Synthesis and antifungal activity of furo[2,3-f]quinolin-5-ols

Article abstract of DOI:10.1016/j.bmcl.2010.12.058

Furo[2,3-f]quinolin-5-ol derivatives were synthesized and tested for in vitro antifungal activity against Candida, Aspergillus species, and Cryptococcus neoformans. Among them tested, many furo[2,3-f]quinolin-5-ols showed good antifungal activity. The results suggest that furo[2,3-f]quinolin-5-ols would be promising antifungal agents.

Full text of DOI:10.1016/j.bmcl.2010.12.058

Bioorganic & Medicinal Chemistry Letters 21 (2011) 952–955
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antifungal activity of furo[2,3-f]quinolin-5-ols
⇑
Chung-Kyu Ryu , Yang Hui Kim, Ji-Hee Nho, Jung An Hong, Joo Hee Yoon, Aram Kim
College of Pharmacy, Ewha Womans University, Seodaemun-ku, Seoul 120-750, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Furo[2,3-f]quinolin-5-ol derivatives were synthesized and tested for in vitro antifungal activity against
Candida, Aspergillus species, and Cryptococcus neoformans. Among them tested, many furo[2,3-f]quino-
lin-5-ols showed good antifungal activity. The results suggest that furo[2,3-f]quinolin-5-ols would be
promising antifungal agents.
Received 6 October 2010
Revised 25 November 2010
Accepted 9 December 2010
Available online 16 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Furo[2,3-f]quinolin-5-ols
Antimicrobial compounds
Antifungal
Fungi
Substitution effects
R1
Benzofuran scaffolds 1 have potent biological properties includ-
ing antifungal activity1,2 as well as antibacterial3,4 (Fig. 1). A benzo-
furan derivative, a novel myristoyltransferase inhibitor, has been
reported as antifungal agent.1,2 N-Myristoyltransferase has been
proven to be essential for the viability of fungi, including medically
important pathogenic fungi, Candida albicans5 and Cryptococcus neo-
formans6 making it a possible target for the development of anti-
fungal agents with a novel mode of action.
NH2
R1
O
O
R2
R3
3
N
R2
R4
OH
1
2
R = alkyl, Cl, CN, ...
R ,R ,R = alkyl, X, ..
In our previous Letters,7 benzofuran-5-ol scaffolds 2 have dem-
onstrated potent antifungal activity against pathogenic fungi
(Fig. 1). We speculated that incorporation of a heterocyclic ring to
the benzofuran-5-ol skeleton would change the physicochemical
properties and lead to a new pharmacophore furo[2,3-f]quinolin-
5-ols 3 with a different biological profile from benzofuran-5-ol
scaffolds 2. Furo[2,3-f]quinolin-5-ols 3 could metabolize to 5,8-qui-
nolinedione derivatives with a quinonoid structure in fungi (Fig. 1).
Quinonoid compounds display potent biological properties includ-
ing antifungal, antimalarial, and antibacterial activity.8 We assumed
that furo[2,3-f]quinolin-5-ols 3 could have similar biological activi-
ties with those of quinonoid compounds. There have been a few
reports9,10 on furo[2,3-f]quinoline derivatives that exhibit cytotoxic
activity against cancer cell lines. The antifungal activity of com-
pounds 3 has not been reported to the best of our knowledge. The
presence of aryl, thio, amino group, or halogen atoms on quinonoid
compounds significantly affects their antifungal activity.11 A variety
offuro[2,3-f]quinolin-5-ols with differentsubstituentscould exhibit
the biological activities throughdifferent actionsand sometimes im-
prove upon the activities.
4
1: R = H
3a-s
4
2: R =OH
R1
R1
O
O
R2
R2
R3
N
R3
N
OH
O
3
5,8-quinolinediones
Figure 1. Benzofuran scaffolds and furo[2,3-f]quinolin-5-ol derivatives.
Based on this speculation, furo[2,3-f]quinolin-5-ols 3a–s with
various substituents were designed and synthesized to elucidate
their contribution to the antifungal activity (Scheme 1). The
in vitro antifungal activity of compounds 3a–s against pathogenic
fungi was determined by the twofold broth dilution method. Addi-
tional data for antifungal activity of 5-aminoquinolin-8-ol (7) and
7-methyl-8-nitroquinoline (8) are provided.
