Correlation between electrochemical and theoretical studies on the leishmanicidal activity of twelve Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1590/S0103-50532012000500015

Enzymatic bioreduction of nitro groups plays an important role on the activity of biologically active nitroaromatic compounds. Electrochemical methods are useful tools to simulate in vivo metabolic processes. This work presents electrochemical studies in

Full text of DOI:10.1590/S0103-50532012000500015

J. Braz. Chem. Soc., Vol. 23, No. 5, 894-904, 2012.
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Article
A
Correlation between Electrochemical and Theoretical Studies on the
Leishmanicidal Activity of Twelve Morita-Baylis-Hillman Adducts
Yen G. de Paiva,a,b Antônio A. de Souza,b,c Claudio G. Lima-Junior,a Fábio P. L. Silva,a
Edilson B. A. Filho,a,d Camila C. de Vasconcelos,b Fabiane C. de Abreu,b
Marília O. F. Goulart*,b and Mário L. A. A. Vasconcellos*,a
aDepartamento de Química, Universidade Federal da Paraíba, Campus I, 58059-900 João Pessoa-PB, Brazil
bInstituto de Química e Biotecnologia, Universidade Federal de Alagoas, 57072-970 Maceió-AL, Brazil
cDepartamento de Química, Instituto Federal de Alagoas, 57020-600 Maceió-AL, Brazil
dColegiado de Ciências Farmacêuticas, Universidade Federal do Vale do São Francisco, 56304-917 Petrolina-PE, Brazil
O processo de biorredução enzimática do grupo nitro é de grande importância para a ação
molecular de nitrocompostos aromáticos biologicamente ativos. Os métodos eletroquímicos são
considerados ferramentas úteis para a simulação de processos metabólicos in vivo. No presente
trabalho, realizaram-se estudos eletroquímicos em meio aprótico (N,N-dimetilformamida
(DMF) mais perclorato de tetrabutilamônio (TBAP) 0,1 mol L-1) utilizando-se as técnicas de
voltametria cíclica (CV), de pulso diferencial (DPV) e de onda quadrada (SWV) de 12 adutos de
Morita-Baylis-Hillman (MBHA) com atividade leishmanicida significativa. Para facilitar a análise,
os adutos foram agrupados em quatro classes de acordo com a cadeia lateral. Os estudos de CV
evidenciam duas ondas referentes à redução do grupo nitro e uma ou duas outras ondas (em potencial
mais negativo) relativas à redução da função carbonila α,β-insaturada ou da olefina ativada por
grupos nitrila.Adutos orto-substituídos apresentam maior facilidade de redução quando comparados
aos demais isômeros (meta e para) em função, provavelmente, da ligação de hidrogênio entre o
grupo nitro e a hidroxila benzílica, o que estabiliza mais o produto eletrogerado do que o composto
de partida. Derivados orto também mostram uma maior atividade leishmanicida em comparação
com seus isômeros em cada série. Estudos conformacionais usando HF/6-31+G(d)/PCM
como nível de cálculo evidenciaram este efeito. Valores calculados de dureza molecular (N) e de
cargas atômicas (QN) explicam corretamente os dados experimentais obtidos.
Enzymatic bioreduction of nitro groups plays an important role on the activity of biologically
active nitroaromatic compounds. Electrochemical methods are useful tools to simulate
in vivo metabolic processes. This work presents electrochemical studies in aprotic media
(N,N-dimethylformamide (DMF) plus tetrabutylammonium perchlorate (TBAP) 0.1 mol L-1) using
cyclic voltammetry (CV), differential pulse voltammetry (DPV) and square wave voltammetry
(SWV) of twelve Morita-Baylis-Hillman adducts (MBHA) with significant leishmanicidal activity.
To facilitate the analysis, the molecules were grouped in four classes according to the side chain.
CV studies show three up to four reduction waves, in which the first two waves are related to nitro
group reduction. The other waves (presenting more negative potential) refer to the reduction of
the α,β-unsaturated carbonyl or to the nitrile activated olefin side-chain. Ortho adducts present
facilitated reduction in comparison to the other isomers (meta and para) possibly due to hydrogen
bond formation between the benzylic–OH and the nitro group, which stabilizes the reduction
product (anion radical nitro) more efficiently than the original compound. Ortho derivatives also
present higher leishmanicidal activity upon comparison to the other derivatives of each class.
Conformational studies using HF/6-31+G(d)/PCM as a calculation level highlight this effect.
Molecular hardness (N) and atomic charges (QN) values corroborate the obtained experimental data.
Keywords: Morita-Baylis-Hillman adducts, electrochemical parameters, nitrocompounds,
biological activity, computational studies, Leishmania
*e-mail: mofg@qui.ufal.br, mlaav@quimica.ufpb.br

