Biological evaluation of substituted quinolines

Article abstract of DOI:10.1016/j.bmcl.2004.05.026

Several quinolines were synthesized and evaluated in vitro against several parasites (Trypanosoma brucei, T. cruzi, Leishmania infantum, L. amazonensis, Plasmodium falciparum). Then, they were evaluated in vitro (at 10μM), against HTLV-1 transformed cells

Full text of DOI:10.1016/j.bmcl.2004.05.026

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3635–3638
Biological evaluation of substituted quinolines
Xavier Franck,a Alain Fournet,a,b Eric Prina,c Renaud Mahieux,d Reynald Hocquemillera
a,
*
ꢀ
and Bruno Figadere
aLaboratoire de Pharmacognosie (associꢁe au CNRS-BioCIS), Facultꢁe de Pharmacie, Universitꢁe de Paris-Sud,
rue J.B. Clꢁement, 92296 Ch^atenay-Malabry, France
bInstitut de Recherche pour le Dꢁeveloppement (IRD), 213 rue Lafayette, 75480 Paris, France
cUnitꢁe d’Immunophysiologie et Parasitisme Intracellulaire, 25 rue du Dr. Roux, Institut Pasteur, 75724 Paris, France
dUnitꢁe d’Epidemiologie et Physiopathologie des Virus Oncogꢀenes, 28 rue du Dr. Roux, Institut Pasteur, 75724 Paris, France
Received 24 March 2004; revised 11 May 2004; accepted 13 May 2004
Available online
Abstract—Several quinolines were synthesized and evaluated in vitro against several parasites (Trypanosoma brucei, T. cruzi,
Leishmania infantum, L. amazonensis, Plasmodium falciparum). Then, they were evaluated in vitro (at 10 lM), against HTLV-1
transformed cells. A few of them displayed interesting activities, comparable to the reference drugs.
Ó 2004 Elsevier Ltd. All rights reserved.
Parasitic diseases such as leishmaniases and trypanoso-
miases have significant impacts in developing countries,
with infections spread over several hundred millions of
people and are the cause of a mortality rate of several
millions per year. Conventional chemotherapies are
often inadequate, toxic or are becoming less effective due
to emergence of numerous resistances.1 There is, thus,
an urgent need for new drugs for the chemotherapy of
these diseases.
of several 2-substituted quinolines and on the in vitro
HTLV-1 activity of some of them.
Alcohols 1–5 were prepared by treating 2-quinaldine
with n-butyllithium (1 equiv) followed by addition of the
required aldehyde. Then compounds 6–9 were obtained
by dehydration of the corresponding alcohols (by
1 (33%)
6 (80%)
2-Alkylquinolines and 2-arylquinolines, isolated from
plants2 or prepared by total synthesis,3a;b;c have been
investigated by us as new drug candidates. These low-
molecular weight compounds exhibit pharmacological
properties such as antiprotozoal activity (e.g. against
Leishmania sp.,4 Plasmodium,5 Trypanosoma sp.6), and
were found to inhibit the human immunodeficiency
virus of type-1 (HIV-1) integrase,7–9 as well as the pro-
liferation of HTLV-1 transformed cell lines (HUT-
102).10 Imidazoquinolinamines such as imiquimod have
also been found to be potent inducers of IFN-a and
cytokines both in in vitro and in vivo experiments.11 In
this letter we report on the in vitro antiprotozoal activity
2 (11%)
3 (51%)
4 (66%)
5 (55%)
MsCl, Et3N
BuLi, ArCHO
7 (40%)
8 (53%)
9 (62%)
N
2-quinaldine
Ac2O, ArCHO
10 (33%)
RNH2, NaBH4
11 (50%), 12 (15%)
N
CHO
2-quinaldehyde
1) CH3NO2, KOH
2) MsCl, Et3N
16 (67%)
1) (COCl)2, DMF
2) RNH2
13 (60%)
14 (99%)
15 (53%)
N
CO2H
Keywords: Protozoa; HTLV-1; Leishmaniases; Trypanozomiases.
* Corresponding author. Tel.: +33-01-46-83-55-92; fax:+33-01-46-83-
53-99; e-mail: bruno.figadere@cep.u-psud.fr
Scheme 1. Synthesis of quinolines 1–16.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.05.026

