Improved synthesis of seven aromatic Baylis-Hillman adducts (BHA): Evaluation against Artemia salina Leach. and Leishmania chagasi

Article abstract of DOI:10.1016/j.ejmech.2008.03.016

We described a very efficient procedure to prepare seven aromatic compounds (1-7), a new class of antileishmanial substances, through Baylis-Hillman reaction (BHR). With one, all the Baylis-Hillman adducts were prepared in quantitative yields by reaction

Full text of DOI:10.1016/j.ejmech.2008.03.016

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European Journal of Medicinal Chemistry 44 (2009) 1726e1730
http://www.elsevier.com/locate/ejmech
Short communication
Improved synthesis of seven aromatic BayliseHillman adducts (BHA):
Evaluation against Artemia salina Leach. and Leishmania chagasi
a
a
a
a
Ticiano P. Barbosa , Cl a´ udio G.L. Junior , F a´ bio P.L. Silva , Horacimone M. Lopes ,
Lucas R.F. Figueiredo , Suervy C.O. Sousa , Guilherme N. Batista , Thiago G. da Silva ,
a
a
b
c
c,d
b,c
a,
Tania M.S. Silva , M a´ rcia R. de Oliveira , M a´ rio L.A.A. Vasconcellos *
a
Departamento de Qu ´ı mica, Universidade Federal da Para ´ı ba, Campus I, 58059-900 Jo ~a o Pessoa, PB, Brazil
b
Departamento de Biologia Molecular, Universidade Federal da Para ´ı ba, Campus I, 58059-900 Jo ~a o Pessoa, PB, Brazil
c
Laborat o´ rio de Tecnologia Farmac eˆ utica, Universidade Federal da Para ´ı ba, Campus I, Jo ~a o Pessoa, PB, Brazil
d
Instituto Multidisciplinar em Sa u´ de, Universidade Federal da Bahia, Campus Avan c¸ ado, An ´ı sio Teixeira, Avenida Ol ´ı via Flores, 3000,
Bairro Candeias 45055-090, Vit o´ ria da Conquista, BA, Brazil
Received 16 June 2007; received in revised form 29 February 2008; accepted 6 March 2008
Available online 29 March 2008
Abstract
We described a very efficient procedure to prepare seven aromatic compounds (1e7), a new class of antileishmanial substances, through
BayliseHillman reaction (BHR). With one, all the BayliseHillman adducts were prepared in quantitative yields by reaction of the corresponding
ꢀ
aromatic aldehydes in acrylonitrile at 0 C in only 10e40 min reaction time. We present our results about the toxicities of these compounds
evaluated on the microcrustaceous Artemia salina Leach. and against promastigote Leishmania chagasi. All substances evaluated in this
work have showed high bioactivity. The 3-hydroxy-2-methylene-3-(4-bromopheny)propanenitrile (4) (LC50 ¼ 30.9 mg/mL on A. salina;
IC50 ¼ 25.2 mM on L. chagasi) was the most active compound evaluated on A. salina Leach. and on promastigote L. chagasi. The 2-[hydrox-
y(pyridin-4-yl)methyl]acrylonitrile (7) (LC50 ¼ 30.9 mg/mL on A. salina Leach.; IC50 ¼ 4.8 mg/mL on L. chagasi) was also a very active sub-
stance evaluated in this work on promastigote L. chagasi.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: BayliseHillman adducts; Green chemistry; Leishmania chagasi; Artemia salina Leach.
1
. Introduction
immunopathologies and degrees of morbidity and mortality
2]. There is so far no approved vaccine for clinical use. Toxicity
and resistance to the pentavalent antimonies (for examples Glu-
[
The leishmaniasis are a complex of diseases caused by dif-
Ò
Ò
ferent species of the protozoan parasite Leishmania and a major
public health problem in many developing countries where 350
million people live at risk of infection [1]. The parasite exists in
two forms: the flagellate promastigote in the female phleboto-
mine sandfly vector, and the amastigote in the mammalian
host. The disease has been traditionally classified into three
different clinical forms, visceral (VL), cutaneous (CL) and
mucocutaneous leishmaniasis (MCL), which have different
cantime and Pentostan ), which have been the mainstay of the
treatment of both visceral leishmaniasis (VL) and cutaneous
leishmaniasis (CL) during the last 60 years are critical problems
[3]. Although new drugs have become available in recent years,
including lipid formulations of amphotericin B, the oral drug
miltefosine for VL, and topical paromomycin for CL, these
are not entirely satisfactory due to the high cost, reported side
effects or ineffectiveness [4,5]. Thus, the currently available
chemotherapy is far from being satisfactory, urging the search
for new safe, affordable and effective drugs.
