In vitro antifungal activity of polyfunctionalized 2-(hetero)arylquinolines prepared through imino Diels-Alder reactions

Article abstract of DOI:10.1016/j.bmc.2008.07.079

Diverse polyfunctionalized quinolines, easily prepared using Lewis acid-catalyzed imino Diels-Alder reactions between corresponding aldimines, were tested for antifungal properties against standardized as well as clinical isolates of clinically important fungi. Among them, 4-pyridyl derivatives displayed the best activities mainly against dermatophytes. The activity appears not to be related neither to the lipophilicity nor to the basicity of compounds.

Full text of DOI:10.1016/j.bmc.2008.07.079

Bioorganic & Medicinal Chemistry 16 (2008) 7908–7920
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
In vitro antifungal activity of polyfunctionalized 2-(hetero)arylquinolines
prepared through imino Diels–Alder reactions
b
Carlos M. Meléndez Gómez a, Vladimir V. Kouznetsov a, , Maximiliano A. Sortino ,
*
Sandra L. Álvarez b, Susana A. Zacchino b,
*
a Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, A.A. 678, Bucaramanga, Colombia
b Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, (2000) Rosario, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Diverse polyfunctionalized quinolines, easily prepared using Lewis acid-catalyzed imino Diels–Alder
reactions between corresponding aldimines, were tested for antifungal properties against standardized
as well as clinical isolates of clinically important fungi. Among them, 4-pyridyl derivatives displayed
the best activities mainly against dermatophytes. The activity appears not to be related neither to the
lipophilicity nor to the basicity of compounds.
Received 17 June 2008
Revised 23 July 2008
Accepted 25 July 2008
Available online 29 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Polyfunctionalized quinolines
Synthesis
Lewis acid-catalyzed imino Diels–Alder
reactions
Antifungal properties
1. Introduction
been considered as good starting materials for the search of novel
antifungal agents.
Fungalinfectionshaveemergedasa majorcauseofmorbidityand
often of mortality in immunocompromised patients over the past
two decades.1 The limited efficacy and high toxicity of the available
antifungal drugs have highlighted the need of new antifungal com-
pounds which could constitute alternatives to the existing drugs.2
An important requirement for new antifungal compounds is that
these structures shouldinhibitnotonly standardized strainsbutalso
clinical isolates of the most clinical relevant fungal spp.3,4 Heterocy-
clic systems with quinoline nucleus represent privileged moieties in
medicinal chemistry, and are ubiquitous sub-structures associated
with biologicallyactive natural products. Quinolinesand theirderiv-
atives have shown to display a wide spectrum of biological activities
such as antiparasitical,5 antibacterial,6 cytotoxic and antineoplas-
tic,7 antimycobacterial,8 and anti-inflammatory behavior.9 Anti-
fungal properties of 8-hydroxyquinoline and its derivatives10 or
substituted indoloquinolines11 were also described. Consequently,
there is great current interest in assembling quinoline ring systems
from acyclicprecursors and anever-increasingdemandfor selective,
cheap, and environmentally safe procedures for their preparation.12
Having broad biological activity, the quinoline compounds have
So, in the course of our ongoing screening program for new bio-
logically important N-heterocycles, we have previously reported
the antifungal activity of different substituted quinolines.13,14
These quinoline derivatives are low molecular weight heterocyclic
aromatic molecules, synthetically acquired. They were easily solu-
ble in organic solvents and showed antifungal activities mainly
against opportunistic pathogenic clinically important fungi. Among
them, 4-methyl-2-phenylquinoline (A) and 6-bromo-4-methyl-2-
(b-pyridyl)quinoline (B) (Fig. 1) showed potent antifungal activi-
ties against dermatophytes.13,14
Both, A and B, have been prepared from the corresponding
N-aldimines via sequential allylation/heterocyclization/aromatiza-
tion processes that do not allow the use of commercially available
anilines as principal starting materials. Moreover, this method does
not offer syntheses of quinolines substituted at the C-2 position and
unsubstituted at the C-3 and C-4 positions, needed in our present re-
Me
Me
Br
N
N
* Corresponding authors. Fax: +57 76 349069 (V.V. Kouznetsov); fax: +54 341
4375315 (S.A. Zacchino).
E-mail addresses: kouznet@uis.edu.co (V.V. Kouznetsov), szaabgil@citynet.net.ar
(S.A. Zacchino).
N
A
B
Figure 1. 2-Substituted quinolines active against dermatophytes.
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.07.079

C. M. Meléndez Gómez et al. / Bioorg. Med. Chem. 16 (2008) 7908–7920
7909
search. It seems that the emerging acid-catalyzed imino Diels–Alder
cycloaddition reactions15 and its multi-component version16 can
overcometheselimitationsandcanbeusefultoolsforthegeneration
of quinoline derivatives with several degrees of structural diversity.
Herein, we report the preparation, physicochemical properties, and
antifungal activities of a new series of several polyfunctionalized
C-2-substituted quinolines and some of their tetrahydroquinoline
precursors, whose syntheses employ mainly imino Diels–Alder
cycloaddition methodology that provides the generation of quino-
line derivatives with structural diversity.
two- or three-step synthetic sequences from commercially available
substituted anilines 1, aromatic aldehydes 2: benzaldehyde and its
3-NO2 analogue, a-furan (or a-thiophene)-carboxyaldehydes or c-
pyridinecarboxyaldehyde. Route a consisted in using cycloaddition
reactions between in situ forming N-aryl aldimines and N-vinylpyrr-
olidin-2-one (NVP) (three-component imino Diels–Alder reaction).
Route b was based on imino Diels–Alder reaction of preformed N-
aryl aldimines 3 and NVP. Finally, route c involved Kametani reaction
between preformed N-aryl aldimines and ethyl vinyl ether (EVE), or
2,2-dimethoxypropane (DMP; Scheme 1).
So, synthesis of new polyfunctionalized 2-arylquinolines 5–26
started with a BiCl3-catalyzed three-component imino Diels–Alder
reaction of various anilines, aromatic aldehydes, and NVP in MeCN
at room temperature to give the corresponding isolable substituted
tetrahydroquinolines 4, whose simple fusion with elemental sulfur
(220–250 °C, 10 min) allowed to obtain the required quinoline
derivatives in good overall yield17 (route a).
2. Results and discussion
2.1. Chemistry
Synthesis of desired polyfunctionalized C-2-(hetero)aryl substi-
tuted quinolines 5–37 (Table 1) was accomplished through different
Table 1
Polyfunctionalized C-2-substituted quinolines prepared through imino Diels–Alder cycloaddition reactions and their molecular formula, molecular weight, pKa, and LogP
Group 1
R4 R5
R4 R5
R4 R5
R3
R3
R2
R3
R2
R2
N
N
R1
14-17
O
O
N
R1
R1
5-13
18-26
NX2
X = O, H
Group 2
R4 R5
R4 R5
R3
R2
R3
X
N
R2
N
R1
R
N
131-37
27-30
X = O, S
Compound
R1
R2
R3
R4
R5
R (Ar or Hetaryl)
Molecular formula
Molecular weight
pKa
LogP
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
MeO
H
H
H
H
H
H
Me
Et
i-Pr
Me
i-Pr
H
H
H
H
H
H
H
Me
H
Me
Et
HO
NO2
F
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
NO2
NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C
C
C
C
15H11
16H13
17H15
N
N
N
205.25
219.28
233.31
221.25
250.25
223.25
239.70
233.31
249.26
268.24
284.70
254.71
278.31
249.26
263.29
279.29
267.25
283.71
277.32
277.32
277.32
309.32
225.24
229.66
241.31
245.73
206.24
220.27
234.30
248.32
262.35
279.29
307.35
4.54 0.40
4.67 0.43
4.65 0.43
4.69 0.43
2.71 0.43
3.79 0.43
3.65 0.43
5.18 0.50
4.81 0.20
2.48 0.50
2.34 0.50
2.36 0.61
3.35 0.50
4.03 0.61
4.15 0.61
3.97 0.61
3.26 0.61
3.13 0.61
4.37 0.61
4.65 0.61
4.18 0.61
2.25 0.61
3.97 0.50
3.12 0.50
4.38 0.43
3.53 0.43
ꢀ0.52 0.10
ꢀ0.49 0.10
ꢀ0.47 0.10
ꢀ0.46 0.10
ꢀ0.51 0.10
ꢀ1.08 0.10
ꢀ1.12 0.10
3.90 0.25
4.36 0.25
4.89 0.25
3.62 0.49
3.66 0.27
3.98 0.35
4.55 0.26
4.82 0.25
4.10 0.33
3.51 0.37
4.08 0.28
2.99 0.60
4.42 0.27
3.76 0.32
4.22 0.32
3.85 0.34
3.84 0.42
4.41 0.34
4.75 0.32
4.68 0.32
4.68 0.32
3.49 0.40
3.30 0.30
3.86 0.29
3.82 0.31
4.37 0.31
2.51 0.26
2.97 0.26
3.43 0.26
3.97 0.26
4.31 0.26
3.21 0.27
4.09 0.28
15H11NO
C15H10N2O2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
C
C
C
15H10FN
15H10ClN
17H15N
Cl
H
–OCH2O–
Ph
3-NO2–Ph
3-NO2–Ph
C16H11NO2
C15H9FN2O2
C15H9ClN2O2
C15H11ClN2
C17H14N2O2
C16H11NO2
C17H13NO2
C17H13NO3
C16H10FNO2
C16H10ClNO2
C18H15NO2
C18H15NO2
C18H15NO2
C18H15NO4
C
C
C
C
C
C
C
C
C
H
H
H
H
H
H
H
H
H
Et
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
F
Cl
Cl
Et
3-NH2–Ph
3-NO2–Ph
(–OCH2O–)Ph
(–OCH2O–)Ph
(–OCH2O–)Ph
(–OCH2O–)Ph
(–OCH2O–)Ph
(–OCH2O–)Ph
(–OCH2O–)Ph
(–OCH2O–)Ph
(–OCH2O–)Ph
2-Fu
2-Fu
2-Thie
2-Thie
4-Py
4-Py
4-Py
4-Py
4-Py
H
Me
MeO
F
Cl
H
H
H
MeO
MeO
Cl
MeO
Cl
H
H
H
H
14H11NO2
13H8ClNO
14H11NOS
13H8ClNS
14H10N2
15H12N2
16H14N2
17H16N2
18H18N2
Me
Me
Me
Me
Me
Me
H
H
H
4-Py
4-Py
C16H13N3O2
C18H17N3O2