⇑
Corresponding author. Tel.: +82 2 3277 3027; fax: +82 2 3277 3051.
E-mail address: ckryu@ewha.ac.kr (C.-K. Ryu).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.058

C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 952–955
953
R1
N
NH2
O
O
O
C
O
R2
R1
O
R1
R2
O
HS
R1
C N
R
a or b
O
+
O
O
R2
c
N
N
O
N
S
O
OH
4a: R1= R2= Cl
4b: R1= R2= Br
4c: R1=H, R2= CH3
6a: R1= CH3CH2, R2= Cl
6b: R1= CH3CH2, R2= Br
6c: R1= CH3, R2= Br
6d: R1= CH3, R2= CH3
6e: R1= CH3CH2, R2= CH3
5a: R = CH3CH2
5b: R = CH3
R2
R3
3f-q: R1= CH3CH2,
R2= H, X, OH, ...
e
d
NH2
O
NH2
O
R1
O
R1
O
O
S
O
R2
N
N
OH R2
OH
3a: R1= CH3CH2, R2= Cl
3b: R1= CH3CH2, R2= Br
3c: R1= CH3, R2= Br
3d: R1= CH3, R2= CH3
3e: R1= CH3CH2, R2= CH3
R1= CH3CH2,
R2= CH3 or CH3CH2
3r-s
Scheme 1. Synthesis of furo[2,3-f]quinolin-5-ol derivatives. Reagents and conditions: (a) 5a for 6a, 6b, or 6e/NH4OH/CeCl3 (0.1 equiv)/EtOH/rt/10 min/47–61%; (b) 5b for 6c
or 6d/NH4OH/CeCl3 (0.1 equiv)/EtOH/rt/10 min/40–55%; (c) 6a/ arylthiol 9 (1 equiv)/EtOH/reflux/5 h/60–86%; (d) 6a–e/ hydrazine hydrate (1 equiv)/EtOH/reflux/2 h/42–72%;
(e) 6a/alkylthiol (1 equiv)/EtOH/reflux/5 h/63–81%.
Methods for the synthesis of furo[2,3-f]quinolin-5-ols 3a–s are
shown in Scheme 1 and Table 1. The 6,7-dichloro-5,8-quinolinedi-
one (4a),12 6,7-dibromo-5,8-quinolinedione (4b),13 and 7-methyl-
5,8-quinolinedione (4c) were prepared from commercially
available 5-aminoquinolin-8-ol (7) and 7-methyl-8-nitroquinoline
(8) according to the known method.
substitution of thiols on quinones.17 The mechanism of formation
of compounds 3 by the cyclization was cited in Ref. 16.
The synthesized furo[2,3-f]quinolin-5-ols 3a–s, compound 7, and
8 were tested in vitro for their growth inhibitory activity against
pathogenic fungi using the standard method.18 The MIC (minimum
inhibitory concentration) values were determined by comparison
with fluconazole and 5-fluorocytosine as standard agents.
Alkyl
2-(7-halo-5,8-dioxo-5,8-dihydroquinolin-6-yl)-2-cya-
noacetates 6a–e were synthesized by regioselective nucleophilic
substitution or addition of compound 4a, 4b, or 4c with 1 equiv
of methyl- or ethylcyanoacetate (5a or 5b) and 0.1 equiv of CeCl3
in the presence of NH4OH according to the reported method14,15
with minor modification. The mechanism of formation of com-
pounds 6 was cited in Ref. 16.
As indicated in Table 1, many of furo[2,3-f]quinolin-5-ols 3a–s
showed potent antifungal activity against all tested fungi. Actually,
the activity of compounds 3h, 3i, and 3k was superior or compara-
ble to those of 5-fluorocytosine against fungi. The compounds 3h,
3i, and 3k completely inhibited the growth of all against Candida
and Aspergillus species tested at the MIC level of 0.8–3.2 lg/mL.
When the equivalent amount of each compound 6a–e and hydra-
zine hydrate were mixed in EtOH and refluxed for 2 h, furo[2,
3-f]quinolin-5-ols 3a–e were formed. 2-Amino-4-arylthio-5-
hydroxyfuro[2,3-f]quinolines 3f–q were synthesized by nucleo-
philic substitution and cyclization of compound 6a with appropriate
arylthiols 9 in EtOH. To a solution ofcompound 6a in EtOH, 1 equiv of
arylthiol was added. The mixture was refluxed for 5 h and concen-
trated in vacuo. Purification of residual crude product by column
chromatography yielded compounds 3f–q. Most of these reactions
went as expected and had overall high yields of 60–86%.