Recently, we described that 16 aromatic BayliseHillman
adducts (BHA) showed selective activity against Leishmania
*
Corresponding author. Tel.: þ55 83 32167413; fax: þ55 83 32167437.
E-mail address: mlaav@quimica.ufpb.br (M.L.A.A. Vasconcellos).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.03.016

T.P. Barbosa et al. / European Journal of Medicinal Chemistry 44 (2009) 1726e1730
1727
amazonensis in vitro [6]. Among them, the compound 2-
hydroxy(4-bromophenyl)methyl]acrylonitrile (4, Fig. 1) pres-
N
[
XH
X
N
EWG
ents two necessary qualities for a potential drug: to present
very antileishmanial activity (IC50 ¼ 12.5 mM) and to be
a safer compound (0.0 (0.9); % macrophage LDH release), be-
ing up to now, our lead compound. The BHA 3 was the most
efficient among the evaluated compounds against L. amazo-
nensis (IC50 ¼ 7.9 mM) but presented some cytotoxicity on
uninfected adherent mouse peritoneal macrophages [6]. Com-
pounds 2, 3, 5e7 (Fig. 1) were never evaluated against Leish-
mania parasites [7].
In our continuing search for bioactive substances [8e11], in
connection with our efforts towards the study of the reactivity
of BayliseHillman reaction and our interest in extending the
scope of this new class of Leishmanicides, our group has
dedicated efforts aiming to discover a practical synthetic meth-
odology objectifying to obtain great quantities of these com-
pounds, potential drugs against several species of Leishmania.
The purpose of this short communication is to present
a very efficient ‘‘one-pot’’ procedure that can prepare com-
pounds 1e7 (Fig. 1) under green conditions [12] and to pres-
ent our results on evaluations of the toxicities of 1e7
compounds against Artemia salina Leach. [13] and promasti-
gote form of Leishmania chagasi, the pivotal parasite in this
endemic disease in Brazil [14].
EWG
+
DABCO
R1
R1
R2
R2
Scheme 1. The MoritaeBayliseHillman reaction: R
¼ H, CO R, alkyl, X ¼ O, NTs, NSO Ph; EWG ¼ electron withdrawing
group: COR, CHO, CN, CO R.
1
¼ alkyl, aryl, heteroaryl;
R
2
2
2
2
synthetic utility of these adducts, several protocols have
been proposed to improve this reaction, such as the use of
microwaves, ultrasound, salt and metal addition, high pressure
and ionic liquids [16].
2
.1. About the procedures
We initiated our synthetic work into the preparation of 2 be-
cause the 3-nitro-benzaldehyde substrate is a good electrophile
and the cheapest one in our selected group of aldehydes. Several
solvents, temperatures and additives were first evaluated in our
work, but all of them were inefficient to prepare pure 2 on rea-
sonable yield. We present in Table 1 the most important results
aiming to increase yields and minimize co-products in the prep-
aration of BHA 2.
In Table 1 we can note that the use of ultrasound does not
significantly increase yields and not minimize the reaction
time (entry 1 versus 2 and 3 versus 4, Table 1) [17]. In our
case, the use of ultrasound retards the reaction time (3 versus
2
. Chemical synthesis
BayliseHillman reaction (BHR) was first reported in 1972
15], and involves the coupling of alkenes containing electron
[
4
). We observe that compound 2 was prepared in quantitative
withdrawing groups (EWG) with aldehydes, ketones and im-
ines (among others), using tertiary amines as nucleophilic cat-
alysts, e.g. the 1,4-diazabicyclo[2.2.2]octane (DABCO), the
most frequently employed catalyst (Scheme 1).
ꢀ
yield, in 20 min at 0 C (entry 3, Table 1). It is important to
point out that no co-product was observed on the medium
reaction. In fact, no further chromatography purification was
necessary by using this procedure. We noted that these effi-
This reaction affords adducts, such as 1 (Fig. 1), from the
simple starting materials (e.g. 2-nitro-benzaldehyde and acry-
lonitrile to prepare 1) where all the atoms in the substrate are
present in the product (a total atom economy). Due to the
ciences reactions (rates and yields) were better in cold
ꢀ
(
0 C) than at room temperature. This effect was already
described by Rafel and Leahy [18] and also by us [19,20]
on reaction using methyl acrylate as Michael acceptor and
p-nitrobenzaldehyde as an electrophile. This has been ex-
plained based on the proposed mechanism for this reaction
[20e24]. We present in Table 2 our results aiming the prepa-
ration of compounds 1e7.