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Introduction
Leishmaniasis is a vector-borne disease caused by
different protozoan species of the genus Leishmania, an
obligate intramacrophage parasite. This neglected disease
is currently one of the most important health problems
in several developing countries, with approximately
350 million people at risk. The current available treatment
is unsatisfactory due to high cost, toxic side effects and
drug resistance developed by the parasites.13
In our continuing efforts towards the synthesis,
bioevaluation against parasites that cause Leishmaniasis and
Chagas disease,5 and conformational studies of
Morita-Baylis-Hillman adducts (MBHA),14 the present
work aimed to investigate the electrochemical behavior of
twelve MBHA in aprotic media (N,N-dimethylformamide
(DMF) plus tetrabutylammonium perchlorate (TBAP)
0.1 mol L-1), as well as theoretical aspects of these
compounds. The correlation between the theoretical and
electrochemical information obtained here with biological
activity against Leishmania amazonensis, previously
observed, was analyzed.
The Morita-Baylis-Hillman reaction (MBHR) is
an important green atom-economical carbon-carbon
bond-forming reaction,1 generating polyfuncionalized
molecules with large biological activity spectra.2 It involves
coupling of alkenes containing electron-withdrawing
groups (EWG) with aldehydes, imines or ketones, among
other starting materials. Most of these reactions are usually
catalyzed by tertiary amines such as 1,4-diazabicyclo[2.2.2]
octane(DABCO)(Scheme1). SeveralMorita-Baylis-Hillman
adducts (MBHA) present functional groups, such as nitro
in their structure, which are capable of interacting with
biomolecules. Kundu et al.3 reported for the first time the
antimalarial activity of these compounds. The effects of
MBHA on biological targets were also investigated, showing
significant activity against the snail Biomphalaria glabrata
(secondary vector of schistosomiasis),4 and parasites
that cause Malaria, Leishmaniasis and Chagas disease.5
Moreover, they also work as bactericidal,6 fungicidal7 and
antitumor compounds against some human cancer cells.8
Experimental
Chemicals
MBHA were synthesized following previously
published procedures.15 Spectroscopic and spectrometric
data of MBHA Ia-IVc are available in the Supplementary
Information (SI) section. It is noteworthy that the spectra
of IIIa, IIIb, IIIc, IVa, IVa, VIb and IVc, also available in
the SI section, were included for the first time.
Scheme 1. General scheme for Morita-Baylis-Hillman reactions.
The biological activity of nitrocompounds is associated
to nitro group reduction that generates RNO2- • or more
reduced intermediates.9 The process of nitro group
enzymatic bioreduction is important for the biological
activity of nitroaromatic compounds. Considering
biotransformation, nitro group can undergo several
reactions and lead to toxic metabolites, i.e., nitro radical
anion and/or hydroxylamine and/or nitroso derivatives.
In vivo, reductive metabolism is carried out by flavines-
dependent reductases, which are able to use these
compounds as electron acceptors. Redox potentials
are considered the main physicochemical parameter to
determine the effectiveness of nitrocompounds, providing
thermodynamic and kinetic information about electron
transfer (ET) process.9,10 Mimicking cell conditions,
hydrophilic (protic media) or lypophilic (aprotic media)
environments are crucial to understand the facilitation of
the reduction process (represented by Epc1), the biological
activity and the mechanism of action against several
parasites, including Trypanosoma cruzi11 and Leishmania.12
Equipment and procedure
All experiments were conducted at room temperature
(25 2 °C) and degassing was performed by purging an
inert gas (Argon). Cyclic voltammetry (CV), differential
pulse voltammetry (DPV) and square wave voltammetry
(SWV) were performed with a conventional three-electrode
cell (with volumetric capacity of 10 mL) in an Autolab
PGSTAT-30 potentiostat (Echo Chemie, Utrecht, the
Netherlands) coupled to a microcomputer, using GPES
4.9 software. The working electrode was a Metrohm GC
electrode of 3 mm diameter, the counter electrode was a
platinum coil and the reference electrode wasAg|AgCl, Cl-
(0.1 mol L-1). The glassy carbon electrode was previously
polished with alumina on a polishing felt until a mirror-
like surface appearance was obtained. The solvent used in
aprotic media studies was distilled under reduced pressure
after stirring with anhydrous copper sulfate. For DPV
measurements, the pulse amplitude was 50 mV, the step