7910
C. M. Meléndez Gómez et al. / Bioorg. Med. Chem. 16 (2008) 7908–7920
O
R4
N
O
N
R3
R2
Route a
R4
R4 R5
N
H
R
R3
R2
b
R3
R2
d
R1
4
+
R
O
NH2
N
R
Route b
2
O
R1
N
N
R1 5-37
c
MeO OMe
Me Me
1
a
R4
OEt
or
R3
R2
e
R
Route c
R1
3
Scheme 1. Reagents and conditions: (a) EtOH,
CH2Cl2,
D
; (b) 20 mol% BiCl3, MeCN,
D
; (c) 1 equiv. BF3 ꢁOEt2, CH2Cl2, rt; (d) S8,
D
(220–230 °C), 10–15 min; (e) excess BF3 ꢁOEt2,
D
.
To obtain the required C-2-hetarylquinolines 27–37, the
respective N-hetaryl imines 3 derived from anilines 1 and -furan-
carboxyaldehyde (or -thiophenecarboxyaldehyde, and -pyridin-
ecarboxyaldehyde) have been easily prepared. The 2-(
furyl)quinolines 27, 28, and 2-( -thienyl)quinolines 29,30 have
(MIC = 31.2
mL) against C. neoformans. Within the 11 compounds of group 2,
quinolines 31 and 32 showed good activity (MIC = 25–50 g/mL)
against C. neoformans and, in contrast to the behavior of B, they
did inhibit C. albicans and S. cerevisiae (MIC range = 50–100 g/mL).
lg/mL) than the model compound A (MIC = 250 lg/
a
a
c
l
a
-
a
l
been synthesized from the respective aldimines 3 and NVP via
the protocols of a BF3 ꢁOEt2-catalyzed imino Diels–Alder reaction
and an aromatization process18 (route b).
The fact that these three active quinolines inhibit C. neoformans
is highly interesting because this fungus remains an important life-
threatening complication for immunocompromised hosts. The fun-
gus is the main cause of fatal meningoencephalitis in AIDs patients,
and new compounds acting against this fungus are highly
welcome.1,21
The preparation of 2-(
has been realized through a modified Povarov–Kametani reaction
of the respective N-( -pyridyliden)anilines 3 with EVE (quinoline
c-pyridyl)quinoline derivatives 31–35
c
31) or with DMP (quinolines 32–35) in dichloromethane in the
In turn, to inhibit species of Candida genus is also an interesting
finding because candidiasis is the fourth most common nosocomial
blood stream infection, C. albicans representing more than 60% of
all isolates from clinical infections.22
Regarding the behavior of quinolines 5–37 against dermato-
phytes, only two molecules 33 and 35 showed very good activity
presence of BF3 ꢁ OEt19 (route c). New 5-nitro substituted quino-
2
lines 36,37 have been obtained by regioselective nitration (nitrat-
ing mixture, 0–5 °C) of the respective quinolines 33,35. The 33
synthesized quinolines have been divided into two groups accord-
ing to their chemical structure, looking mainly at the chemical nat-
ure of the C-2 substituent. Group 1 includes simple phenyl
substituted quinolines 5–17 and quinolines with a 3,4-methylene-
dioxyphenyl moiety 18–26, alkaloid dubamine structural ana-
logues. Group 2 includes hetaryl substituted quinolines 26–37
(Table 1). Molecules of group 1 can be considered as derivatives
from quinoline A, while second group compounds as derivatives
from quinoline B.
(MICs = 12.5 lg/mL) against the three fungi tested, similar than
that showed by compound B.
From the analysis of the structures and the activities displayed,
some relationships can be extracted: (a) the quinoline moiety is
not by itself sufficient for antifungal activity as this is clearly sug-
gested by the lack of activity of many compounds of groups 1 and
2; (b) within group 1, the 2-phenyl quinoline skeleton without any
substituent (compound 5) was the most active against C. neofor-
2.2. Antifungal assays
mans (MIC = 31
dermatophytes (MICs = 16–25
possessing an hetaryl substituent at C-2 position (group 2), struc-
tures with an -furan or -thiophene moieties (compounds 27–
30) appeared to be inactive. In contrast, four (31–33, 35) out of
the seven 2-( -pyridyl) quinolines (31–37) showed interesting
antifungal activities. Those without substituents on the quinoline
skeleton (compound 31) or with a methyl in the C-4 position
(compound 32) act against all fungi tested including yeasts
l
g/mL) and displayed a very good activity against
l
g/mL); (c) within the structures
The minimum inhibitory concentrations (MIC) of quinolines 5–
37 were determined in the range of concentrations from 250 to
0.98 lg/mL. The standardized microbroth dilution methods, M-27
a
a
A2 for yeasts and M-38 A for filamentous fungi, were used accord-
ing to the guidelines of Clinical and Laboratory Standards Institute
(CLSI, formerly National Committee for Clinical and Laboratory
Standards NCCLS), which assure confident and reproducible re-
sults.20 Table 2 summarizes the minimum concentration of each
quinoline derivative necessary to completely inhibit (MIC100) the
growth of nine standardized opportunistic pathogenic fungi
including yeasts (Candida albicans, Cryptococcus neoformans, and
Saccharomyces cerevisiae), hialohyphomycetes (Aspergillus spp.) as
well as dermatophytes (Microsporum and Trichophyton spp.). The
structure of each quinoline is included in Table 2, allowing a better
analysis of results.
c
(MIC = 25–100
dermatophytes (MIC = 25–50
methyl-8-substituted (methyl or isopropyl) quinolines (33 and 35)
displayed the best antifungal activities (MIC = 12.5 g/mL) but with
lg/mL) Aspergillus spp. (MIC = 50–100
lg/mL), and
lg/mL). Interesting enough, 4-
l
a lower spectrum of action (active only against dermatophytes).
In order to correlate the qualitative structure–activity relation-
ships described above, with quantitative parameters, we calculated
logP and pKa for all 2-arylquinolines (5–37)23 and attempted to
find a relationship between these values and their MICs against
two sensitive fungi, a yeast (C. neoformans) and a filamentous fun-
gus (T. mentagrophytes), which are clinically important.
Regarding the activity showed by prepared quinolines against
yeasts, only compound 5 out of the 22 compounds of group 1
showed about eight times better antifungal properties