NO2 OH
OH
OH
CN O2N
CN
O N
CN
2
1
2
3
Table 1
Preparation of the adduct 2
OH
O
OH
CN
O N
O2N
CN
2
CN
DABCO(1mmol)
condition
+
Br
4
1mmol 0.4mL (6mmol)
2
OH
OH
OH
Entry
Condition
Reaction time (min)
Isolated yield (%)
N
CN
CN
CN
ꢀ
ꢀ
a
1
2
3
4
25 C
25 C, ultrasound
20
70
20
40
85
N
a
90
100
N
ꢀ
0 C
0 C, ultrasound
a
84
5
6
7
ꢀ
a
Fig. 1. The selected BH adducts prepared and evaluated in this paper.
A dimeric co-product was also observed.

1728
T.P. Barbosa et al. / European Journal of Medicinal Chemistry 44 (2009) 1726e1730
Table 2
BH adducts’ preparation in acrylonitrile at low temperature
was filtered into silica gel (150 g), using EtOAcehexane
1 L; 2:8 to 1:1, respectively, of the solvent) and concentrated
under reduced pressure (20.2 g of 2; 100% yield). After,
(
O
OH
DABCO
CN
1
mmol
DABCO could be easily recycled through silica gel using
ꢀ
+
CN
°
500 mL of ethanol 96 as solvent and concentrated under
reduced pressure (95% recyclable of DABCO).
0
C
R
1
R
mmol.
0.4 mL (6mmol)
1-7
Entry
Adduct
Reaction time (min)
Isolated yield
a
2
2
.5. Spectroscopic data
(
%)
1
2
3
4
5
6
7
a
1
2
3
4
5
6
7
40
25
100
100
100
98
.5.1. 2-[Hydroxy(2-nitrophenyl)methyl]acrylonitrile (1)
ꢁ
1 1
IR (KBr): 3345, 2228, 1348, 1609, 1520 cm ; H NMR
200 MHz, CDCl ) d 8.01 (dd, J ¼ 8.0/1.4 Hz, 1H); 7.84 (dd,
15
(
240
30
3
100
100
100
J ¼ 6.0/1.8, 1H); 7.72 (ddd, J ¼ 8.0/1.8/1.4 Hz, 1H); 7.52
50
10
(
(
ddd, J ¼ 8.0/1.6/1.4 Hz, 1H); 6.12 (d, J ¼ 1.4 Hz, 1H); 6.09
3
13
d, J ¼ 1.2 Hz, 1H); 5.98 (s, 1H).
00 MHz) d 69.13 (1C), 116.51 (1C), 124.30 (1C), 125.07
1C), 129.11 (1C), 129.71 (1C), 132.03 (1C), 134.16 (1C),
34.30 (1C), 147.93 (1C).
C NMR (CDCl ,
No purification by chromatography was necessary.
1
(
1
This experimental procedure directly leads to substances
e7 in quantitative yields (no co-products were detected in
1
2.5.2. 2-[Hydroxy(3-nitrophenyl)methyl]acrylonitrile (2)
ꢁ
1 1
IR (KBr): 3345, 3105, 2239, 1583, 1520, 1348 cm ; H
the reaction media), avoiding further chromatography purifica-
tion. We found that this protocol is also adaptable to the prep-
aration of the bioactives BHA 1e7 on scale up. These crude
products are fully purified after a simple filtration on silica
gel using hexaneeacetate (8:2) as solvent.
NMR (200 MHz, CDCl ) d 8.24 (dd, J ¼ 1.8/1.6 Hz, 1H);
3
8.18 (ddd, J ¼ 8.0/1.0/1.2 Hz, 1H); 7.57 (t, J ¼ 8.0 Hz, 1H);
7.75 (ddd, J ¼ 7.8/1.6 Hz, 1H); 6.09 (d, J ¼ 0.8 Hz, 1H);
6.20 (d, J ¼ 1.6 Hz, 1H); 5.43 (s, 1H); 3.02 (br s, 1H, CHOH ).
1
3
C NMR (CDCl , 100 MHz) d 72.66 (1C), 116.31 (1C),
3
2
.2. Experimental section
121.14 (1C), 123.35 (1C), 125.01 (1C), 129.73 (1C), 131.52
1C), 132.53 (1C), 141.21 (1C), 147.98 (1C).
