Synthesis and antileishmanial activity of lipidic amino alcohols

Article abstract of DOI:10.1111/j.1747-0285.2009.00923.x

In this work, a number of lipidic amino alcohols wereas synthesized and evaluated in vitro on cultures of Leishmania amazonensis and Leishmania chagasi. Nine amino alcohols showed inhibition of L. chagasi growth, and seven of them showed inhibition of L. amazonensis with IC₅₀ below 10 μm. Compound 11f was more active than the reference drug amphotericin B against L. chagasi promastigote forms.

Full text of DOI:10.1111/j.1747-0285.2009.00923.x

ª 2009 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2009.00923.x
Chem Biol Drug Des 2010; 75: 233–235
Research Letter
Synthesis and Antileishmanial Activity of Lipidic
Amino Alcohols
1
2
Elaine S. Coimbra , Mauro V. de Almeida ,
bition of L. amazonensis with IC50 below 10 lM.
Compound 11f was more active than the reference
drug amphotericin B against L. chagasi promasti-
gote forms.
2
2
Celso O. R. J u´ nior , Aline F. Taveira ,
2
1
Cristiane F. da Costa , Ana C. de Almeida ,
Elaine F. C. Reis and Adilson D. da Silva *
2
2,
Key words: amino alcohols, antileishmanial activity, lipophilicity
1
Departamento de Parasitologia, Microbiologia e Imunologia,
Instituto de CiÞncias Biolꢀgicas, Universidade Federal de Juiz de
Fora, Cidade Universitꢁria, 36036-900 Juiz de Fora, MG, Brazil
Departamento de Quꢂmica, Instituto de CiÞncias Exatas,
Received 4 December 2008, revised 25 September 2009 and accepted
for publication 1 November 2009
2
Universidade Federal de Juiz de Fora, Cidade Universitꢁria, 36036-
9
*
00 Juiz de Fora, MG, Brazil
Corresponding author: Adilson D. da Silva, david.silva@ufjf.edu.br
Leishmaniasis is a complex infection caused by multiple species of
the intracellular protozoan parasite Leishmania. This disease is
endemic in some tropical areas of the world and affects an esti-
mated 12 million people with 2 million new cases annually (1,2).
The clinical spectrum of leishmaniasis is varied and encompasses
subclinical (inapparent), localized (skin lesions) and disseminated
infection (cutaneous, mucosal or visceral) (2). Visceral manifestation
is the more severe form of leishmaniasis, because it is fatal if
In this work, a number of lipidic amino alcohols
wereas synthesized and evaluated in vitro on cul-
tures of Leishmania amazonensis and Leishmania
chagasi. Nine amino alcohols showed inhibition of
L. chagasi growth, and seven of them showed inhi-
R2
R2
H3C
OMs
H3C
OH
(CH )n
OH
a
b
2
(CH2)n
(CH2)n
N
(CH2)m
H3C
R1
1
1
1
1
1
a n = 7
2a n = 7
2b n = 9
2c n = 11
2d n = 13
2e n = 15
3
4
5
5
5
5
6
6
6
6
a n = 7; R1=R2=H; m=1
a n = 9; R1=R2=H; m=1
a n = 11; R1=R2=H; m=1
b n = 9
c n = 11
d n = 13
e n = 15
b n = 11; R1=H; R2=CH ; m=1
3
c n = 11; R1=2-hydroxyethyl; R2=H; m=1
d n = 11; R1=R2=H; m=2
a n = 13; R1=R2=H; m=1
b n = 13; R1=H; R2=CH ; m=1
c n = 13; R1=2-hydroxyethyl; R2=H; m=1
3
d n = 13; R1=R2=H; m=2
7a n = 15; R1=R2=H; m=1
OH
OH
H3C
OH
a
H3C
OMs
(
CH2)n
(CH2)n
b
8
a n = 9
9a n = 9
9b n = 11
R1
N
OH
8b n = 11
H3C
R2
(
CH2)n
1
1a n = 9; R1=H; R2=2-hydroxyethyl
1b n = 9; R1=H; R2=3-hydroxypropyl
1
OH
11c n = 9; R1=R2=2-hydroxyethyl
Scheme 1: Synthesis of lipidic
amino alcohols. (a) MsCl, CH Cl , Py,
1
1
1
1d n = 9; R1=H; R2=1,1-dimethyl-2-hydroxyethyl
1e n = 9; R1=H; R2=2-aminoethyl
1f n = 9; R1=H; R2=3-aminopropyl
H3C
NH2
2
2
(
CH2)n
0
ꢀC to room temperature; (b) amino
alcohol or diamine, EtOH reflux;
c) NaN , DMF; (d) H , Pd ⁄ C, EtOH,
1
1
0a n =9
0b n =11
12a n = 11; R1=H; R2=2-hydroxyethyl
1
1
1
2b n = 11; R1=H; R2=3-hydroxypropyl
(
3
2
2c n = 11; R1=R2=2-hydroxyethyl
2d n = 11; R1=H; R2=1,1-dimethyl-2-hydroxyethyl
room temperature.