C. M. Meléndez Gómez et al. / Bioorg. Med. Chem. 16 (2008) 7908–7920
7911
Table 2
Minimum inhibitory concentrations (MICs in
l
g/mL) of 2-substituted quinolines
Compound
Ca
Sc
Cn
Afu
Afl
An
Mg
Tr
Tm
A
>250
>250
250
>250
>250
>250
12.5
25
12.5
N
Br
B
>250
>250
250
>250
>250
>250
12.5
12.5
12.5
N
N
Group 1
5
250
125
31.2
250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
16
25
25
N
6
>250
>250
>250
>250
>250
>250
250
250
125
250
250
125
250
250
250
N
7
>250
>250
N
HO
8
N
O2N
9
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
250
>250
250
>250
250
N
F
10
N
Cl
11
>250
>250
>250
>250
>250
>250
>250
>250
>250
N
(continued on next page)

7912
C. M. Meléndez Gómez et al. / Bioorg. Med. Chem. 16 (2008) 7908–7920
Table 2 (continued)
Compound
Ca
Sc
Cn
Afu
Afl
An
Mg
Tr
Tm
12
>250
>250
>250
>250
>250
>250
>250
>250
>250
N
O
13
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
125
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
250
250
250
O
N
F
N
14
>250
>250
>250
>250
>250
>250
>250
125
>250
>250
125
>250
>250
125
Cl
NO2
N
15
Cl
NO2
N
16
17
18
19
NH2
N
>250
>250
>250
NO2
O
O
>250
>250
>250
N
O
O
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
N
MeO
20
O
O
N
(continued on next page)

C. M. Meléndez Gómez et al. / Bioorg. Med. Chem. 16 (2008) 7908–7920
7913
Table 2 (continued)
Compound
Ca
Sc
Cn
Afu
Afl
An
Mg
Tr
Tm
F
21
O
O
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
N
Cl
22
O
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
N
O
23
24
25
>250
>250
>250
>250
>250
>250
>250
>250
>250
O
N
O
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
O
O
N
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
O
O
N
MeO
O
O
26
>250
>250
>250
>250
>250
>250
>250
>250
>250
N
OMe
Group 2
MeO
27
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
125
125
125
O
N
Cl
28
>250
>250
>250
>250
>250
>250
O
N
MeO
29
S
N
(continued on next page)

7914
C. M. Meléndez Gómez et al. / Bioorg. Med. Chem. 16 (2008) 7908–7920
Table 2 (continued)
Compound
Ca
Sc
Cn
Afu
Afl
An
Mg
Tr
Tm
Cl
30
>250
>250
>250
>250
>250
>250
>250
>250
>250
S
N
31
100
50
50
50
50
50
50
50
50
N
N
N
N
N
N
32
100
50
25
50
100
200
25
25
25
33
>250
>250
>250
>250
>250
>250
12.5
12.5
12.5
34
>250
>250
>250
>250
>250
>250
>250
>250
>250
N
N
N
N
35
>250
>250
>250
>250
>250
>250
12.5
12.5
12.5
NO2
36
>250
>250
>250
>250
>250
>250
>250
>250
>250
N
N
N
NO2
37
>250
>250
>250
>250
>250
>250
>250
>250
>250
N
(continued on next page)

C. M. Meléndez Gómez et al. / Bioorg. Med. Chem. 16 (2008) 7908–7920
7915
Table 2 (continued)
Compound
Ca
Sc
Cn
Afu
Afl
An
Mg
Tr
Tm
St drugs
Amp
Keto
1
0.5
—
0.5
0.5
—
0.25
0.25
—
0.5
0.125
—
0.5
0.5
—
0.5
0.25
—
—
0.05
0.04
—
0.025
0.01
—
0.025
0.04
Terb
Amp, amphotericin B; Keto, ketoconazole; Terb, terbinafine; n.t., not tested; St, standard.
It is known that logP (the logarithm of the partition coefficient
in a biphasic system, e.g. n-octanol/water) describes the macro-
scopic hydrophobicity of a molecule, which is a factor that deter-
mines its ability to penetrate the membranes of fungal cells and
to reach the interacting sites, thus influencing the antifungal activ-
ity of compounds.24 The comparison of logP values and MICs
against T. mentagrophytes showed that the logP would not play a
role in the antifungal activity since logP has similar values for ac-
tive as well as for inactive compounds. As an example, active quin-
oline 1 and inactive quinoline derivatives 10, 20, 28, and 34
possess similar logP values (about 3.90). Additionally, active com-
pounds (5, 31–33, and 35) possess varied logP ranging from 2.51
(31) to 4.31 (35). The same can be concluded for the yeast C.
neoformans.
2), they were tested against clinical isolates of T. mentagrophytes
and T. rubrum (Table 4).
These two quinolines (33 and 35) displayed very strong activi-
ties (MICs’ range: 7.8–31.25
and, interesting enough, they completely inhibited 4/5 T. rubrum
and 4/5 T. mentagrophytes strains at 7.8 g/mL. These results are
lg/mL) against the 10 strains tested
l
very encouraging since these fungi are responsible for approxi-
mately 80–93% of chronic and recurrent dermatophyte infections
in human beings, which are very difficult to eradicate. They are
the etiological agents of tinea unguium (producer of invasive nail
infections), tinea manuum (palmar and interdigital areas of the
hand infections), and tinea pedis (Athlete’s foot), the last one being
the most prevalent fungal infection in developed countries, and the
first one accounting for 50% and 90% of all fingernail and toenail
infections, respectively.26
Regarding the comparison of pKa and MICs, the variation of ba-
sicity of quinolines did not appear to play a role in the activity nei-
ther. For example, compounds with completely different pKa such
3. Conclusion
as 2-phenylquinoline 5 (pKa = 4.54) and 2-(
c
-pyridyl)quinolines 31
g/mL) against T.
or 32 (pKa ꢂ ꢀ0.50) possess similar MICs (25–50
l
We have synthesized, by a short and efficient pathway, a new
series of quinoline derivatives possessing an aromatic substituent
(carbocyclic or heterocyclic) at C-2 position. All of them were
tested for antifungal properties against a panel of standardized
fungi including yeasts, hyalohyphomycetes, and dermatophytes,
at first. The most active quinoline molecules were then tested
against a panel of clinical isolates in order to get an overview of
their actual antifungal capacity. Results showed that the most ac-
tive compounds were 2-hetaryl quinolines particularly those con-
mentagrophytes or C. neoformans.
From the data of both quantitative parameters pKa and LogP, we
can deduce that the lipophilicity or basicity of the quinolines tested
would not have a direct influence into their antifungal activity.
2.3. Second-order studies with clinical isolates
In order to gain insight into the potential of active compounds
not only against standardized strains but also on clinical isolates
of medical important fungi, quinolines 5, 31, and 32 were tested
against an extended panel of fungal strains isolated from patients
suffering from mycoses. The % of inhibition displayed by each quin-
oline was determined at five concentrations: 100, 50, 25, 12.5, and
taining a
devoid of antifungal properties. Nevertheless, it is clear that the
activity is not due only to the 2-( -pyridyl) ring since quinolines
34, 36 and 37 did not display any antifungal activity up to
250 g/mL. The activity could be related to the C-4 and/or C-8 sub-
c-pyridyl ring. a-Furyl (a-thienyl) derivatives were
c
l
6.25 l
g/mL.25 So, compounds 5, 31, and 32 were tested at first
stitution on the quinoline ring and would not be related neither to
the lipophilicity nor to the basicity of compounds. These results are
important data for the design and synthesis of new quinoline
derivatives, which could be hits for the development of antifungal
agents.
against 10 isolates of C. neoformans and in turn structures 31 and
32 were tested against ten Candida strains including five clinical
isolates of C. albicans and the rest, non-albicans Candida spp. These
last spp. were included in the panel because there has been an in-
crease in the percentage of non-albicans Candida infections in the
last ten years, being C. glabrata, C. tropicalis, C. parapsilosis, and C.
krusei the most isolated spp.22 Results are shown in Table 3.
4. Experimental
4.1. Chemistry
Results in C. neoformans showed that 2-(c-pyridyl)quinolines 31
and 32 exert more than 75% inhibition on 10 out of the 11 Crypto-
coccus strains tested (that will be expressed as 10/11 in future) at
The melting points (uncorrected) were determined on a Fisher–
Johns melting point apparatus. The IR spectra were recorded on a
Lumex infralum FT-02 spectrophotometer in KBr. 1H NMR spectra
were recorded on Bruker AM-400 or AC-300 spectrometers. Chem-
ical shifts are reported in ppm (d) relative to the solvent peak
(CHCl3 in CDCl3 at 7.24 ppm for protons). Signals are designated
as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, dou-
blet of doublets of doublets; t, triplet; dt, doublet of triplets; td,
triplet of doublets; q, quartet; quint., quintet; m, multiplet; br,
broad. A Hewlett–Packard 5890a series II Gas Chromatograph
interfaced to an HP 5972 mass selective detector (MSD) with an
HP MS Chemstation Data system was used for MS identification
at 70 eV using a 60 m capillary column coated with HP-5 [5%-phe-
nyl-poly(dimethyl-siloxane)]. Elemental analyses were performed
on a Perkin–Elmer 2400 Series II analyzer, and were within 0.4
100
l
g/mL, 6/11 at 50
lg/mL, 3/11 at 25 lg/mL, 2/11 at 12.5 lg/
mL, and 1/11 at 6.25
lg/mL. Moreover, compounds 31 and 32 pro-
duce 50% inhibition on 11/11, 8/11, 8/11, 2/11, and 1/11 at the con-
centrations detailed above, respectively. In turn, quinoline 5 was
active in the ten Cryptococcus strains tested, however with a lower
effectivity, inhibiting 75 % of the growth of 6/11, 4/11, 1/11, 0/11,
and 0/11 and 50 % of 10/11, 6/11, 0/11, 0/11, and 0/11 strains, at
the different concentrations tested.
Regarding the activity against Candida isolates, it is clear that
compounds 31 and 32 are better inhibitors of C. albicans and C.
tropicalis, since the
100 g/mL against C. glabrata, C. parapsilosis, and C. krusei. In addi-
tion, considering that compounds 33 and 35 displayed MICs as low
as 12.5 g/mL against the dermatophytes of the first panel (Table
% of inhibition drastically drops below
l
l

