.5 Hz), 7.74e7.65 (m, 4H), 7.08e7.22 (m, 5H), 5.05 (t,
2H, J ¼ 7.5 Hz), 2.60 (t, 2H, J ¼ 7.5 Hz), 2.13e2.07 (m, 2H), 1.72e1.67
(m, 2H), 1.45e1.39 (m, 2H). Anal. Calcd for C27H25F3INS: C 55.96; H
4.35; N 2.42. Found: C 55.72; H 4.32; N 2.48.
4.8.4. 3-(3-methoxyphenylsulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11d
Yield 191 mg, 93%; Mp 147e148 ꢀC; 1HNMR (DMSO-d6):
d 9.37
(d, 1H, J ¼ 2.1 Hz), 8.91 (s, 1H), 8.49 (d, 1H, J ¼ 8.7 Hz), 8.27e8.17 (m,
2H), 7.98 (t, 1H, J ¼ 7.5 Hz), 7.42 (t, 1H, J ¼ 8.1 Hz), 7.19e7.17 (m, 2H),
7.08e7.05 (m,1H), 5.02 (t, 2H, J ¼ 7.2 Hz), 3.81 (s, 3H), 2.07e2.02 (m,
2H), 1.70e1.67 (m, 5H), 1.25e1.17 (m, 10H), 0.88e0.85 (m, 2H). Anal.
Calcd for C27H34INOS: C 59.23; H 6.26; N 2.56. Found: C 59.15; H
6.22; N 2.53.
4.7.14. 3-(2-Methyl-phenysulfanyl)-1-(5-phenylpentyl)quinolinium
iodide, 10n
Yield 156 mg, 75%; Mp 166e167 ꢀC; 1HNMR (CD3OD):
d 9.28 (d,
1H, J ¼ 2.1 Hz), 8.59 (s, 1H), 8.45 (d, 1H, J ¼ 8.7 Hz), 8.21e8.14 (m,
2H), 7.96 (t,1H, J ¼ 7.5 Hz), 7.60 (d,1H, J ¼ 7.5 Hz), 7.47e7.46 (m, 2H),
7.37e7.32 (m, 1H), 7.22e7.07 (m, 5H), 5.01 (t, 2H, J ¼ 7.2 Hz), 2.60 (t,
2H, J ¼ 7.2 Hz), 2.45 (s, 3H), 2.14e2.04 (m, 2H), 1.71e1.66 (m, 2H),
1.41e1.36 (m, 2H). Anal. Calcd for C27H28INS: C 61.71; H 5.37; N 2.67.
Found: C 61.44; H 5.36; N 2.58.
4.8.5. 3-(2-trifluoromethyl-phenylsulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11e
Yield 101 mg, 53%; Mp 172e173 ꢀC; 1HNMR (CD3OD):
d 9.48 (d,
1H, J ¼ 2.1 Hz), 8.95 (d,1H, J ¼ 1.5 Hz), 8.54 (d,1H, J ¼ 9 Hz), 8.31e8.21
(m, 2H), 8.03e7.92 (m, 1H), 7.95e7.92 (m, 1H), 7.76e7.67 (m, 3H),
5.07 (t, 2H, J ¼ 7.5 Hz), 2.09e2.04 (m, 2H), 1.71e1.67 (m, 5H),
1.39e1.18 (m,10H), 0.88e0.84 (m, 2H). Anal. Calcd for C27H31F3INS: C
55.39; H 5.34; N 2.39. Found: C 55.32; H 5.43; N 2.42.
4.7.15. 3-(3-Methyl-phenysulfanyl)-1-(5-phenylpentyl)quinolinium
iodide, 10o
Yield194mg, 93%;Mp175e176 ꢀC;1HNMR(CD3OD):
d9.31(s,1H),
8.83 (s, 1H), 8.46 (d, 1H, J ¼ 8.7 Hz), 8.25e8.16 (m, 2H), 7.97 (t, 1H,
J¼ 7.8Hz), 7.47e7.33 (m, 4H), 7.21e7.07(m, 5H), 5.01(t, 2H, J¼ 7.2Hz),
2.59 (t, 2H, J ¼ 7.5 Hz), 2.37 (s, 3H), 2.09e2.04 (m, 2H), 1.70e1.65 (m,
2H), 1.41e1.36 (m, 2H). Anal. Calcd for C27H28INS$0.3H20: C 61.08; H
5.32; N 2.64. Found: C 61.07; H 5.38; N 2.67.