2
33

Coimbra et al.
Table 1: Values of IC50 (lM) for the activity of the compounds
against Leishmania amazonensis and Leishmania chagasi promasti-
gote forms
dodecanol, tetradecanol and hexadecanol) were first treated with
methanesulfonyl chloride in methylene chloride and pyridine to fur-
nish the corresponding mesylates 2a–e. The crude mesylates were
treated with amino alcohols (2-amino-ethanol, 3-amino-1-propanol,
diethanolamine and 2-amino-2-methy-1-propanol) in ethanol at
reflux to furnish the desired compounds 3a, 4a, 5a–d, 6a–d and
7a in 50–90% yield in two steps. For the preparation of the lipo-
philic compounds 10a and 10b, mesylated derivative 9a and 9b
were treated with sodium azide in dimethylformamide (DMF) at
Compound
L. amazonensis
L. chagasi
3
4
5
5
5
5
6
6
6
6
7
a
a
a
b
c
76.38 (€2.79)
11.74 (€0.50)
8.57 (€1.90)
>227
14.82 (€0.10)
25.14 (€0.20)
Nd
>227
4.90 (€0.06)
>227
16.92 (€1.62)
26.00 (€1.20)
Nd
11.78 (€0.53)
5.09 (€0.33)
9.16 (€0.59)
12.30 (€0.10)
2.82 (€0.11)
4.09 (€0.34)
Nd
9.65 (€0.015)
5.50 (€0.35)
5.42 (€0.96)
119.56 (€12.97)
4.90 (€0.07)
3.20 (€0.20)
Nd
>227
9.22 (€0.93)
>227
19.60 (€2.34)
14.58 (€0.91)
Nd
2.17 (€0.05)
Nd
11.28 (€0.10)
16.38 (€0.59)
Nd
1.26 (€0.08)
Nd
120 ꢀC, leading to the corresponding azides in quantitative yield.
d
a
b
c
These azides were hydrogenated in presence of palladium on char-
coal 10% in ethanol, furnishing amino alcohols 10a and 10b in
74% and 76% yield, respectively. Amino alcohols 11a–f and 12a–
d were obtained in a similar way from 1,2-dodecanediol and 1,2-te-
tradecanediol by treatment of mesylates 9a and 9b with four
d
a
1
1
1
1
1
1
1
1
1
1
1
1
0a
0b
1a
1b
1c
1d
1e
1f
amino alcohols and two diamines (1,2-diaminoethane and 1,3-diami-
1
nopropane) (Scheme 1). All compounds were characterized by
NMR and C NMR spectroscopy.
H
13
Leishmania amazonensis (MHOM ⁄ Br ⁄ 75 ⁄ Josefa isolated from a
patient with diffuse cutaneous leishmaniasis) and Leishmania chag-
asi (MHOM ⁄ Br ⁄ 74 ⁄ PP75 isolated from a patient with visceral leish-
maniasis) promastigotes were used for in vitro screening. The
antiproliferative activity of compounds was determined by colorimet-
ric 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT)
method based on tetrazolium salt reduction by mitochondrial dehy-
drogenases, as previously described (8,14). The results are
expressed as the concentrations inhibiting parasite growth by 50%
2a
2b
2c
2d
>227
8.07 (€0.11)
>227
7.70 (€0.03)
16.40 (€1.37)
45.60 (€0.94)
1.90 (€0.25)
Amphotericin B (reference drug)
0.90 (€0.07)
Nd, not determined.