In a similar manner, 4-alkylthio-5-hydroxyfuro[2,3-f]quinolines
3r–s were synthesized by cyclization of compound 6a with 1 equiv
of methyl- or ethylthiol in EtOH.
The mechanism for the formation of compounds 6 involves Mi-
chael-type addition of the anion of compounds 5 to quinones 4 fol-
lowed by subsequent dechlorination.7 The substitution of
compounds 6 with nucleophilic thiols resulted in the formation
of aromatic hydroquinone system as intermediates and subse-
quent cyclization to compounds 3. The substitution was similar
to the formation of stable aromatic hydroquinone system by the
Many of furo[2,3-f]quinolin-5-ols 3a–s also showed potent anti-
fungal activity against Candida krusei, C. neoformans, and Aspergillus
species. Actually, the activity of compounds 3j or 3q were superior
or comparable to those of 5-fluorocytosine against C. krusei or C.
neoformans.
Generally, the 4-arylthio-furo[2,3-f]quinolin-5-ols scaffolds 3f–
qexhibitedthegreatestactivity, indicatinga correlationthatmay of-
fer insight into the mode of action of these compounds. In contrast,
furo[2,3-f]quinolin-5-ols 3a–e and 4-alkylthio-moieties of com-
pounds 3r–s did not show significant antifungal activity against
tested fungi, although they exhibited good activity against C. neofor-
mans andAspergillus flavus. 4-Alkylthio-moieties of compounds 3r–s
did not improve their antifungal activity in comparison to 4-aryl-
thio-compounds 3f–q. The structure–activity relationship may not
exist between properties of substituents (R1, R2: H, Me, Et, X, . . .)
for the 4-arylthio moieties of compounds 3f–q and alkyl substitu-
ents for the compounds 3a–e and 3r–s. In addition, the 5-amino-
quinolin-8-ol (7) and 7-methyl-8-nitroquinoline (8) exhibited no
or poor, if any, antifungal activity. Thus, furo[2,3-f]quinolin-5-ols
moiety is important for the antifungal activity.

954
C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 952–955
Table 1
Structures and antifungal activity for furo[2,3-f]quinolin-5-ols
NH
S
NH
2
2
NH
S
2
O
O
1
O
O
1
O
R
O
R
O
O
O
2
N
R
N
N
OH
OH
R
2
OH
3r-s
3a-e
3f-q
1
R
2
R
Compound
R1
R2
MICa
(lg/mL)
b
C. albicans
C. tropicalis
C. krusei
C. neoformans
A. niger
A. flavus
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
CH3CH2
CH3CH2
CH3
CH3
CH3CH2
F
H
H
H
H
F
CH3
CH3
H
H
H
Cl
CH3CH2
CH3CH2
—
—
—
—
Cl
Br
Br
CH3
CH3
H
F
Br
Cl
H
>50.0
12.5
50.0
0.8
50.0
6.3
6.3
6.3
6.3
25.0
25.0
12.5
25.0
12.5
50.0
50.0
25.0
25.0
25.0
50.0
3.2
12.5
12.5
25.0
12.5
1.6
>50.0
6.3
>50.0
6.3
25.0
3.2
12.5
12.5
6.3
0.8
3.2
3.2
1.6
25.0
25.0
25.0
50.0
50.0
1.6
1.6
3.2
1.6
25.0
25.0
25.0
6.3
50.0
6.3
50.0
>50.0
>50.0
>50.0
12.5
3.2
25.0
12.5
>50.0
25.0
50.0
1.6
3.2
3.2
1.6
25.0
12.5
3.2
3.2
3.2
6.3
6.3
25.0
50.0
50.0
0.8
0.8
1.6
50.0
50.0
1.6
0.8
3.2
F
H
0.8
1.6
12.5
25.0
12.5
6.3
6.3
6.3
12.5
50.0
50.0
>50.0
50.0
3.2
25.0
12.5
6.3
12.5
6.3
CH3
OH
CH3O
CH3
H
CH3
CH3CH2
—
—
—
—
25.0
12.5
50.0
12.5
50.0
6.3
>50.0
>50.0
25.0
1.6
6.3
12.5
12.5
12.5
25.0
50.0
>50.0
6.3
3q
3r
3s
7
3.2
6.3
50.0
25.0
50.0
>50.0
12.5
3.2
>50.0
>50.0
50.0
6.3
8
Fluconazole
5-Fluorocytosine
3.2
6.3
a
The MIC value was defined as the lowest concentration of the antifungal agent. MIC values were read after one day for Candida species and Cryptococcus neoformans, and
two days for Aspergillus species in 37 °C. The inoculum sizes contained approximately 1 ꢀ 105 cells/mL. Culture media tested were the modified Sabouraud dextrose broth
(Difco Lab.). The final concentration of antifungal agents was between 0.2 and 50.0 lg/mL.