4.8.6. 3-(3-trifluoromethylphenysulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11f
Yield 54 mg, 28%; Mp 137e140 ꢀC; 1HNMR (CD3OD):
d 9.55 (d,
1H, J ¼ 1.8 Hz), 9.10 (s, 1H), 8.54 (d, 1H, J ¼ 9 Hz), 8.34e8.22 (m, 2H),
8.02 (t,1H, J ¼ 8.1 Hz), 7.94 (s, 1H), 7.85 (t, 1H, J ¼ 7.5 Hz), 7.76 (d, 1H,
J ¼ 7.8 Hz), 7.67 (t, 1H, J ¼ 7.5 Hz), 5.06 (t, 2H, J ¼ 7.8 Hz), 2.07e2.05
(m, 2H), 1.70e1.67 (m, 5H), 1.38e1.17 (m, 10H), 0.91e0.84 (m, 2H).
Anal. Calcd for C27H31F3INS$0.4H20: C 54.71; H 5.27; N 2.36. Found:
C 54.73; H 5.25; N 2.31.
4.7.16. 3-(4-Methyl-phenysulfanyl)-1-(5-phenylpentyl)quinolinium
iodide, 10p
Yield 157 mg, 75%; Mp 179e181 ꢀC; 1HNMR (DMSO-d6):
d 9.60
(d, 1H, J ¼ 2.1 Hz), 9.02 (d, 1H, J ¼ 1.5 Hz), 8.55 (d, 1H, J ¼ 9.0 Hz),
8.36e8.34 (m,1H), 8.22e8.16 (m, 1H), 7.98 (t,1H, J ¼ 7.8 Hz), 7.48 (d,
2H, J ¼ 7.8 Hz), 7.31e7.11(m, 7H), 5.01 (t, 2H, J ¼ 7.2 Hz), 2.56e2.40
(m, 2H), 2.33 (s, 3H), 2.01e1.91 (m, 2H), 1.64e1.54 (m, 2H),
1.40e1.30 (m, 2H). Anal. Calcd for C27H28INS: C 61.71; H 5.37; N
2.67. Found: C 61.83; H 5.47; N 2.80.
4.8.7. 3-(4-trifluoromethyl-phenylsulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11g
Yield 25.8 mg, 13%; Mp 143e144 ꢀC; 1HNMR (CD3OD):
d 9.58 (d,
1H, J ¼ 1.8 Hz), 9.21 (s, 1H), 8.56 (d, 1H, J ¼ 9.0 Hz), 8.37e8.25 (m,
2H), 8.04 (t,1H, J ¼ 7.5 Hz), 7.75e7.76 (m, 4H), 5.07 (t, 2H, J ¼ 7.2 Hz),
2.08e2.05 (m, 2H), 1.70e1.67 (m, 5H), 1.39e1.37 (m, 10H),
0.88e0.84 (m, 2H). Anal. Calcd for C27H31F3INS: C 55.39; H 5.34; N
2.39. Found: C 55.28; H 5.31; N 2.42.
4.8. General procedure for the synthesis of 3-(substituted-
phenylsulfanyl)-1-(5-cyclohexylpentyl) quinolinium iodide, 11a-p
4.8.8. 3-(2-methyl-phenysulfanyl)-1-(5-cyclohexylpentyl)
4.8.1. 3-(phenylsulfanyl)-1-(5-cyclohexylpentyl)quinolinium iodide,
quinolinium iodide, 11h
11a
Yield 48 mg, 32%; Mp 162e163 ꢀC; 1HNMR (DMSO-d6):
d 9.30 (d,
Yield 160 mg, 73%; Mp 174e176 ꢀC; 1HNMR (DMSO-d6):
d
9.66 (d,
1H, J ¼ 1.8 Hz), 8.62 (s, 1H), 8.47 (d, 1H, J ¼ 9.0 Hz), 8.21e8.15 (m,
2H), 7.96 (t, 1H, J ¼ 6.9 Hz), 7.63 (d, 1H, J ¼ 8.1 Hz), 7.48e7.47 (m,
2H), 7.38e7.35 (m, 1H), 5.02 (t, 2H, J ¼ 7.5 Hz), 2.47 (s, 3H),
2.05e2.00 (m, 2H),1.71e1.67 (m, 5H),1.36e1.18 (m,10H), 0.88e0.85
(m, 2H). Anal. Calcd for C27H34INS: C 61.01; H 6.45; N 2.64. Found: C
61.24; H 6.43; N 2.62.