Table 1
Compounds
P. falciparume
T. bruceia
T. cruzib
L. infantumc L. amazonensisd Cytox. macrophages
Cytox. MRC-5 HTLV-1f (%) at 10 lM
IC50 lM
W2
IC50 lM
Ghana
IC50 lM
IC50 lM
IC50 lM
IC50 lM
IC50 lM
IC50 lM
OH
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
15
4
>32
>32
>32
0
10
0
N
N
N(CH3)2
NO2
1
OH
>32
>32
>32
>32
>32
>32
6
1
2
OH
N
F
3
OH
O
>32
>32
>32
>32
>32
>32
>32
>32
0
N
4
OH
OCH3
OCH3
>32
6
>32
17
>32
>32
>32
16
>32
16
>32
>32
>32
>32
>32
>32
0
N
5
26
N
N(CH )
3 2
6
>32
>32
28
22
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
0
N
NO
F
2
7
26
N
8
OCH3
26
18
>32
>32
>32
22
>32
>32
>32
>32
>32
>32
>32
>32
>32
30
>32
>32
>32
>32
>32
>32
0
0
0
N
OCH3
9
N
OCH3
10
H3CO
NH
>32
>32
N
11
F

Table 1 (continued)
T. bruceia
T. cruzib
L. infantumc L. amazonensisd Cytox. macrophages
Cytox. MRC-5 HTLV-1f (%) at 10 lM
IC50 lM
Compounds
P. falciparume
W2
IC50 lM
Ghana
IC50 lM
IC50 lM
IC50 lM
IC50 lM
IC50 lM
IC50 lM
OCH3
OCH3
>32
>32
>32
13
>32
>32
>32
>32
>32
12
>32
>32
0
0
NH
N
OCH3
12
N
N
O
18
>32
>32
16
N
13
14
O
N
N CH
3
>32
>32
>32
17
>32
16
>32
18
>32
>32
>32
17
>32
15
>32
>32
0
0
N
O
N
15
16
O
18
1
>8
>32
>32
14
16
22
76
N
NO2
19
1
5
2
2
4
3
9
ND
ND
31
16
34
N
N
CHO
Br
17
0.15
13
>32
>32
ND
18
Suramin
Nifurtimox
0.09
ND
ND
ND
0.45
ND
ND
ND
ND
ND
7.15
ND
ND
ND
ND
ND
3.12
ND
ND
ND
ND
12.5
ND
ND
ND
ND
ND
0.11
ND
ND
ND
ND
0.018
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
Glucantime
Miltefosine
Chloroquine
ND
ND
ND––not determined.
a Trypanosoma brucei strain S427.
b T. cruzi strain Tulahuen CL2.
c Leishmania infantum strain MHOM-ET-67/L82.
d L. amazonensis strain MHOM/ET/L82/LV9.
e P. falciparum sensitive strain W2 and resistant strain Ghana.
f HTLV-1 infected HUT-102 cells.