b
Fungi tested: Candida albicans Berkout KCCM 50235, C. tropicalis Berkout KCCM 50662, C. krusei Berkout KCCM 11655, Cryptococcus neoformans KCCM 50564, Aspergillus
niger KCTC 1231, and Aspergillus flavus KCCM 11899.
2. Masubuchi, M.; Ebiike, H.; Kawasaki, K.; Sogabe, S.; Morikami, K.; Shiratori, Y.;
In conclusion, 4-arylthio-furo[2,3-f]quinolin-5-ol scaffolds 3f–q
were synthesized by cyclization of compounds 4 with 1 equiv of
Tsujii, S.; Fujii, T.; Sakata, K.; Hayase, M.; Shindoh, H.; Aoki, Y.; Ohtsuka, T.;
Shimma, N. Bioorg. Med. Chem. 2003, 11, 4463.
3. Abdel-Aziz, H. A.; Mekawey, A. A. I.; Dawood, K. M. Eur. J. Med. Chem. 2009, 44,
3637.
4. Chen, Y.; Chen, S.; Lu, X.; Cheng, H.; Ou, Y.; Cheng, H.; Zhou, G.-C. Bioorg. Med.
Chem. Lett. 2009, 19, 1851.
5. Weinberg, R. A.; McWherter, C. A.; Freeman, S. K.; Wood, D. C.; Gordon, J. I.; Lee,
S. C. Mol. Microbiol. 1995, 16, 241.
6. (a) Lodge, J. K.; Jackson-Machelski, E.; Toffaletti, D. L.; Perfect, J. R.; Gordon, J. I.
Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 12008; (b) Lodge, J. K.; Jackson-Machelski,
E.; Higgins, M.; McWherter, C. A.; Sikorski, J. A.; Devadas, B.; Gordon, J. I. J. Biol.
Chem. 1998, 273, 12482.
7. Ryu, C.-K.; Song, A. L.; Lee, J. Y.; Hong, J. A.; Yoon, J. H.; Kim, A. Bioorg. Med.
Chem. Lett. 2010, 20, 6777.
8. Middleton, R. W.; Parrick, J. In The Chemistry of The Quinonoid Compounds;
Patak, S., Rappoport, Z., Eds.; John Wiley & Sons: London, 1988; pp 1019–1066.
9. Nebois, P.; Cherkaoui, O.; Benameur, L.; Boitard, M.; Bartoli, M.-H.; Fillion, H.
Pharmazie 1999, 54, 215.
appropriate arylthiols 9. Furo[2,3-f]quinolin-5-ols 3a–e were
synthesized by cyclization of compounds with hydrazine.
4
4-Alkylthio-furo[2,3-f]quinolin-5-ols 3r–s were synthesized by
cyclization of compound 6a with 1 equiv of alkylthiols in EtOH.
Most of these reactions went as expected and had overall high
yields. We have identified a lead compound that has antifungal
activity by screening of our furo[2,3-f]quinolin-5-ols 3a–s. Among
them tested, many of furo[2,3-f]quinolin-5-ols showed potent anti-
fungal activity. The results suggest that furo[2,3-f]quinolin-5-ol
scaffolds would be promising leads for the development of anti-
fungal agents. Moreover, the results should encourage the synthe-
sis of furo[2,3-f]quinolin-5-ol analogs for improving antifungal
properties.
10. Benameur, L.; Bouaziz, Z.; Nebois, P.; Bartoli, M.-H.; Boitard, M.; Fillion, H.
Chem. Pharm. Bull. 1996, 44, 605.