(
Commercially available reagents were purchased from Al-
drich and used without further purification. The compounds
synthesized in this work are not new. The adducts 1e7 were
characterized using NMR by comparison with the compounds
2.5.3. 2-[Hydroxy(4-nitrophenyl)methyl]acrylonitrile (3)
IR (KBr): 3447, 3115, 2228, 1599, 1520, 1348, 736 cm
ꢁ
1
;
1
H NMR (200 MHz, CDCl ) d 8.21(d, J ¼ 8.8 Hz, 2H); 7.58
3
1
13
described in literature [10,19,25e29]. H and C NMR spec-
tra were obtained by using a Mercury Spectra AC 200
(d, J ¼ 9.0 Hz, 2H); 6.07 (d, J ¼ 0.8 Hz, 1H); 6.16 (d,
1
3
J ¼ 0.6 Hz, 1H); 5.42 (s, 1H); 3.23 (br s,1H, CHOH ).
C
NMR (CDCl , 50 MHz): d 73.01; 116.62; 123.92 (2C);
1
13
200 MHz for H and 50.3 MHz for C) in CDCl or Varian
(
3
3
1
3
Spectra VNMR S-500 (100 MHz for C). The IR spectra
were obtained using spectrophotometer 1600 FT-IR and
126.13; 127.34 (2C); 130.51; 146.80; 147.82.
2
000 FT-IR (PerkineElmer). TLC was done by using silica
2.5.4. 2-[Hydroxy(4-bromophenyl)methyl]acrylonitrile (4)
1
gel Kieselgel 60 (E. Merck) and spots were visualized with
short wavelength UV light.
H NMR (CDCl , 200 MHz): d 7.54 (dd, J ¼ 6.0/2.0 Hz,
3
2H); 7.28 (dd, J ¼ 6.0/1.8 Hz, 2H); 6.11 (d, J ¼ 1.6 Hz, 1H);
1
3
C
6
.04 (d, J ¼ 1.0 Hz, 1H); 5.27 (s, 1H); 2.71 (s, CHOH ).
2
.3. Experimental procedure
NMR (CDCl , 100 MHz): d 73.29 (1C); 116.66 (1C); 122.74
3
(1C); 125.77 (1C); 128.10 (2C); 130.34 (1C); 131.89 (2C);
138.12 (1C).
Reactions were carried out using the corresponding alde-
hydes (1 mmol), 0.4 mL of acrylonitrile (6 mmol) and
ꢀ
1
mmol of DABCO at 0 C for x min (Table 2). After the
2.5.5. 2-[Hydroxy(pyridin-2-yl)methyl]acrylonitrile (5)
ꢁ1
1
end of the reaction, the reaction media was directly filtered
on silica gel, using AcOEtehexane (2:8) as solvent and the re-
action products were concentrated under reduced pressure.
The products are ready to be bioevaluated as they are by using
this procedure.
IR (film) 3200, 2225, 1600 cm
.
H NMR (CDCl3,
200 MHz): d 8.56 (ddd, J ¼ 8.0/1.4 Hz, 1H); 7.75 (ddd,
J ¼ 7.8/7.6/1.6 Hz, 2H); 7.37 (d, J ¼ 7.8 Hz, 1H); 7.29 (ddd,
J ¼ 0.8/1.0/1.2 Hz, 1H); 5.28 (s,1H); 6.21 (s, 1H); 6.05 (s,
1
3
1H). C NMR (CDCl , 100 MHz) d 72.89 (1C), 116.69
3
(1C), 121.19 (1C), 123.67 (1C), 125.82 (1C), 130.86 (1C),
137.43, 148.47 (1C), 156.09 (1C).
2
.4. A scale up procedure to BHA
Reactions were also carried out using, for example, m-ni-
trobenzaldehyde 0.1 mol (15.1 g), 40 mL of acrylonitrile and
2.5.6. 2-[Hydroxy(pyridin-3-yl)methyl]acrylonitrile (6)
1
H NMR (CDCl , 200 MHz): d 8.41 (m, 2H); 7.79 (ddd,
3
J ¼ 7.8/1.8/1.6 Hz, 1H); 7.33 (dd, J ¼ 8.0 Hz, 1H); 6.05 (d,
ꢀ
1
equiv. of DABCO at 0 C for 30 min. The reaction mixture

T.P. Barbosa et al. / European Journal of Medicinal Chemistry 44 (2009) 1726e1730
1729
1
3
J ¼ 1.0 Hz, 1H); 6.17 (d, J ¼ 1.2, 1H); 5.33 (s, 1H). C NMR
100
1
0 µM
25 µM
50 µM
(
CDCl , 100 MHz) d 71.51 (1C), 116.69 (1C), 124.09 (1C),
3
1
(
25.99 (1C), 130.39 (1C), 135.04 (1C), 136.13 (1C), 147.40
1C), 148.94 (1C).