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Correlation between Electrochemical and Theoretical Studies on the Leishmanicidal Activity
J. Braz. Chem. Soc.
potential was 10 mV, and the scan rate was 10 mV s-1. In CV
experiments, the scan rate varied from 35 to 1000 mV s-1.
Argon was used to degas the solution, which was covered
with an Argon blanket during the experiments.
are shown in Figures 2, 3, 4 and 5. In this medium, three to
four reduction waves were observed. The first two waves
were related to the nitroaromatic function, and the third
(and fourth) to the acrylate moiety (Figure 6).9
The generation of stable nitro-anion radical was observed
(system Ic/Ia) (Figures 2, 3, 4 and 5: b, d, f, Figure 6,
equation 1) in a diffusion-controlled reversible system
(Epc1 independent of scan rate and Ipa/Ipc ca. 1), followed
by a second wave related to generation of hydroxylamine
(Figure 6, equation 2) that would suffer oxidation at Epa2,
except for the ortho derivative. There was no corresponding
response in the second successive scan related to the
reversible 2-electron RNO/RNHOH couple, suggesting an
instability of hydroxylamine in this medium10,18 (data not
shown). Table 1 lists the main electrochemical parameters
(Epc1) for the studied compounds.
These compounds were also studied by SWV
(Figure 7) and DPV (Figure 8). DPV showed three
reduction waves, except for Ia adduct. Nitro radical anion
wave was characterized as a well-defined and intense
current peak. The other waves were related to olefin system
reduction (Figure 8). SWV forward and backward currents
for the second scan clearly showed the reversibility of
the electrogenerated nitro anion radical system and the
irreversibility of the following waves. Table 2 lists the main
obtained values.
Computational details
Computational analyses were performed using
GAUSSIAN09W® package version for Linux.16 Initially,
relaxed potential energy surfaces scan (RPESS) was
performed in a semi-empirical AM1 level, considering the
relevant rotational degrees of freedom for MBHAs (sigma
bonds). Dihedral angles were frozen in steps of 10°, while
the remaining portion of the molecule was optimized. At
the end, potential energy curves for each dihedral angle
were obtained, were the conformation of minimum energy
was selected. They were, then, subjected to calculation at
HF/6-31G+(d) level, considering a polarized continuum
model (PCM) by introducing DMF dielectric constant
(ε = 37.50).
The HOMO (highest occupied molecular orbital) and
LUMO (lowest unoccupied molecular orbital) and
the Mulliken charge (of -NO2 nitrogen atom) values
were obtained from the most stable conformations of
MBHA. The molecular hardness (N) was calculated from
N = [(LUMO + HOMO)/2] equation.17
One or two additional irreversible cathodic waves
(Epc3 and Epc4) were related to α,β-unsaturated ester or
nitrile activated olefin reduction. Souza and co-workers9
were the first to perform electrochemical investigations
of MBHA. According to these authors, compound
IIc (1 mmol L-1) shows an irreversible cathodic wave
(Epc = −2.24 V at 100 mV s-1; Ep – Ep1/2 = 152 mV).9
Thus, the similarities between MBHA reduction potential
observed here and the study by Souza and co-workers9
suggest that the additional cathodic waves may be related to
the α,β-unsaturated ester or nitrile-conjugated double bond.
Corroborating this, the electrochemical studies performed
with methyl 2-phenylhydroxymethyl acrylate revealed this
profile (Figure 9).
Results and Discussion
The syntheses of the studied compounds (Figure 1),
as well as their physicochemical data, have been
previously reported.15 Purity of all compounds was
assessed by gas chromatography (SI section). Classes I,
II, III and IV were classified as nitrile, methyl acrylate,
2-hydroxyethylacrylate and propyl acrylate, based on the
side chain. Letters a, b and c refer to ortho, meta and para
substitution of the side chain on the aromatic ring.
Electrochemical studies: aprotic media
The cyclic voltammetry of nitro derivatives in all series
(on a glassy carbon electrode) in DMF + TBAP 0.1 mol L-1
In general, the isolated double bonds are not reducible
under electrochemical conditions, however, electron
Figure 1. Chemical structures of the studied MBHA.