Table 3
Antifungal activity (% inhibition) of selected 2-substituted quinolines against clinical isolates of Candida spp. and C. neoformansa
Strain
Compound 5
Compound 31
Compound 32
Amp (
mL)
l
g/
Keto
g/mL) (lg/
Concentrations (
lg/mL)
Concentrations (
lg/mL)
Concentrations (
lg/mL)
(lg/mL)
(
l
mL)
100
50
25
12.5
6.25
100
50
25
12.5
6.25
100
50
25
12.5
6.25
6.25
6.25
ATCC
Ca
Ca
Ca
Ca
Ca
Ca
Cg
Ct
10231
C 126
C 127
C 128
C 129
C 130
C 115
C 131
C 124
C 117
0
0
0
0
0
100
69
80
88
85
84
75
100
55
66
73
32
65
3
4
5
63
0
0
3
41
0
0
0
3
2
1
54
0
0
4
19
0
0
0
0
0
0
22
0
0
3
100
69
80
88
85
84
75
100
55
66
73
32
65
3
4
5
63
0
0
3
41
0
0
0
3
2
1
54
0
0
4
19
0
0
0
0
0
0
22
0
0
3
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
6
4
3
5
4
5
6
4
3
5
4
15 3.6
0
15 3.6
0
82
84
4
75
5
4
4
1
8
3
2
50
48
4
60
0
4
3
0.2
0.7
0.1
5
82
84
4
75
5
4
4
1
8
3
2
50
48
4
60
0
4
3
2
0.2
0.7
0.1
5
2
7
3
6
7
3
6
Cp
Ck
3
6
3
6
3
0
3
0
Cn
ATCC
32264
100
100
77
9
32
4
1
0
100
100
100
90
5
83
100
100
100
90
5
83
100
100
Cn
Cn
Cn
Cn
Cn
Cn
Cn
Cn
Cn
Cn
IM 983040
IM 972724
IM 042074
IM 983036
IM 00319
IM 972751
IM 031631
IM 031706
IM 961951
IM 052470
50
99
84
32
3
4
7
4
29
87
77
12
34
54
34
46
32
3
8
4
3
2
5
3
4
7
13
35
33
0
14
22
15
17
10
35
2
4
3
4
13
7
0
0
0
5
0
0
1
0
0
0
0
0
0
0
0
0
0
45
74
92 10
79
92
5
5
34
23
87 12
69
80 10
20
75
69
89
75
6
4
12
8
87
45 12
52
9
57 12
57
78
53
3
9
0
0
0
0
68
0
12
0
12
21
4
0
45
74
92 10
79
92
5
5
34
23
87 12
69
80 10
20
75
69
89
75
6
4
12
8
87
45 12
52
9
57 12
57
78
53
3
9
0
0
0
0
68
0
12
0
12
21
4
0
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
1
1
1
76
20
32
0
36
41
34
24
7
2
6
6
1
76
20
32
0
36
41
34
24
7
2
6
6
1
8
3
7
9
8
3
7
9
47 10
2
4
3
2
3
5
3
3
83
74
67
45
88
9
5
6
4
7
98
3
6
4
8
5
2
98
3
6
4
8
5
2
2
100
100
97
2
5
3
2
3
5
100
100
97
2
5
3
2
3
5
7
9
6
7
9
6
2
4
1
2
4
1
76 11
21
3
99
99
Ca, Candida albicans; Cg, C. glabrata; Ct, C. tropicalis; Cp, C. parapsilosis; Ck, C. krusei; Cn, Cryptococcus neoformans; IM, Instituto Malbrán, Buenos Aires; ATCC, American Type Culture Collection, Manassas, USA; C, Reference Center in
Mycology, Rosario, Argentina. Amp B, amphotericin B; Keto, ketoconazole.
a
For the aim of comparison, standardized strains of C. albicans and C. neoformans are included in the table.