8
6
0
0
2
.5.7. 2-[Hydroxy(pyridin-4-yl)methyl]acrylonitrile (7)
1
HNMR(CDCl , 200 MHz):d8.50(d, J ¼ 6 Hz, 2H);7.36(d,
3
J ¼ 5.8 Hz, 2H); 5.31(s, 1H); 6.16 (d, J ¼ 0.6 Hz, 1H); 6.06 (s,
13
40
1
1
H). C NMR (CDCl , 100 MHz) d 72.48 (1C), 116.50 (1C),
3
21.42(2C), 125.67(1C), 130.63(1C), 149.14(1C), 149.58(2C).
. Toxicity against A. salina Leach.
2
0
3
0
The brine shrimp assay has been established as a safe, prac-
1
2
3
4
Adducts
5
6
7
tical, and economic method for the synthetic compounds bio-
activity determination [10,13]. The brine shrimp lethality
bioassay was performed following the reported procedure
Fig. 2. Effect of different concentrations of BayliseHillman adducts against
promastigote forms of L. chagasi. The parasites were cultivated in Schneider
[
13]. The growth medium was prepared with filtered sea water
ꢀ
6
medium at 26 C for 72 h. The initial number of cells was 1 ꢂ 10 promasti-
gotes/mL. The graph represents the meaning of three independent experiments
performed in triplicate.
in a small tank divided into two compartments. The shrimp
eggs were added to the covered compartment and a lamp
was placed above the open side of the tank to attract hatched
shrimps through perforations in the partition wall. After 48 h,
the shrimps mature as nauplii (A. salina Leach.) and are ready
for the assay. Stock solutions of the test compounds were pre-
pared by dissolving 25 mg in 2 mL of DMSO, and filtered sea
water to complete 5 mL of the total volume. Appropriate vol-
umes were then added to tubes with sea water containing 10
nauplii to afford four different drug concentrations in quadru-
plicate for each one. The control samples containing sea water
and DMSO, under the same conditions, do not cause signifi-
cant brine shrimp mortality. After 24 h of incubation under
light, the number of dead and survivor brine shrimps in each
tube was counted. The LC50 values were calculated by
graphics of concentration drug versus lethality percentage
using a probit adjust scale. Data analysis was performed
with Origin 6.0 software. Tested compounds are considered in-
active when LC50 > 1000 mg/mL [30,31]. We present in
Table 3 the results of the toxicities of 1e7 in A. salina Leach.
Following a 72 h parasite culture in the presence of the ad-
ducts, L. chagasi growth was inhibited with IC50 values be-
tween 25.2 and 38.8 mM (Table 4), 4 being the most active
compound (IC50 ¼ 25.2 mM). Note in Table 4 that all seven
adducts revealed high antipromastigote activity.
4
.2. Experimental section
Promastigote forms of L. chagasi (MCAN/BR/99/JP15) in
6
the log phase of growth (1 ꢂ 10 parasites/mL) were incubated
ꢀ
at 26 C in Schneider’s Drosophila medium supplemented
with 20% of FBS in the presence or absence of different con-
centrations of 1e7 BayliseHillman adducts. The reference
Ò
drug Glucantime was used as control. After 72 h, parasites
were collected, fixed on isotonic solution (10.5 g citric acid,
7
.0 g NaCl, 5.0 mL formalin and 1000 mL distilled water)
and examined under light microscopy. The inhibitory effect
of the fraction on cell growth was estimated by cell counting
using a Neubauer chamber. The concentration that inhibits
50% of the growth (IC ) was determined by regression anal-
ysis using the program SPSS 8.0 for Windows. All
4
. Bioevaluation on L. chagasi
.1. Results
50
4
The compounds of BayliseHillman 1e7 in the present
work showed strong antileishmanial activity against promasti-
gote forms of L. chagasi (Fig. 2).