Vol. 23, No. 5, 2012
Paiva et al.
897
Figure 2. Cyclic voltammograms of MBHA class I (1 mmol L-1) in aprotic media (DMF + TBAP 0.1 mol L-1), v = 100 mV s-1. Working electrode: GCE
Metrohm (3 mm diameter); counter electrode: platinum coil; reference electrode: Ag|AgCl, Cl- (0.1 mol L-1).
capture is facilitated when olefins are electron-poor,
for instance, when they are conjugated to an electron
withdrawing p-system such as carboalkoxyl or nitrile groups.
α,β-Unsaturated esters have a complex electrochemical
behavior profile, nevertheless, saturation of the double
bound is the most common event, thus, Epc3 can be related
to the formation of the methyl derivative side-chain.19
Some substituents may affect the electron distribution of
several chemicals, changing their reduction potentials and
influencing the stability of electrogenerated species.20 In

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Correlation between Electrochemical and Theoretical Studies on the Leishmanicidal Activity
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Figure 3. Cyclic voltammograms of MBHA class II (1 mmol L-1) in aprotic media (DMF + TBAP 0.1 mol L-1), v = 100 mV s-1. Working electrode: GCE
(Metrohm, 3 mm diameter); counter electrode: platinum coil; reference electrode: Ag|AgCl, Cl- (0.1 mol L-1).
qualitative terms, electron-donating groups turn the reduction
process more difficult, whereas electron withdrawing groups
facilitate it.10,11,20 The ortho-substituent must be carefully
analyzed due to effects other than the usual interactions such
as hydrogen bonding and field effects.10
The reduction of nitrocompounds as well as
formation and stabilization of electrogenerated species
are environment-dependent molecular processes.10
The ortho-substituted MBHA (a) exhibited easier
reduction followed by its isomers meta (b) and para (c).

Vol. 23, No. 5, 2012
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Figure 4. Cyclic voltammograms of MBHA class III (1 mmol L-1) in aprotic media (DMF + TBAP 0.1 mol L-1), v = 100 mV s-1. Working electrode: GCE
(Metrohm, 3 mm diameter); counter electrode: platinum coil; reference electrode: Ag|AgCl, Cl- (0.1 mol L-1).
The order of nitro reduction facilitation in each class
(represented by Epc1) (Table 1) is:
The observed differences in reduction potentials
may be due to hydrogen bond formation between the
benzylic-OH and the nitro group, giving a 7-membered
ring, which stabilizes the reduction product (nitro anion
radical) more than the original compound. In regards to the
Ia > Ib > Ic; IIa > IIb > IIc; IIIa > IIIb > IIIc and IVa >
IVb > IVc

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Correlation between Electrochemical and Theoretical Studies on the Leishmanicidal Activity
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Figure 5. Cyclic voltammograms of MBHA class IV (1 mmol L-1) in aprotic media (DMF + TBAP 0.1 mol L-1), v = 100 mV s-1. Working electrode: GCE
(Metrohm, 3 mm diameter), counter electrode: platinum coil; reference electrode: Ag|AgCl, Cl- (0.1 mol L-1).
side chain, MBHA with the nitrile group (class I) showed
higher reduction potential (facilitated reduction) compared
to the ester derivatives (Tables 1 and 2):
Despite the slight difference in potential values
(Table 1), it is noteworthy the higher reduction values of
Ia and IVa.
As reduction generates more polar compounds, some
effects are much stronger in these species than in starting
Ia>IIIaca.IVa>IIa;Ib>IIIbca.IVb>IIb;Ic>IIIcca.IVc>IIc