C. M. Meléndez Gómez et al. / Bioorg. Med. Chem. 16 (2008) 7908–7920
7917
CH3–CH2–); 13C NMR (CDCl3, 100 MHz): d 156.5, 147.1, 142.3,
139.8, 136.2, 130.8, 129.5, 129.0, 128.7 (2C), 127.4 (2C), 127.2,
124.9, 118.9, 28.8, 15.3. MS m/z (EI) 233 (M+). Found: C, 87.41; H,
6.33; N, 6.25. Calcd for C17H15N: C, 87.52; H, 6.48; N, 6.00.
Table 4
Minimum inhibitory concentration (MIC100
clinical isolates of Trichophyton genus
, lg/mL) of quinolines 33 and 35 against
Strain
Voucher sp.
Compound 33
Compound 35
Terb
T. rubrum
T. rubrum
T. rubrum
T. rubrum
T. rubrum
C 110
C 133
C 135
C 136
C 137
7.8
15.6
7.8
7.8
7.8
7.8
15.6
7.8
7.8
7.8
0.006
0.006
0.006
0.006
0.012
4.1.1.4. 6-Hydroxy-2-phenylquinoline (8). White solid. Mp
112–115 °C. Yield 56%. IR (KBr):
m 3456, 1592, 1537, 1476,
873 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.01–8.10 (1H, m, 8H),
.
8.01–8.10 (2H, m, 20-HPh and 60-HPh), 7.83 (1H, d, J = 8.9 Hz, 3H),
7.75 (1H, d, J = 8.9 Hz, 4H), 7.53–7.54 (1H, m, 30-HPh and 50-HPh),
7.46 (1H, s, 5H), 7.45–7.48 (1H, m, 40-HPh), 6.90 (1H, s, –OH); 13C
NMR (CDCl3, 100 MHz): d 160.5, 149.6, 143.0, 139.2, 129.7, 128.2,
127.1, 126.6 (2C), 126.4, 124.8 (2C), 123.6, 118.7, 113.7. MS m/z
(EI) 221 (M+). Found: C, 81.15; H, 5.34; N, 6.12. Calcd for
T mentagrophytes
T mentagrophytes
T mentagrophytes
T mentagrophytes
T mentagrophytes
C 131
C 132
C 364
C 539
C 943
31.25
7.8
7.8
7.8
7.8
15.6
7.8
7.8
7.8
7.8
0.006
0.006
0.006
0.006
0.006
C, Reference Center in Mycology (Rosario, Argentina); Terb, Terbinafine.
C15H11NO: C, 81.43; H, 5.01; N, 6.33.
of theoretical values. The reaction progress was monitored using
thin layer chromatography on a silufol UV254 TLC aluminum sheet.
4.1.1.5. 6-Nitro-2-phenylquinoline (9). Brown solid. Mp 175–
178 °C. Yield 56%. IR (KBr):
3456, 1592, 1537, 1476, 873 cmꢀ1
m
.
1H NMR (CDCl3, 400 MHz): d 8.78 (1H, d, J = 2.4 Hz, 6-H), 8.47
(1H, dd, J = 9.2, 2.5 Hz, 7-H), 8.37 (1H, d, J = 8.7 Hz, 3-H), 8.26
(1H, d, J = 9.2 Hz, 8-H), 8.22–8.20 (2H, m, 20-HPh and 60-HPh),
7.56–7.54 (2H, m, 30-HPh and 50-HPh), 7.48–7.50 (1H, m, 40-HPh);
13C NMR (CDCl3, 100 MHz): d 160.6, 150.4, 138.4, 131.4, 130.5,
129.0 (2C), 127.8 (2C), 127.5, 127.4, 124.3, 123.2, 120.6, 77.0. MS
m/z (EI) 250 (M+). Found: C, 71.78; H, 4.27; N, 11.05. Calcd for
4.1.1. Group 1. General procedure for synthesis of 2-
arylquinolines 5–13, 18–26
To a solution of the appropriate aniline (1.00 mmol) and alde-
hyde (benzaldehyde or piperonal) (1 mmol) in anhydrous CH3CN
(15 mL) under N2, 20 mol% BiCl3 was added, and to the resulting
mixture was added N-vinylpyrrolidone (2.0 mmol). The reaction
mixture was stirred at gentle reflux for 4 h and then quenched with
a solution of Na2CO3. The organic layer was separated, and dried
with Na2SO4. The organic solvent was removed in vacuo to afford
the respective 2-aryl-1,2,3,4-tetrahydroquinolines, which were
purified or used in subsequent synthetic step without careful puri-
fication. The corresponding tetrahydroquinolines were heated
quickly (10–15 min) in the presence of elemental sulfur S8 to
220–230 °C, the reaction mixture was adsorbed under silica gel
and separated by chromatography column to afford the 2-aryl-
quinolines 5–13 and 18–20.
C15H10N2O2: C, 71.99; H, 4.03; N, 11.19.
4.1.1.6. 6-Fluoro-2-phenylquinoline (10). Beige solid. Mp 128–
131 °C. Yield 58 %. IR (KBr):
1484, 1231, 831, 750, 686 cmꢀ1 1H
m
.
NMR (CDCl3, 400 MHz): d 8.19–8.15 (1H, m, 8-H), 8.19–8.15 (2H,
m, 20-HPh and 60-HPh), 8.15–8.13 (1H, m, 3-H), 7.86 (1H, d,
J = 8.7 Hz, 4-H), 7.56–7.52 (2H, m, 30-HPh and 50- HPh), 7.50–7.46
(1H, m, 7-H), 7.50–7.46 (1H, m, 5-H), 7.43 (1H, dd, J = 8.8, 2.8 Hz,
40-HPh); 13C NMR (CDCl3, 100 MHz): d 161.7, 156.7, 145.5, 139.4,
135.9, 132.2, 129.4, 128.8 (2C), 127.4 (2C), 119.8, 119.6, 110.5,
110.3. MS m/z (EI) 223 (M+). Found: C, 80.66; H, 4.75; N, 6.39. Calcd
for C15H10FN: C, 80.70; H, 4.51; N, 6.27.
4.1.1.1. 2-Phenylquinoline (5). White solid. Mp 67–69 °C. Yield
54 %. IR (KBr):
m .
1589, 1473, 1439, 849, 748 cmꢀ1 1H NMR (CDCl3,
400 MHz): d 8.22 (1H, d, J = 8.6 Hz, 3-H), 8.19–8.16 (1H, m, 8-H),
8.19–8.16 (2H, m, 20-HPh and 60-HPh), 7.88 (1H, d, J = 8.6 Hz, 4-H),
7.83 (1H, d, J = 8.1 Hz, 5-H), 7.73 (1H, ddd, J = 7.2, 7.2, 0.7 Hz, 6-
H), 7.55–7.52 (1H, m, 7-H), 7.55–7.52 (2H, m, 30-HPh and 50-HPh),
7.47 (1H, t, J = 7.2 Hz, 40-HPh); 13C NMR (CDCl3, 100 MHz): d
157.3, 148.3, 139.7, 136.7, 129.7, 129.6, 129.2, 128.9 (2C), 127.5
(2C), 127.4, 127.1, 126.2, 118.9. MS m/z (EI) 205 (M+). Found: C,
87.55; H, 5.67; N, 6.79. Calcd for C15H11N: C, 87.77; H, 5.40; N, 6.82.
4.1.1.7. 6-Chloro-2-phenylquinoline (11). Beige solid. Mp 134–
137 °C. Yield 50%. IR (KBr):
m .
1495, 1223, 835, 752, 687 cmꢀ1 1H
NMR (CDCl3, CDCl3, 400 MHz): d 8.16–8.14 (1H, m, 3-H), 8.16–
8.14 (1H, m, 8-H), 8.11 (2H, d, J = 7.8 Hz, 20-HPh and 60-HPh), 7.89
(1H, d, J = 8.5 Hz, 4-H), 7.80 (1H, d, J = 2.3 Hz, 6-H), 7.65 (1H, dd,
J = 9.0, 2.3 Hz, 7-H), 7.53 (2H, t, J = 7.5 Hz, 30-HPh and 50-HPh), 7.47
(1H, t, J = 7.2 Hz, 40-HPh); 13C NMR (CDCl3, 100 MHz): d 157.5,
146.6, 139.2, 135.8, 131.9, 131.3, 130.5, 129.5, 128.9 (2C), 127.7
(2C), 127.5, 126.1, 119.7. MS m/z (EI) 239 (M+). Found: C, 75.01;
H, 4.44; N, 5.82. Calcd for C15H10ClN: C, 75.16; H, 4.21; N, 5.84.
4.1.1.2. 6-Methyl-2-phenylquinoline (6). Yellow solid. Mp 70–
72 °C. Yield 62 %. IR (KBr):
m .
2898, 1490, 1460, 1246, 738 cmꢀ1
1H NMR (CDCl3, 400 MHz): d 8.16 (2H, dt, J = 7.2, 1.5 Hz, 20-HPh
and 60-HPh), 8.11 (1H, d, J = 8.8 Hz, 3-H), 8.08 (1H, d, J = 8.37 Hz,
8-H), 7.83 (1H, d, J = 8.6 Hz, 4-H), 7.57 (1H, s, 5-H), 7.55–7.51
(1H, m, 7-H), 7.55–7.51 (2H, m, 30-HPh and 50-HPh), 7.46 (1H, tt,
J = 7.3, 1.3 Hz, 40-HPh), 2.55 (3H, s, 6-CH3); 13C NMR (CDCl3,
100 MHz): d 156.4, 146.8, 139.8, 136.1, 136.0, 131.9, 129.4, 129.1,
128.7 (2C), 127.4 (2C), 127.1, 126.3, 118.9, 21.5. MS m/z (EI) 219
(M+). Found: C, 87.53; H, 6.14; N, 6.21. Calcd for C16H13N: C,
87.64; H, 5.98; N, 6.39.
4.1.1.8. 5,7-Dimethyl-2-phenylquinoline (12). White solid. Mp
71–74 °C. Yield 70%. IR (KBr):
m 3014, 2974, 1589, 1473,
1439 cmꢀ1
.
1H NMR (CDCl3, 400 MHz): d 8.32 (1H, d, J = 8.8 Hz,
3-H), 8.17 (2H, dd, J = 7.2 Hz, 20-HPh and 60-HPh), 7.83 (1H, s, 8-H),
7.81 (1H, d, J = 8.8 Hz, 4-H), 7.53 (2H, t, J = 7.0 Hz, 30-HPh and 50-
H
Ph), 7.46 (1H, t, J = 7.1 Hz, 40-HPh), 7.19 (1H, s, 6-H), 2.66 (3H, s,
7-CH3), 2.53 (3H, s, 5-CH3); 13C NMR (CDCl3, 100 MHz): d 156.7,
148.8, 139.8, 139.4, 133.9, 132.9, 129.1, 129.0, 128.7 (2C), 127.4
(2C), 127.0, 124.5, 117.6, 21.8, 18.4. MS m/z (EI) 233 (M+). Found:
C, 87.33; H, 6.60; N, 6.13. Calcd for C17H15N: C, 87.52; H, 6.48; N,
6.00.
4.1.1.3. 6-Ethyl-2-phenylquinoline (7). White solid. Mp 63–
66 °C. Yield 51%. IR (KBr):
m .
2960, 2895, 1493, 1443 cmꢀ1 1H
NMR (CDCl3, 400 MHz): d 8.17–8.13 (2H, m, 20-HPh and 60-HPh),
8.15–8.13 (1H, m, 3-H), 8.11 (1H, d, J = 9.3 Hz, 8-H), 7.84 (1H, d,
J = 8.6 Hz, 4-H), 7.61–7.59 (1H, m, 5-H), 7.61–7.59 (1H, m, 7-H),
7.53 (2H, t, J = 7.1 Hz, 30-HPh and 50- HPh), 7.46 (1H, t, J = 7.3 Hz,
40-HPh), 2.85 (2H, q, J = 7.6 Hz, CH3-CH2–), 1.36 (3H, t, J = 7.6 Hz,
4.1.1.9. 6,7-(Methylenedioxy)-2-phenylquinoline (13). Beige
solid. Mp 109–111 °C. Yield 54%. IR (KBr):
m 1457, 1228, 1029,
849, 748 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.11 (2H, dd, J = 7.1,
.
1.5 Hz, 20-HPh and 60-HPh), 7.98 (1H, d, J = 8.5 Hz, 3-H), 7.69 (1H,
d, J = 8.5 Hz, 4-H), 7.51 (2H, dd, J = 7.1, 1.7 Hz, 30-HPh and 50-HPh),