(IC50) after a 3-day incubation period. The IC50 values represent
means of three separate experiments. Amphotericin B was used as
the reference drug.
untreated (2,3). There is so far no vaccine approved for clinical use.
Chemotherapy of all leishmaniasis manifestations has been based
on the pentavalent antimonials such as sodium stibogluconate
As observed in Table 1, the diamine alcohol derivative 11f dis-
played the best antiproliferative activity against L. chagasi pro-
mastigote forms (IC50 = 1.26 lM), being more active than the
reference drug amphotericin B. In this series, compounds 5a,
(
pentostam) and meglumine antimoniate (glucantime), since their
discovery in 1940s (4–6). These drugs induce toxic side effects and
require lengthy treatments with parenteral administration (4,5).
Strains of Leishmania donovani resistant to antimonials are fre-
quent in India, where most of the cases are not responsive to these
drugs (5). The inefficacy of the treatment with antimonials is partic-
ularly elevated in the HIV–Leishmania co-infection, where therapeu-
tical effectiveness is diminished during relapses (4,5). Pentamidine,
amphotericin B and paromomycin are used as a second option in
resistant cases, despite their great toxicity to the host (2,6). New
alternative leishmaniasis treatment have been developed, including
colloidal and lipid formulations and recently the oral drug miltefo-
sine (4–6). Nevertheless, all therapies have some limitations as sev-
eral toxic effects and unaffordable cost (5,6). In a previous study,
we have shown that lipophilic diamine derivatives have proved
inhibitory effects in Leishmania (7,8). So, the aim of this study was
to evaluate in vitro some lipidic amino alcohols against different
species of Leishmania. These types of compounds can interact with
membrane lipids and possibly, to interfere with the lipid or poly-
amine transport or metabolism of the parasite (9–14).
6
c, 11b, 11c, 11e and 12c (against L. amazonensis) and com-
pounds 3a, 4a, 5a, 5c, 5d, 6c, 11a and 12b (against
L. chagasi) displayed good in vitro activity (IC50 below 10 lM).
Ramified amino alcohols 5b, 6b and 12d showed little activity.
Importantly, compounds containing alkyl chains with 10 and 12
carbon atoms showed better activity against both species of
Leishmania promastigotes.
In summary, this work describes the synthesis and antileishmanial
evaluation of several lipidic amino alcohols derivatives. The results
showed here, together with previously published data, provided evi-
dence that the N-alkyl lipophilic diamines and amino alcohols could
be prototypes for new antileishmanial drugs. Further studies in vitro
and in vivo are required to assess its biological activity in order to
better understand its mechanism of action and pharmacological
effects.
In this context, we describe in this work the synthesis of several N-
alkyl amino alcohols and their antileishmanial evaluation. Amino
alcohols were prepared using a similar methodology previously
described (Scheme 1) (8,15–18). Alcohols 1a–e (octanol, decanol,
Acknowledgments
The authors gratefully acknowledge UFJF, CAPES and CNPq for fel-
lowships. This research was supported by FAPEMIG.
2
34
Chem Biol Drug Des 2010; 75: 233–235

Antileishmanial Activity of Amino Alcohols
References
of 2-aminocyclohexanol and 1,2-cyclohexanediamine derivatives.
Bioorg Med Chem Lett;18:184–187.
1
. WHO (2005) Tropical Disease Research. Progress 2003–2004.
Special Programme for Research and Training in Tropical Dis-
eases. Geneva.
11. Bacchi C.J., Yarlett N. (2002) Polyamine metabolism as chemo-
therapeutic target in protozoan parasites. Mini Rev Med
Chem;2:553–563.
2
3
. Murray H.W., Berman J.D., Davies C.R., Saravia N.G. (2005)
Advances in leishmaniasis. Lancet;366:1561–1577.