Table 4
Promastigote antileishmania activity of BayliseHillman adducts 1e7
a
Compounds
IC50 (mM)
IC50 (mg/mL)
1
2
3
4
5
6
7
38.8
34.6
37.4
25.2
32.0
36.9
30.1
e
7.9
7.1
7.6
6.0
5.1
5.9
4.8
Table 3
Toxicity against Artemia salina of the BayliseHillman adducts
Adduct
LC50 (mg/mL)
LC50 (mM)
1
2
3
4
5
6
7
87.8
96.1
36.8
30.9
87.2
88.8
70.9
430.39
471.07
180.39
129.83
545.00
555.00
443.12
Ò
b
Glucantime
1620.3
a
IC50 values obtained from a minimum of three separate experiments per-
formed in triplicate are shown.
b
Ò
The reference drug (Glucantime ) used in this study does not show in vitro
activity on the promastigote forms of L. chagasi.

1730
T.P. Barbosa et al. / European Journal of Medicinal Chemistry 44 (2009) 1726e1730
experiments were done at least three times and each experi-
ment was performed in triplicate.
[7] M.K. Kundu, N. Sundar, S.K. Kumar, S.V. Bhat, S. Biswas, N. Valecha,
Bioorg. Med. Chem. Lett. 9 (1999) 731e736.
[
8] L.S.M. Miranda, B.G. Marinho, S.G. Leit ~a o, M.E. Matheus,
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5
. Conclusion
(
2004) 1573e1575.
[
9] L.S.M. Miranda, B.G. Marinho, S.G. Leit ~a o, M.E. Matheus,
P.D. Fernandes, M.L.A.A. Vasconcellos, N.M. Gomes, Eur. J. Pharmacol.
We presented in this short communication a very efficient pro-
cedure to prepare compounds 1e7 (10e40 min reaction time,
0 C, 98e100%) a new class of antileishmanial compounds.
The results reveal the biological activity of seven aromatic Bayl-
5
50 (2006) 47e53.
ꢀ
[10] M.L.A.A. Vasconcellos, T.M.S. Silva, C.A. C aˆ mara, R.M. Martins,
K.M. Lacerda, H.M. Lopes, V.L.P. Pereira, R.O.M.A. de Souza,
L.T.C. Crespo, Pest. Manag. Sci. 62 (2006) 288e292.
iseHillman adducts 1e7 against the promastigote form of L. cha-
[
11] R.O.M.A.
de
M.L.A.A. Vasconcellos, Synthesis (2004) 1595e1600.
Souza,
B.A.
Meireles,
L.S.
Sequeira,
gasi
parasites.
The
compound
2-[hydroxy(4-
[
12] R.O.M.A. de Souza, P.H. Fregadolli, L.C. Aguiar, K.M. Gon c¸ alves,
V.L.P. Pereira, L.C. Filho, P.M. Esteves, M.L.A.A. Vasconcellos,
O.A.C. Antunes, Lett. Org. Chem. 3 (2006) 936e939.
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M.D. Vargas, Bioorg. Med. Chem. 13 (2005) 6464e6469.
bromophenyl)methyl]acrylonitrile(4)presentedthemosttoxicity
against A. salina Leach. indicating that the use of A. salina Leach.
was efficient to the biological replay control, in our search for
antileishmanial substances. The fact of 2-[hydroxy(4-bromophe-
nyl)methyl]acrylonitrile (4) was also a very active and safe com-
pound on L. amazonensis in our previous article [6], focusing our
attention on these new potential drugs on L. chagasi
[
[14] A.J.M. Caldas, D.R.C. Silva, C.C.R. Pereira, P.M.S. Nunes, B.P. Silva,
A.A.M. Silva, A. Barral, J.M.L. Costa, Rev. Soc. Bras. Med. Trop. 34
(
2001) 445e451.
[
15] A.B. Baylis, M.E.D. Hillman, Chem. Abstr. 77 (1972) 34174q1;
German Patent 2155113, 1972.
[16] D. Basavaiah, J. Rao, T. Satyanarayana, Chem. Rev. 103 (2003)
(
IC ¼ 25.2 mM or 6.0 mg/mL). Finally, we could detach the in-
5
0
teresting profile of the pyridine nucleus on 5, 6 and 7 (LC50 ¼ 5.1,
.9 and 4.8 mg/mL, respectively) and the nitro compounds 1, 2
5
811e891.
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[
and3(LC ¼ 7.9, 7.1and7.6 mg/mL,respectively)asveryactive
5
0
ones against the promastigote form of L. chagasi.
7
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[
[
Acknowledgment
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1
383e1389.
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1e24.
FAPESQ (Funda c¸ ~a o de Amparo a` Pesquisa do Estado da
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2
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