1H, J ¼ 2.1 Hz), 9.16 (d, 1H, J ¼ 1.5 Hz), 8.58 (d, 1H, J ¼ 9.0 Hz), 8.38 (t,
1H, J ¼ 7.2 Hz), 8.25e8.19 (m, 1H), 8.01 (t, 1H, J ¼ 7.5 Hz), 7.56e7.41
(m, 5H), 5.01 (t, 2H, J ¼ 7.2 Hz),1.93e1.91 (m, 2H),1.64e1.61 (m, 5H),
1.30e1.11 (m, 10H), 0.86e0.79 (m, 2H). Anal. Calcd for C26H32INS: C
60.34; H 6.23; N 2.71. Found: C 60.48; H 6.27; N 2.75.

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C.A. Boateng et al. / European Journal of Medicinal Chemistry 46 (2011) 1789e1797
4.8.9. 3-(3-methyl-phenysulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11i
4.8.16. 3-(4-hydroxyphenysulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11p
Yield 135 mg, 71%; Mp 163e164 ꢀC; 1HNMR (CD3OD):
d
9.35 (d,
Yield 30 mg, 26%; Mp 121e122 ꢀC; 1HNMR (DMSO-d6):
d 10.05
1H, J ¼ 2.1 Hz), 8.85 (s, 1H), 8.48 (d, 1H, J ¼ 9.0 Hz), 8.26e8.17 (m,
2H), 7.97 (t,1H, J ¼ 8.1 Hz), 7.49e7.34 (m, 4H), 5.02 (t, 2H, J ¼ 7.2 Hz),
2.38 (s, 3H), 2.07e2.00 (m, 2H), 1.70e1.67 (m, 5H), 1.37e1.17 (m,
10H), 0.91e0.85 (m, 2H). Anal. Calcd for C27H34INS: C 61.01; H 6.45;
N 2.64. Found: C 60.92; H 6.56; N 2.63.
(s, 1H), 9.51 (d, 1H, J ¼ 1.8 Hz), 8.75 (s, 1H), 8.51 (d, 1H, J ¼ 9.0 Hz),
8.32 (d, 1H, J ¼ 7.5 Hz), 8.14 (t, 1H, J ¼ 7.5 Hz), 7.92 (t, 1H, J ¼ 7.8 Hz),
7.47 (d, 2H, J ¼ 8.4 Hz), 6.91 (d, 2H, J ¼ 8.7 Hz), 4.98 (t, 2H,
J ¼ 7.5 Hz), 1.96e1.92 (m, 2H), 1.65e1.61 (m, 5H), 1.28e1.06 (m,
10H), 0.83e0.79 (m, 2H). Anal. Calcd for C26H32INOS: C 58.53; H
6.05; N 2.63. Found: C 58.47; H 5.98; N 2.65.
4.8.10. 3-(4-methyl-phenysulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11j
4.9. Antifungal testing
Yield 121 mg, 64%; Mp 157e158 ꢀC;1HNMR(CD3OD):
d 9.32(d,1H,
J¼ 2.1 Hz), 8.77(d,1H, J¼ 1.8Hz), 8.47 (d,1H, J ¼ 8.4 Hz), 8.23e8.15 (m,
2H), 7.96 (t, 1H, J ¼ 7.8 Hz), 7.57e7.54 (m, 2H), 7.37 (d, 2H, J ¼ 7.8 Hz),
5.02 (t, 2H, J ¼ 7.8 Hz), 2.41 (s, 3H), 2.06e2.02 (m, 2H), 1.71e1.67 (m,
5H),1.38e1.13 (m,10H), 0.92e0.85 (m, 2H). Anal. Calcd for C27H34INS:
C, 61.01; H, 6.45; N, 2.64. Found: C, 61.15; H, 6.53; N, 2.67.