. Dantas-Torres F., Brand¼o-Filho S.P. (2006) Visceral leishmaniasis
in Brazil: revisiting paradigms of epidemiology and control. Rev
Inst Med Trop Sao Paulo;48:151–156.
. Croft S.L., Barret M.P., Urbina J.A. (2005) Chemotherapy and
trypanosomiases and leishmaniasis. Trends Parasitol;21:508–512.
. Mishra J., Saxena A., Singh S. (2007) Chemotherapy of leish-
maniasis: past, present and future. Curr Med Chem;14:1153–1169.
. Santos D.O., Coutinho C.E.R., Madeira M.F., Bottino C.G., Vieira
R.T., Nascimento A.B., Bourguignon S.C., Corte-Real S., Pinho
R.S., Rodrigues C.R., Castro H.C. (2008) Leishmaniasis treatment
12. Heby O., Roberts S.C., Ullman B. (2003) Polyamine biosynthetic
enzymes as drug targets in parasitic protozoa. Biochem Soc
Trans;31:415–419.
13. Basselin M., Robert-Gero M. (1998) Alterations in membrane flu-
idity, lipid metabolism, mitochondrial activity, and lipophospho-
glycan expression in pentamidine-resistant Leishmania. Parasitol
Res;84:78–83.
14. Braga F.G., Coimbra E.S., Matos M.O., Carmo A.M.L., Cancio
M.D., Da Silva A.D. (2007) Synthesis and biological evaluation of
some 6-substituted purines. Eur J Med Chem;42:530–537.
15. Giordani R.B., De Almeida M.V., Fernandes E., Da Costa C.F., De
Carli G.A., Tasca T., Zuanazzi J.A.S. (2008) Anti-Trichomonas vag-
inalis activity of synthetic lipophilic diamine and amino alcohol
derivatives. Biomed Pharmacother;63:613–617.
16. Taveira A.F., Le Hyaric M., Reis E.F.C., Araffljo D.P., Ferreira A.P.,
Souza M.A., Alves L.L., LourenÅo M.C.S., Vicente F.R.C., De Al-
meida M.V. (2007) Preparation and antitubercular activities of
alkylated amino alcohols and their glycosylated derivatives.
Bioorg Med Chem;15:7789–7794.
17. Reis E.F.C., Junior C.O.R., Alves L.L., Ferreira A.P., De Almeida M.V.
(2008) Synthesis and immunosuppressive activity of lipophilic
amino alcohols and diamines. Chem Biol Drug Des;72:596–598.
18. Jfflnior C.O.R., Le Hyaric M., Costa C.F., CorrÞa T.A., Taveira A.F.,
Araffljo D.A., Reis E.F.C., LourenÅo M.C.S., Vicente F.R.C., Almeida
M.V. (2009) Preparation and antitubercular activity of lipophilic
diamines and amino alcohols. Mem Inst Oswaldo Cruz;104:703–
705.
4
5
6
–
a challenge that remains: a review. Parasitol Res;103:1–10.
7
8
9
. Coimbra E.S., Almeida C.G., Jfflnior W.V., Dos Reis R.C.N., De Al-
meida A.C.F., Forezi L.S.M., De Almeida M.V., Le Hyaric M.
(2008) Antileishmanial activity of aldonamides and N-acyl-dia-
mine derivatives. ScientificWorldJournal;8:752–756.
. Da Costa C.F., Coimbra E.S., Braga G.B., Dos Reis R.C.N., Da
Silva A.D., De Almeida M.V. (2009) Preparation and antileishma-
nial activity of lipophilic N-alkyl diamines. Biomed Pharmacoth-
er;63:40–42.
. Del Olmo E.M., Alves M., LopØz J.L., Inchaustti A., Yaluff G., De
Arias A.R. (2002) Leishmanicidal activity of some aliphatic
diamines and amino alcohols. Bioorg Med Chem Lett;12:659–
662.
1
0. Rebollo O., Del Olmo E., Ruiz G., López-PØrez J.L., GimØnez A.,
San Feliciano A. (2008) Leishmanicidal and trypanocidal activities
Chem Biol Drug Des 2010; 75: 233–235
235