7918
C. M. Meléndez Gómez et al. / Bioorg. Med. Chem. 16 (2008) 7908–7920
7.46 (1H, s, 8-H), 7.03 (1H, s, 5-H), 6.08 (2H, s, –OCH2O–); 13C NMR
(CDCl3, 100 MHz): d 155.2, 150.7, 147.6, 146.4, 139.7, 135.4, 128.8,
128.7 (2C), 127.1 (2C), 124.0, 117.1, 106.1, 102.4, 101.6. MS m/z (EI)
249 (M+). Found: C, 77.18; H, 4.55; N, 5.54. Calcd for C16H11NO2: C,
77.10; H, 4.45; N, 5.62.
J = 8.1 Hz, 50-HPh), 6.04 (2H, s, —OCH2O—); 13C NMR (CDCl3,
100 MHz): d 151.4, 150.0, 146.2, 144.2, 133.0, 130.5, 131.0, 128.8,
127.4, 127.1, 126.4, 125.5, 124.4, 113.7, 113.4, 101.1. MS m/z (EI)
283 (M+). Found: C, 67.59; H, 3.76; N, 4.75. Calcd for C16H10ClNO2:
C, 67.74; H, 3.55; Cl, 12.50; N, 4.94.
4.1.1.10–4.1.1.13 Quinolines 14–17 were prepared by our pub-
lished protocol.17
4.1.1.19. 2-(30,40-Methylenedioxyphenyl)-7-ethylquinoline
(23). Yellow solid. Mp 175–177. Yield 40 %. IR (KBr):
m 2959,
4.1.1.14. 2-(30,40-Methylenedioxyphenyl)quinoline (18) (alka-
2898, 1585, 1490, 1442 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.16
.
loid dumanine). Yellow solid. Mp 90–92 °C. Yield 50%. IR
(KBr):
(1H, d, J = 8.6 Hz, 3-H), 8.12 (1H, d, J = 8.7 Hz, 4-H), 7.8 (1H, d,
J = 1.8 Hz, 20-HPh), 7.77 (1H, d, J = 8.0 Hz, 5-H), 7.68 (1H, dd,
J = 8.1, 1.74 Hz, 60-HPh), 7.50 (1H, d, J = 1.6 Hz, 8-H), 7.49 (1H, dd,
J = 8.0, 1.4 Hz, 6-H), 7.08 (1H, d, J = 8.1, 50- HPh), 5.94 (2H, s,
m .
2884, 1594, 1495, 1248, 1042 cmꢀ1 1H NMR (CDCl3,
400 MHz): d 8.16 (1H, d, J = 8.6 Hz, 3-H), 8.12 (1H, d, J = 8.5 Hz, 4-
H), 7.80 (1H, m, 8-H), 7.77 (1H, m, 5-H), 7.74 (1H, d, J = 1.7 Hz,
20-HPh), 7.70 (1H, ddd, J = 8.4, 8.4, 1.5 Hz, 7-H), 7.65 (1H, dd,
J = 8.0, 1.7 Hz, 60-HPh), 7.50 (1H, ddd, J = 8.1, 8.0, 1.1 Hz, 6-H),
6.95 (1H, d, J = 8.1 Hz, 50-HPh), 6.03 (2H, s, —OCH2O—); 13C NMR
(CDCl3, 100 MHz): d 156.6, 148.8, 148.4, 148.2, 136.6, 134.1,
129.6, 129.5, 127.4, 127.0, 126.0, 121.7, 118.5, 108.4, 107.9,
101.3. MS m/z (EI) 249 (M+). Found: C, 77.24; H, 4.60; N, 5.49. Calcd
for C16H11NO2: C, 77.10; H, 4.45; N, 5.62.
—OCH2O—), 1.84 (2H, q, J = 8.0 Hz, 8-CH2CH3–), 1.18 (3H, t, J = 13
C
NMR (CDCl3, 100 MHz): d 151.4, 150.0, 146.2, 144.2, 133.0, 130.5,
131.0, 128.8, 127.4, 127.1, 126.4, 125.5, 124.4, 113.7, 113.4,
101.1. Hz, 8-CH2CH3–). MS m/z (EI) 277 (M+). Found: C, 77.75; H,
5.67; N, 5.18. Calcd for C18H15NO2: C, 77.96; H, 5.45; N, 5.05.
4.1.1.20. 2-(30,40-Methylenedioxyphenyl)-5,8-dimethylquino-
line (24). Yellow solid. Mp 170–173. Yield 58 %. IR (KBr):
m 2896,
4.1.1.15. 2-(30,40-Methylenedioxyphenyl)-6-methylquinoline
1591, 1487, 1463, 1251 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.28
.
(19). Yellow solid. Mp 166–168. Yield 41%. IR (KBr):
m
2898,
(1H, d, J = 8.8 Hz, 3-H), 7.88 (1H, d, J = 1.7 Hz, 20-HPh), 7.81 (1H, d,
J = 8.8 Hz, 4-H), 7.73 (1H, dd, J = 8.2, 1.7 Hz, 60-HPh), 7.44 (1H, d,
J = 7.1 Hz, 7-H), 7.20 (1H, d, J = 7.1 Hz, 6-H), 6.95 (1H, d,
J = 8.1 Hz, 50-HPh), 6.04 (2H, s, —OCH2O—), 2.84 (3H, s, 5-CH3),
2.64 (3H, s, 8-CH3); 13C NMR (CDCl3, 100 MHz): d 151.3, 147.6,
147.4, 146.2, 140.6, 136.9, 135.9, 132.9, 132.3, 127.4, 126.4,
125.7, 124.4, 113.7, 113.3, 101.1, 28.1, 15.5. 13C NMR (CDCl3,
100 MHz): d 154.2, 148.6, 148.3, 147.2, 135.3, 134.4, 133.2, 131.8,
129.2, 126.2, 126.1, 121.4, 117.1, 108.3, 107.8, 101.2, 18.3, 17.8.
MS m/z (EI) 277 (M+). Found: C, 77.94; H, 5.66; N, 4.93. Calcd for
1587, 1490, 1460, 1246 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.07
.
(1H, d, J = 8.6 Hz, 3-H), 8.00 (1H, d, J = 8.6 Hz, 4-H), 7.74 (1H, d,
J = 8.6 Hz, 8-H), 7.72 (1H, d, J = 1.7 Hz, 20-HPh), 7.63 (1H, dd,
J = 8.3, 1.7 Hz, 60-HPh), 6.92 (1H, d, J = 8.3 Hz, 50-HPh), 7.54 (1H, m,
7-H), 7.52 (1H, d, J = 1.7 Hz, 5-H), 6.03 (2H, s, —OCH2O—), 2.53
(3H, s, 6-CH3); 13C NMR (CDCl3, 100 MHz): d 155.9, 148.7, 148.4,
146.8, 136.0, 135.9, 134.3, 131.9, 129.3, 127.0, 126.3, 121.6,