Vol. 23, No. 5, 2012
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Figure 6. Scheme for reduction of adduct Ib in aprotic medium DMF + TBAP 0.1 mol L-1 (also applied to other members of this class).
Table 1. Reduction potentials of MBHA classes I, II, III and IV in aprotic media DMF + TBAP 0.1 mol L-1, v = 100 mV s-1. Working electrode: glassy
carbon electrode (GCE) (Metrohm 3 mm); auxiliary electrode: platinum wire; reference electrode: Ag|AgCl, Cl-
MBHA
Epc1 / V
–0.944
−1.028
–1.029
–1.061
–1.062
–1.084
Epc2 / V
–1.470
–1.520
–1.429
–1.644
–1.602
–1.716
Epc3 / V
Epc4 / V
–2.537
AMBH
IIIa
Epc1 / V
–1.014
–1.077
–1.056
–1.009
–1.063
–1.058
Epc2 / V
–1.597
–1.751
–1.527
–1.634
–1.541
–1.648
Epc3 / V
–2.137
Epc4 / V
a
Ia
–2.425
a
a
a
Ib
–2.291
IIIb
–1.962
a
a
Ic
IIIc
–2.116
–2.441
a
a
a
IIa
–2.178
–1.904
–2.144
IVa
–2.153
–1.702
–2.188
IIb
IVb
IVc
–1.948
a
IIc
anot present.
Figure 7. Square wave voltammogram MBHA class I (1 mmol L-1) in
aprotic media (DMF + TBAP 0.1 mol L-1), v = 100 mV s-1. Working
electrode: GCE (Metrohm, 3 mm diameter); counter electrode: platinum
coil; reference electrode: Ag|AgCl, Cl- (0.1 mol L-1).
Figure 8. Differential pulse voltammogram of MBHA class I (1 mmol L-1)
in aprotic media (DMF + TBAP 0.1 mol L-1). Working electrode: GCE
(Metrohm, 3 mm diameter); counter electrode: platinum coil; reference
electrode: Ag|AgCl, Cl- (0.1 mol L-1).
Table 2. SWV and DPV reduction potentials of MBHA classes I, II, III and IV in aprotic medium DMF + TBAP (0.1 mol L-1), v = 100 mV s-1. Working
electrode: glassy carbon electrode (GCE) (Metrohm, 3 mm); auxiliary electrode: platinum wire; reference electrode: Ag|AgCl, Cl-
SWV
DPV
AMBH
Epc1 / V
−0.914
−0.986
−0.999
−1.017
AMBH
IIIa
Epc1 / V
−0.976
−1.032
−1.040
−0.979
−1.021
−1.027
AMBH
Ia
Epc1 / V
−0.889
−0.965
−0.970
−0.985
AMBH
IIIa
Epc1 / V
−0.951
−1.009
−0.988
−0.981
−0.990
−0.998
Ia
Ib
IIIb
Ib
IIIb
Ic
IIIc
Ic
IIIc
IIa
IIb
IVa
IIa
IVa
−1.026
IVb
IVc
IIb
IIc
−1.003
IVb
IVc
a
a
IIc
anot present.

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Correlation between Electrochemical and Theoretical Studies on the Leishmanicidal Activity
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Table 3. Calculated frontier orbitals, molecular hardness and charge of
MBHA nitrogen atoms
b
MBHA
Ia
HOMO / eV LUMO / eV
Na
QN
–0.36546
–0.36309
–0.36622
–0.35704
–0.35713
–0.36295
–0.36218
–0.35741
–0.36322
–0.35681
–0.35674
–0.36275
+0.04060
+0.03556
+0.03495
+0.04747
+0.03776
+0.03774
+0.04327
+0.03703
+0.03754
+0.04742
+0.03744
+0.03783
–0.162430
–0.163765
–0.165635
–0.154785
–0.159685
–0.162605
–0.159455
–0.160190
–0.16284
–0.154695
–0.159650
–0.162460
+0.219
+0.123
+0.114
+0.112
+0.091
+0.105
+0.288
+0.130
+0.103
+0.106c
+0.124
+0.104
Ib
Ic
IIa
IIb
IIc
IIIa
IIIb
IIIc
IVa
IVb
IVc
Figure 9. Cyclic voltammograms of methyl 2-phenylhydroxymethyl
acrylate (c = 1 mmol L-1) in aprotic media (DMF + TBAP 0.1 mol L-1),
v= 100 mV s-1.Working electrode: GCE (Metrohm, 3 mm diameter); counter
electrode: platinum coil; reference electrode: Ag|AgCl, Cl- (0.1 mol L-1).
materials. Conformational effects are also very important
in this type of analysis and were performed (Figure 10),
indicating that an internal hydrogen bonding is formed in
compounds Ia and IVa, which might be intensified in the
anion-radical intermediates by allowing a better resonance
stabilization. Hydrogen bonding was also observed on the
side chain of acrylate derivatives, a feature that does not
influence nitro reduction potential.
b
aN = molecular hardness; QN = Mulliken charges of nitrogen atoms of
NO2 groups; can exception.
of MBHA. However, according to Paula and co-workers,17
when HOMO and LUMO values were used to calculate the
molecular hardness, a more relevant parameter regarding
to molecular reactivity,17 these correlations could be noted.
The hardness can be used to evaluate the resistance of the
electron to be dispersed on molecules, which will lead to
modifications of the chemical reactivity and/or the interaction
with an enzyme (or other biological target). The calculated
values of molecular hardness (N) showed in Table 3 revealed
that the ortho-substituent in the same class of compounds
(I, II, III or IV) are softer than their congeners MBHA. It
is possible that the lower values of N indicate that adducts
may stabilize more efficiently the radical anion, facilitating
their formation. It is worth noting that there is a good
relationship between the values of Epc1 (Table 1), with the
calculated values of hardness (Table 3) to their isomeric
compounds, and the corresponding IC50 values presented in
our previous work.15
Table 4 lists the main electrochemical parameters and
data on leishmanicidal activity.
This evaluation is in accordance with values obtained
from electrochemical (Epc1) parameters and bioactivities.
Moreover, the calculated charges for nitrogen atoms
on -NO2 (QN, Table 3) indicated that in most cases, the
most bioactive compounds carried more positive nitrogen
charge, indicating a facilitated acceptance of electrons
(higher electron affinity). In fact, it becomes evident that
the intramolecular hydrogen bonding formation between
NO2…HO has an important role in molecular dispersion
(softness) and the largest atomic charge on the nitrogen
atom and both of these effects increasing the molecular
bioactivity. Finally, a strong relationship between IC50 and
Figure 10. Conformational minima of MBHA Ia-IVc calculated from
HF/6-31+G(d)/PCM on DMF simulations (see geometrical parameters
for the conformational minima of MBHA Ia-IVc, in the SI section).
Analyses of HOMO and LUMO frontier orbitals were
also performed (Table 3). It was not found a clear relationship
between LUMO energies and the reduction potentials (see
Epc1, Table 1) of the nitro group attached to the aromatic ring