All organisms were obtained from the American Type Culture
Collection (Manassas, VA) and include C. neoformans ATCC 90113,
C. albicans ATCC 90028, C. glabrata ATCC 90030, C. krusei ATCC 6258,
and A. fumigatus ATCC 90906. Susceptibility testing was performed
using a modified version of the CLSI methods [14] as described by
Samoylenko et al. [15]. Amphotericin B (ICN Biomedicals, Ohio) was
used as a positive control in each assay.
4.8.11. 3-(2-cyanophenysulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11k
Briefly, DMSO solutions of samples were serially diluted in
saline and transferred in duplicate to 96-well microplates.
Microbial suspensions were diluted in broth to afford desired
colony forming units/mL according to the 0.5 McFarland Standard
[C. albicans: either Saboraud Dextrose broth (SDB) or RPMI 1640,
C. neoformans: SDB, A. fumigatus: either YM broth (for MICs) or
RPMI-1640 þ 5% Alamar Blue (for IC50 determination). After
adding microbial cultures to the samples affording a final volume
Yield 96.3 mg, 57%; Mp 174e175 ꢀC; 1HNMR (DMSO-d6):
d 9.76
(d, 1H, J ¼ 1.8 Hz), 9.35 (d, 1H, J ¼ 1.8 Hz), 8.61e8.59 (m, 1H),
8.43e8.40 (m, 1H), 8.30e8.25 (m, 1H), 8.07e7.99 (m, 2H),
7.73e7.56 (m, 3H), 5.02 (t, 2H, J ¼ 7.5 Hz), 1.96e1.94 (m, 2H),
1.64e1.61 (m, 5H), 1.29e1.10 (m, 10H), 0.85e0.79 (m, 2H). Anal.
Calcd for C27H31IN2S: C 59.77; H 5.76; N 5.16. Found: C 59.99; H
5.85; N 5.09.
of 200
mL and final test concentration starting with 20 mg/mL,
4.8.12. 3-(3-cyanophenysulfanyl)-1-(5-cyclohexylpentyl)
plates were read prior to and after incubation using either fluo-
rescence at 544ex/590em (A. fumigatus) using the Polarstar Galaxy
Plate Reader (BMG LabTechnologies, Germany) or optical density
at 630 nm using the EL-340 Biokinetics Reader (Bio-Tek Instru-
ments, Vermont). Growth (saline only), solvent, and blank (media
only) controls were included on each test plate. Drug control
amphotericin B (ICN Biomedicals, Ohio) for fungi was included in
each assay. Percent growth was calculated and plotted versus test
concentration to afford the IC50 (sample concentration that affords
50% growth of the organism). The minimum inhibitory concen-
tration (MIC) was determined by visually inspecting the plate, and
is defined as the lowest test concentration that allows no detect-
able growth (for Alamar Blue assays, no color change from blue to
pink).
quinolinium iodide, 11l
Yield 16.7 mg,17%; Mp 162e164 ꢀC; 1HNMR (DMSO-d6):
d 9.71 (d,
1H, J ¼ 2.1 Hz), 9.36 (s, 1H), 8.61 (d, 1H, J ¼ 9.0 Hz), 8.42 (d, 1H,
J ¼ 7.2 Hz), 8.29e8.24 (m, 1H), 8.07e7.97 (m, 2H), 7.85e7.81 (m, 2H),
7.63e7.58(m,1H), 5.00 (t,2H,J¼ 7.2Hz),1.96e1.92(m, 2H),1.64e1.60
(m, 5H), 1.31e1.12 (m, 10H), 0.85e0.78 (m, 2H). Anal. Calcd for
C27H31IN2S: C 59.77; H 5.76; N 5.16. Found: C 59.76; H 5.82; N 5.13.
4.8.13. 3-(4-cyanophenysulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11m
Yield 98.7 mg, 53%; Mp 149e150 ꢀC; 1HNMR (DMSO-d6):
d 9.76
(d, 1H, J ¼ 1.5 Hz), 9.47 (s, 1H), 8.63 (d, 1H, J ¼ 9.0 Hz), 8.44 (d, 1H,
J ¼ 6.9 Hz), 8.32e8.27 (m, 1H), 8.09e8.04 (m, 1H), 7.83e7.81 (m,
2H), 7.60e7.57 (m, 2H), 5.01 (t, 2H, J ¼ 7.2 Hz), 1.96e1.93 (m, 2H),
1.62e1.61 (m, 5H), 1.32e1.11 (m, 10H), 0.86e0.79 (m, 2H). Anal.