118.6, 108.4, 107.9, 101.3, 21.5. MS m/z (EI) 263 (M+). Found: C,
77.36; H, 5.11; N, 5.22. calcd for C17H13NO2: C, 77.55; H, 4.98; N,
5.32.
C18H15NO2: C, 77.96; H, 5.45; N, 5.05.
4.1.1.16. 2-(30,40-Methylenedioxyphenyl)-6-methoxyquinoline
4.1.1.21. 2-(30,40-Methylenedioxyphenyl)-5,7-dimethylquino-
line (25). Yellow solid. Mp 115–117. Yield 60 %. IR (KBr): 2896,
1590, 1480, 1436, 1244 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.27
(20). Brown solid. Mp 139–141. Yield 59 %. IR (KBr):
m
2960,
m
2037, 1612, 1588, 1489 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.06
.
.
(1H, d, J = 8.6 Hz, 3-H), 8.02 (1H, d, J = 9.2 Hz, 4-H), 7.69 (1H, d,
J = 1.7 Hz, 20-HPh), 7.61 (1H, dd, J = 8.1, 1.7 Hz, 60-HPh), 7.74 (1H,
d, J = 8.6 Hz, 8-H), 7.36 (1H, dd, J = 9.3, 2.8 Hz, 7-H), 7.07 (1H, d,
J = 2.8 Hz, 5-H), 6.93 (1H, d, J = 8.1 Hz, 50-HPh), 6.03 (2H, s,
—OCH2O—), 3.94 (3H, s, 6-OCH3); 13C NMR (CDCl3, 100 MHz): d
158.3, 151.3, 150.1, 146.2, 145.9, 133.0, 127.4, 127.3, 126.5,
126.4, 124.1, 115.6, 114.6, 113.7, 113.4, 101.1, 55.4. MS m/z (EI)
279 (M+). Found: C, 73.27; H, 4.83; N, 4.88. Calcd for C17H13NO3:
C, 73.11; H, 4.69; N, 5.02.
(1H, d, J = 8.8 Hz, 3-H), 7.77 (1H, br.s, 8-H), 7.74–7.72 (1H, m, 20-
HPh and 50-HPh), 7.65 (1H, dd, J = 8.1, 1.7 Hz, 60-HPh), 7.17 (1H,
br.s, 6-H), 6.95 (1H, d, J = 8.1 Hz, 4-H), 6.03 (2H, s, —OCH2O—),
2.65 (3H, s, 7-CH3), 2.52 (3H, s, 5-CH3); 13C NMR (CDCl3,
100 MHz): d 151.3, 148.8, 147.3, 146.2, 144.5, 143.8, 132.9, 129.2,
127.8, 126.4, 125.1, 123.8, 123.6, 113.7, 113.3, 101.1, 21.5, 20.1.
MS m/z (EI) 277 (M+). Found: C, 77.88; H, 5.63; N, 5.10. Calcd for
C18H15NO2: C, 77.96; H, 5.45; N, 5.05.
4.1.1.22. 2-(30,40-Methylenedioxyphenyl)-6,8-dimethoxyquino-
line (26). Yellow solid. Mp 146–148. Yield 62 %. IR (film): 2955,
2899, 1607, 1478, 1451 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.02
4.1.1.17. 2-(30,40-Methylenedioxyphenyl)-6-fluoroquinoline
m
(21). Yellow solid. Mp 153–155. Yield 56 %. IR (KBr):
m
2899,
.
1585, 1236, 833, 752 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.09
.
(1H, d, J = 8.7 Hz, 3-H), 7.76 (1H, d, J = 8.6 Hz, 4-H), 7.71 (1H, d,
J = 1.7 Hz, 20-HPh), 7.62 (1H, dd, J = 8.1, 1.8 Hz, 60-HPh), 6.91 (1H,
d, J = 8.07 Hz, 50-HPh), 6.71 (1H, d, J = 2.5 Hz, 5-H), 6.65 (1H, d,
J = 2.5 Hz, 7-H), 6.01 (2H, s, —OCH2O—), 4.05 (1H, s, 8-OCH3),
3.92 (1H, s, 6-H); 13C NMR (CDCl3, 100 MHz): d 158.0, 156.4,
153.3, 148.3, 148.2, 136.6, 135.5, 134.4, 128.6, 121.3, 119.4,
108.3, 107.8, 101.5, 101.2, 96.8, 56.1, 55.5. MS m/z (EI) 309 (M+).
Found: C, 69.55; H, 4.99; N, 4.32. Calcd for C18H15NO4: C, 69.89;
H, 4.89; N, 4.53.
(1H, dd, J = 9.3, 5.4 Hz, 8-H), 8.07 (1H, d, J = 8.4 Hz, 3-H), 7.77
(1H, d, J = 8.6 Hz, 4-H), 7.71 (1H, d, J = 1.7 Hz, 20-HPh), 7.62 (1H,
dd, J = 8.1, 1.8 Hz, 60-HPh), 7.46 (1H, ddd, J = 8.8, 8.8, 2.9 Hz, 7-H),
7.38 (1H, dd, J = 8.8, 2.8 Hz, 5-H), 6.93 (1H, d, J = 8.1 Hz, 50-HPh),
6.03 (2H, s, —OCH2O—); 13C NMR (CDCl3, 100 MHz): d 148.8,
148.4, 145.2, 135.9, 133.7, 131.9, 127.3, 121.5, 119.8, 119.5,
119.2, 110.5, 110.2, 108.4, 107.7, 101.3. MS m/z (EI) 267 (M+).
Found: C, 71.69; H, 3.94; N, 5.15. Calcd for C16H10FNO2: C, 71.91;
H, 3.77; F, N, 5.24.
4.1.2. Group 2
4.1.1.18. 2-(30,40-Methylenedioxyphenyl)-6-chloroquinoline
4.1.2.1–4.1.2.4. Quinolines 27–30 were prepared by our pub-
(22). Yellow solid. Mp 150–152. Yield 54 %. IR (KBr):
m
2957,
lished protocol.18
1584, 833, 757, 685 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.08 (1H,
.
d, J = 8.8 Hz, 3-H), 8.04 (1H, d, J = 9.0 Hz, 8-H), 7.81 (1H, d,
J = 8.7 Hz, 4-H), 7.78 (1H, d, J = 2.3 Hz, 6-H), 7.72 (1H, d,
J = 1.7 Hz, 20-HPh), 7.65–7.62 (2H, m, 7-H and 60-HPh), 6.94 (1H, d,
4.1.2.5. 2-(Pyridin-4-yl)quinoline (31). To a solution of the
appropriate aldimine 3 (1.00 mmol) in anhydrous CH2Cl2 (15 mL)
was cooled to 0 °C. Over a period of 20 min, BF3 ꢁOEt2(0.39 g;