3638
X. Franck et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3635–3638
treatment with mesyl chloride and triethyl amine),
whereas compound 1012 was directly produced by the
treatment of quinaldine and 2,4-dimethoxybenzaldehyde
under reflux of acetic anhydride. Compounds 11 and 12
were obtained by reductive amination of 2-quinaldehyde
with the corresponding amines. Amides 13–15 were
obtained by coupling reaction of the unsaturated car-
boxylic acid chloride with the corresponding amines.
Compound 1613 was obtained by nitroaldol condensa-
tion of 2-quinaldehyde with nitromethane, followed
by mesyl chloride and triethyl amine treatment.
Compounds 17 and 18 were prepared by published
methods3a;b;c (Scheme 1). All the synthesized compounds
gave satisfactory spectral data.
Acknowledgements
CNRS is acknowledged for financial support, and
thanks are due to G. Epane, B. Vidovic, M. dos Santos
for their technical helps. We wish to thank particularly
Dr. J. R. L. Pink of Special Programme for Research
and Training in Tropical Diseases (TDR) and Pro-
gramme Drug Discovery (DDR). Association pour la
Recherche contre le Cancer (ARC) is acknowledged for
a financial support to R.M.
References and notes
Anti-protozoal, anti-retroviral and cytotoxicity activi-
ties of the synthesized quinolines 1–18 are presented in a
single Table 1. The tests against the amastigote forms of
T. brucei and T. cruzi, were performed as described.9
Compounds 6, 16, 17 showed the best activity, but were
still less active than suramin and nifurtimox, whereas 18
(T. cruzi: IC50 ¼ 0.15 lM) was more active than the
reference drug, nifurtimox (T. cruzi: IC50 ¼ 0.45 lM).
Against the amastigote forms of L. infantum9 the same
compounds 17 and 18 were more active than the refer-
ence drug, glucantime (IC50 ¼ 2 lM, with glucantime
IC50 ¼ 7.15 lM), whereas 16 was as active as the refer-
ence drug (IC50 ¼ 8 lM) and amides 13 and 15 showed
some interesting activity (IC50 ¼ 18 and 16 lM, respec-
tively). Again, compounds 17 and 18 were as active as
miltefosine, the oral reference drug (IC50 ¼ 3 lM),
against the amastigote forms of L. amazonensis. Against
P. falciparum resistant W2 strain, compound 3 showed a
1. Antoine, J. C.; Jouanne, C.; Ryter, A. Parasitology 1989,
99, 1547–1552.
ꢁ
2. (a) Fournet, A.; Hocquemiller, R.; Roblot, F.; Cave, A.;
Richomme, P.; Bruneton, J. J. Nat. Prod. 1993, 56, 1547–
1552; (b) Fournet, A.; Vagneur, B.; Richomme, P.;
Bruneton, J. Can. J. Chem. 1989, 67, 2116–2118.
3. (a) Fakhfakh, M. A. 2001, Ph.D. Thesis. University of
^
Pari-Sud, Chatenay-Malabry, France; (b) Fakhfakh, M.
A.; Franck, X.; Fournet, A.; Hocquemiller, R.; Figadere,
ꢀ
B. Tetrahedron Lett. 2001, 42, 3847–3850; (c) Fakhfakh,
ꢀ
M. A.; Franck, X.; Hocquemiller, R.; Figadere, B. J.
Organomet. Chem. 2001, 624, 131–135; (d) Fakhfakh, M.
ꢀ
A.; Franck, X.; Fournet, A.; Hocquemiller, R.; Figadere,
B. Synth. Commun. 2002, 32, 2863–2875; (e) Seck, M.;
ꢀ
Franck, X.; Hocquemiller, R.; Figadere, B.; Peyrat, J. F.;
Provot, O.; Brion, J. D.; Alami, M. Tetrahedron Lett.
2004, 45, 1881–1884.
4. Fournet, A.; Ferreira, M. E.; Torres de Ortiz, S.; Fuentes,
S.; Nakayama, H.; Rojas de Arias, A.; Schinini, A.;
Hocquemiller, R. Antimicrob. Agents Chemother. 1996, 40,
2447–2451.
5. Gantier, J. C.; Fournet, A.; Munos, M. H.; Hocquemiller,
R. Planta Med. 1996, 62, 285–286.
6. Nakayama, H.; Ferreira, M. E.; Rojas de Arias, A.; de
Bilbao, N. V.; Schinini, A.; Fournet, A. Phytother. Res.
2001, 15, 630–632.
surprising
activity
(IC50 ¼ 1 lM,
chloroquine:
IC50 ¼ 0.11 lM), whereas the corresponding dehydrated
compound 8 showed no activity. Against P. falciparum
sensitive Ghana strain, the same compound 3 showed
the best activity (IC50 ¼ 4 lM) but by far less active
than chloroquine (IC50 ¼ 0.018 lM). Then, the synthe-
sized compounds were tested against HTLV-1 trans-
formed cells, as already reported.10 The most active
compound was 16, showing 76% inhibition of the cells
proliferation at 10 lM. Compounds 6, 8, 17 showed a
weaker activity (26%, 26%, 34%, respectively) at 10 lM.
It is interesting to note that the tested compounds did
not show any cytotoxicity against normal cells, such as
macrophages, except for compounds 17 and 18.
€
7. Mekouar, K.; Mouscadet, J. F.; Desmaele, D.; Subra, F.;
Leh, H.; Savoure, D.; Auclair, C.; d’Angelo, J. J. Med.
ꢁ
Chem. 1998, 41, 2846–2857.
8. Zouhiri, F.; Mouscadet, J. F.; Mekouar, K.; Desmaele,
€
D.; Savoure, D.; Leh, H.; Subra, F.; Le Bret, M.; Auclair,
ꢁ
C.; d’Angelo, J. J. Med. Chem. 2000, 43, 1533–1540.
9. Fakhfakh, M. A.; Prina, E.; Mouscadet, J. F.; Fournet,
ꢀ
A.; Franck, X.; Hocquemiller, R.; Figadere, B. Bioorg.
Med. Chem. 2003, 11, 5013–5023.
10. Fournet, A.; Mahieux, R.; Fakhfakh, M. A.; Franck, X.;
In conclusion, this study showed that among the quin-
olines tested in these assays, a new 2-substituted quin-
oline, compound 16, was found to exhibit promising
antiprotozoal activity (against T. cruzi). A fluorinated
product, compound 3, showed an interesting activity
against P. falciparum. Against HTLV-1 transformed
cells, again compound 16 showed a significant inhibition
activity. Further studies are now under way to evaluate
their in vivo activity.
ꢀ
Hocquemiller, R.; Figadere, B. Bioorg. Med. Chem. Lett.
2003, 13, 891–894.
11. Buates, S.; Matlashewski, G. J. Infect. Dis. 1999, 179,
1485–1494.
12. Bahner, C. T.; Rives, L. M.; McGaha, S. W.; Rutledge,
D.; Ford, D.; Gooch, E.; Westberry, D.; Ziegler, D.
Arzneimittelforschung 1981, 31, 404–406.
13. Shoeb, H. A.; Korkor, M. I.; Tammam, G. H. Pharmazie
1978, 33, 581–583.