Calcd for C27H31IN2S: C 59.77; H 5.76; N 5.16. Found: C 59.93; H
5.81; N 5.17.
4.10. Cytotoxicity assay
In vitro cytotoxicity was determined against mammalian kidney
fibroblast (VERO) cells. The assay was performed in 96-well tissue
culture-treated microplates and compounds were tested up to
4.8.14. 3-(2-hydroxyphenysulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11n
a highest concentration of 10 mg/mL as described earlier [16]. In
Yield 44 mg, 37%; Mp 172e174 ꢀC; 1HNMR (DMSO-d6):
d
10.32
brief, cells (25,000 cells/well) were seeded to the wells of the plate
and incubated for 24 h. Samples were added and plates were again
incubated for 48 h. The number of viable cells was determined by
the neutral red assay as previously described [16]. IC50 values were
determined from dose curves of growth inhibition versus concen-
tration. Doxorubicin was used as a positive control, while DMSO
was used as the negative (vehicle) control.
(s, 1H), 9.55 (s, 1H), 8.84 (s, 1H), 8.53 (d, 1H, J ¼ 9.0 Hz), 8.34e8.31
(m, 1H), 8.15e7.95 (m, 2H), 7.41e7.29 (m, 2H), 7.01e6.86 (m, 2H),
4.99 (t, 2H, J ¼ 6.6 Hz), 1.91e1.90 (m, 2H), 1.64e1.60 (m, 5H),
1.28e1.10 (m, 10H), 0.81e0.78 (m, 2H). Anal. Calcd for C26H32INOS:
C 58.53; H 6.05; N 2.63. Found: C 58.57; H 6.10; N 2.75.
4.8.15. 3-(3-hydroxyphenysulfanyl)-1-(5-cyclohexylpentyl)
quinolinium iodide, 11o
Acknowledgments
Yield 33 mg, 44%; Mp 129e131 ꢀC; 1HNMR (CD3OD):
d 10.10 (s,
1H), 9.34 (d, 1H, J ¼ 2.1 Hz), 8.88 (s, 1H), 8.48 (d, 1H, J ¼ 8.7 Hz),
8.27e8.17 (m, 2H), 7.98 (t, 1H, J ¼ 15.6 Hz), 7.32 (t, 1H, J ¼ 7.8 Hz),
7.06e7.01 (m, 2H), 6.93e6.89 (m, 1H), 5.02 (t, 2H, J ¼ 7.2 Hz),
2.14e2.00 (m, 2H), 1.70e1.67 (m, 5H), 1.38e1.36 (m, 10H),
0.88e0.80 (m, 2H). Anal. Calcd for C26H32INOS: C 58.53; H 6.05; N
2.63. Found: C 58.28; H 5.98; N 2.52.
We gratefully acknowledge research support from the National
Institutes of Health, National Institute of Allergy and Infectious
Diseases, Research Centers at Minority Institutions (RCMI) grant
number G12 RR 03020, and Title III grant to Florida A&M University.
This research was supported in part by the Pharmaceutical
Research Center NIH/NCRR 1C06-RR12512-01 Grant. One of us, CAA

C.A. Boateng et al. / European Journal of Medicinal Chemistry 46 (2011) 1789e1797
1797
(b) L.G. Mardenborough, X.Y. Zhu, P. Fan, M.R. Jacob, S.I. Khan, L.A. Walker,
S.Y. Ablordeppey, Identification of bis-quindolines as new antiinfective agents,
Bioorg. Med. Chem. 13 (2005) 3955e3963.
is grateful for financial support from AFPE. We also appreciate the
generous contributions of Dr. Wang Zhang, Senior Technician
responsible for instrumentation for the generation of NMR spectra
of compounds in this paper and Ms. Marsha Wright for antifungal
testing. Antifungal testing was supported by the NIH, NIAID, Divi-
sion of AIDS, Grant No. AI 27094.
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