C. M. Meléndez Gómez et al. / Bioorg. Med. Chem. 16 (2008) 7908–7920
7919
2.8 mmol) was added dropwise. The resulting mixture was allowed
to warm to room temperature, and EVE (0.70 g; 9.8 mmol) in
CH2Cl2 (10 mL) was then rapidly added with vigorous stirring.
The reaction mixture was stirred at gentle reflux for 10 h and then
quenched with a solution of Na2CO3. The organic layer was sepa-
rated, and dried with Na2SO4. The organic solvent was removed
in vacuo. The residue was purified by chromatography column (sil-
ica gel) to afford the respective 2-pyridylquinoline 31 as a yellow
are presented in Tables 3 and 4. Strains were grown on Sabouraud-
chloramphenicol agar slants for 48 h at 30 °C, and were maintained
on slopes of Sabouraud-dextrose agar (SDA, Oxoid) and sub-cultured
every 15 days to prevent pleomorphic transformations. Inocula
were obtained according to reported procedures and adjusted to
1–5 ꢃ 103 cells/spores with colony forming units (CFU)/mL.20
4.2.2. Antifungal susceptibility testing
solid. Mp 90–93 °C. Yield 73 %. IR (KBr):
RMN (CDCl3, 400 MHz) d 8.83 (2H, d, J = 4.6 Hz, H
m
3038, 2947 cmꢀ1
.
1H
4.2.2.1. MIC determinations. Minimum inhibitory concentra-
tion of each quinoline was determined by using broth microdilution
techniques according to the guidelines of CLSI (formerly NCCLS).
MIC values were determined in RPMI-1640 (Sigma, St. Louis,
Mo, USA) buffered to pH 7.0 with MOPS. Microtiter trays were
incubated at 35 °C in a moist, dark chamber, and MICs were visu-
ally recorded at 48 h. For the assay, stock solutions of pure com-
0
and Ha -Py),
a
-Py
8.31 (1H, d, J = 8.6 Hz, 3-H), 8.21 (2H, dd, J = 4.8, 1.3 Hz, Hb-Py and
0
H
b -Py), 7.98 (1H, d, J = 8.3 Hz, 4-H), 7.75 (1H, br. d, J = 8.1 Hz, 5-
H), 7.67 (1H, br. d, J = 6.8 Hz, 7-H), 7.53 (1H, t, J = 7.6 Hz, 6-H),
2.97 (3H, s, 8-CH3); 13C NMR (CDCl3, 100 MHz): d 151.4 (2C),
150.6, 149.1, 142.0, 134.3, 129.9, 128.5, 125.4, 125.1, 124.7,
123.2, 120.4 (2C). MS m/z (EI) 206 (M+). Found: C, 81.54; H, 4.91;
N, 13.62. Calcd for C14H10N2: C, 81.53; H, 4.89; N, 13.58.
pounds were twofold diluted with RPMI from 250 to 0.98
(final volume = 100 L) and a final DMSO concentration 6 2%. A
volume of 100 L of inoculum suspension was added to each well
lg/mL
l
l
4.1.2.6–4.1.2.9. 4-Methyl-2-(pyridin-4-yl)quinolines 32–35 were
prepared by our published protocol.19
with the exception of the sterility control where sterile water was
added to the well instead. Ketoconazole, Amphotericin B (Sigma
Chemical Co, St Louis, MO, USA), and Terbinafine (Novartis, Buenos
Aires) were used as positive controls.
Endpoints were defined as the lowest concentration of drug
resulting in total inhibition (MIC100) of visual growth compared
to the growth in the control wells containing no antifungal.
Generalprocedureforsynthesisof4-methyl-5-nitroquinolines36,
37. To a solution of the corresponding 4-methylquinolines 33,35
(1.00 mmol) in H2SO4 (15 mL) was added KNO3. The resulting mix-
ture was stirred at room temperature for 24 h and then neutralized
with a solution of NaOH 1 N. The organic layer was separated with
CH2Cl2, and dried with Na2SO4. The organic solvent was removed in
vacuo. The residue was purified by chromatography column (silica
gel) to afford the respective 4-methyl-5-nitroquinolines 36,37.
4.2.2.2. Determination of percentages of fungal growth inhibi-
tion. The test was performed in 96-wells microplates. Quinoline
test wells (QTW) were prepared with stock solutions of each quin-
oline in DMSO (6 2%), diluted with RPMI-1640 to final concentra-
4.1.2.10. 4,8-Dimethyl-5-nitro-2-(pyridin-4-yl)quinoline (36). Yel-
low solid. Mp 169–172 °C.; IR (KBr): 1354, 1510 cmꢀ1
.
1H RMN
tions 100–6.25
lg/mL. Inoculum suspension (100
lL) was added to
0
(CDCl3, 400 MHz) d 8.85 (2H, dd, J = 4.5, 1.5 Hz, H
and Ha -Py),
each well (final volume in the well = 200 l
L). A growth control well
a
ꢀPy
0
8.21 (2H, dd, J = 4.5, 1.5 Hz, Hb-Py and
H
b -Py), 7.92 (1H, d,
(GCW) (containing medium, inoculum, the same amount of DMSO
used in QTW, but compound-free) and a sterility control well
(SCW) (sample, medium, and sterile water instead of inoculum)
were included for each strain tested. Microtiter trays were incu-
bated in a moist, dark chamber at 35 °C, 24 or 48 h for Candida
spp or Cryptococcus sp., respectively. Microplates were read in a
VERSA Max microplate reader (Molecular Devices, Sunnyvale, CA,
USA). Amphotericin B and Ketoconazole were used as positive con-
trols (100% inhibition at the concentration tested). Tests were per-
formed by triplicate. Reduction of fungal growth due to each
quinoline concentration was calculated as follows: % of inhibition:
100 ꢀ (OD405 PTW ꢀ OD405 SCW)/OD405 GCW ꢀ OD405 SCW.
J = 0.8 Hz, 3-H), 7.74 (1H, d, J = 7.8 Hz, 6-H), 7.66 (1H, dd, J = 7.7,
1.0 Hz, 7-H), 2.99 (3H, d, J = 0.8 Hz, 4-CH3), 2.69 (3H, d, J = 0.8 Hz,
8-CH3); 13C NMR (CDCl3, 100 MHz): d 151.4 (2C), 151.1, 151.0,
145.6, 144.1, 143.2, 139.6, 134.8, 130.2, 123.5, 119.6 (2C), 113.8,
19.4, 18, 0. MS m/z (EI) 279 (M+). Found: C, 68.77; H, 4.83; N,
15.13. Calcd. for C16H13N3O2: C, 68.81; H, 4.69; N, 15.05.
4.1.2.11. 8-Isopropyl-5-nitro-2-(pyridin-4-yl)quinoline (37). Yel-
low solid. Mp 177–180 °C. IR (KBr): 1352, 1592 cmꢀ1
(CDCl3, 400 MHz) d 8.87 (2H, dd, J = 4.5, 1.5 Hz, H
.
1H RMN
0
and Ha -Py),
a
ꢀPy
0
8.24 (2 H, dd, J = 4.9, 1.9 Hz, Hb-Py and Hb -PyÞ, 7.93 (1H, d,
J = 0.8 Hz, 3-H), 7.81 (1H, d, J = 7.9 Hz, 6-H), 7.70 (1H, d,
J = 8.1 Hz, 7-H), 4.56 (1H, sep, J = 6.7 Hz, 8-CH(CH3)2), 2.70 (3H, d,
J = 0.8, 4-CH3), 1.48 (6H, d, J = 6.9 Hz, 8-CH(CH3)2); 13C NMR (CDCl3,
100 MHz): d 152.0, 151.9, 151.4 (2C), 145.1, 144.3, 144.0, 142.8,
132.1, 129.8, 123.3, 119.8 (2C), 112.5, 31.6, 23.5 (2C), 19.4. MS
m/z (EI) 307 (M+). Found: C, 70.15; H, 5.87; N, 13.58. Calcd. for
4.2.2.3. Statistical analysis. Data were statistically analyzed by
one-way analysis of variance. A p < 0.05 was considered significant.
Acknowledgments
C
18H17N3O2: C, 70.34; H, 5.58; N, 13.67.
V.K. thanks Instituto Colombiano para el Desarrollo de la Cien-
cia y la Tecnología ‘‘Francisco José de Caldas” (COLCIENCIAS-CENI-
VAM, contract no. 432-2004). CMMG thanks COLCIENCIAS for his
fellowship. SAZ and MS thank Agencia de Promoción Científica y
Tecnológica de Argentina (ANPCyT), grants PICTR 260 and PICT
995. MS acknowledges CONICET for the fellowship RIBIOFAR
(CYTED).
4.2. Antifungal evaluation
4.2.1. Microorganisms and media
For the antifungal evaluation, standardized strains from the
American Type Culture Collection (ATCC), Rockville, MD, USA,
and Reference Center in Mycology (CEREMIC, C, Rosario, Argentina)
were used. Candida albicans ATCC 10231, S. cerevisiae ATCC 9763,
C. neoformans ATCC 32264, Aspergillus flavus ATCC 9170, A. fumiga-
tus ATTC 26934, A. niger ATCC 9029, Trichophyton rubrum C 110,
T. mentagrophytes ATCC 9972, and M. gypseum C 115.
References and notes
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cluded nine strains of Candida genus, 10 strains of each
C. neoformans and Trichophyton genus, which voucher specimens

7920
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