Acknowledgments
11. Ryu, C.-K.; Choi, K. U.; Shim, J.-Y.; You, H.-J.; Choi, I. H.; Chae, M. J. Bioorg. Med.
Chem. 2003, 11, 4003.
12. (a) Pratt, Y. T.; Drake, N. L. J. Am. Chem. Soc. 1960, 82, 1155; (b) Yasuda, M.;
Boger, D. L. J. Med. Chem. 1987, 30, 1918.
13. Schellhammer, C. W.; Petersen, S. Ann. der Chem. 1959, 624, 108.
14. Ryu, C.-K.; Lee, J. Y.; Jeong, S. H.; Nho, J.-H. Bioorg. Med. Chem. Lett. 2009, 19,
146.
This study was supported by a Grant of the Korea Healthcare
Technology R&D Project, Ministry for Health, Welfare and Family
Affairs, Republic of Korea (A08-0414-AA1723-08N1-00010A).
15. (a) Pratt, Y. T. J. Org. Chem. 1962, 27, 3905; (b) Yoshida, K.; Ishiguro, M.; Honda,
H.; Yamamoto, M.; Kubo, Y. Bull. Chem. Soc. Jpn. 1988, 61, 4335.
References and notes
16. Compounds
6 were formed by regioselective nucleophilic substitution or
1. Masubuchi, M.; Kawasaki, K.; Ebiike, H.; Ikeda, Y.; Tsujii, S.; Sogabe, S.; Fujii, T.;
Sakata, K.; Shiratori, Y.; Aoki, Y.; Ohtsuka, T.; Shimma, N. Bioorg. Med. Chem.
Lett. 2001, 11, 1833.
addition of compounds 4 with 1 equiv of alkylcyanoacetates 5 and 0.1 equiv of
CeCl3 in the presence of NH4OH. As results of catalytic action of Ce3+ ions, the
substitution or addition in compounds 4 gave mainly 6-substituted products 6.

C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 952–955
955
The regioselectivity should be originated from the selective increment of the
electrophilicity of 6-position in compounds by the formation of Ce(III)
17. Kutyrev, A. A. Tetrahedron 1991, 47, 8043.
4
18. Mcginnis, M. R.; Rindali, M. G. In Antibiotics in Laboratory Medicine; Lorian, V.,
Ed., 4th ed.; Williams and Wilkins: Baltimore, 1996; pp 176–211.
19. Bernatek, E. Acta Chem. Scand. 1956, 10, 273.
chelate between carbonyl oxygen at 8-position and nitrogen at 1-position. The
catalysis by Ce3+ ions is understood from the intermediate 40. The 6-substituted
products
6 were formed by a Michael-type addition of the anion of
alkylcyanoacetates 5 to 40. These substitutions or additions were similar to
the regioselective reaction of arylamines on 5,8-quinolinedione in the presence
of Ce(III).15 The substitution of 6 with nucleophilic thiols 9 resulted in the
formation of aromatic hydroquinone system7,17 as intermediates 3’ and
subsequent cyclization to compounds 3. The mechanism of cyclization was
similar to the formation of furo[2,3-f]quinolin-5-ols9,10 by cyclization of N,N’-
dimethylhydrazone on 5,8-quinolinedione and naphthofuranol19 by
cyclization of acetylacetone on 1,4-naphthoquinone. Most of these reactions
went as expected. The products
3 were separated by silica gel column
chromatography. Purity of products 3 was determined both by to TLC and GC.
The results showed that a single compound was contained in each product. TLC
was performed on precoated silica gel (60G 254, Merck) using CHCl3 for
solvent. The compounds were detected under UV light (254 nm). The purity of
products was also verified by GC (Hewlett Packard 5890A, HP-5 capillary
column at 260 °C, N2, 17 mL/mim as carrier gas, FID). The compounds 3 were
identified by 1H NMR, 13C NMR, or Mass spectra.
O
O
+
6
X
X
X
X
C
N
-
N
N
COOR
1
8
-
O
O
Ce3+
Ce3+
5
4'
4: X= Cl,
Br,H,..
H
N
N
O
C
S
O
C
X
COOR
COOR
HS
R2
N
N
O
O
H
R1
R1
6
9
3'
R2
NH2
NH
O
O
O
O
C
S
COOR
COOR
N
S
N
H
H
R1
R1
R2
R2
3