Vol. 23, No. 5, 2012
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903
Table 4. Comparison between the 50% inhibitory concentration (IC50) against Leishmania amazonensis and the nitro reduction potential (Epc1) in aprotic
medium (DMF + TBAP 0.1 mol L-1), obtained by CV
MBHA
Ia
IC50 / µM
62.00
Epc1 / V vs. Ag|AgCl, Cl- (0.1 mol L-1)
MBHA
IIIa
IC50 / µM
20.52
64.57
53.03
28.38
72.23
52.04
Epc1 / V vs. Ag|AgCl, Cl- (0.1 mol L-1)
–0.944
–1.028
–1.029
–1.061
–1.062
–1.084
–1.014
–1.077
–1.056
–1.009
–1.063
–1.058
Ib
238.27
128.27
50.08
IIIb
Ic
IIIc
IIa
IVa
IIb
IIc
451.58
196.16
IVb
IVc
Epc1 values was observed (Table 4) when comparing the
inter-series of MBHA compounds. For instance, MBHA Ia
presented higher leishmanicidal activity (lower IC50) than
Ib and Ic MBHA congeners and at the same time had the
least negative Epc1 (higher electron affinity). This tendency
is recurrent throughout all Table 4.
This conclusion, however, has to be cautiously
considered as the bioactivity does not depend solely on the
ease of reduction of the nitro group but upon the mechanism
of action involving the global molecular structure of the
substrates.
to Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq), Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior (CAPES), Fundação de
Apoio à Pesquisa do Estado da Paraíba (FAPESQ-PB) and
Fundação de Amparo à Pesquisa do Estado de Alagoas
(FAPEAL) and Instituto Nacional de Ciência e Tecnologia
(INCT-Bioanalítica) for financial support.
References
1. Morita, K.; Suzuki, Z.; Hirose, H.; Bull. Chem. Soc. Jpn. 1968,
41, 2815; Baylis, A. B.; Hillman, M. E. D.; German Patent
2,155,113 1972 (CA 77: 34174q).
Conclusions
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P. D.; Hyma, R. S.; Tetrahedron 1996, 52, 8001; Drewes, S. E.;
Roos, G. H. P.; Tetrahedron 1988, 44, 4653.
The α,β-unsaturated ester and nitrile moieties seem to
be crucial in the mechanism of action of these compounds,
especially in regards to biological nucleophilic targets
of Leishmania. The presence of a 7-membered ring
intramolecular hydrogen bond (IHB) in the MBHA
ortho-substituted seems to be a structural requirement for
the remarkable bioactivities of these adducts in comparison
to their respective isomers. Finally, a strong correlation was
obtained between Epc1 and IC50 values when compared to
their isomeric compounds. The most stable conformers
in in silico solvated environment of all MBHA were
obtained and frontier orbitals were calculated. Softer
compounds (lower molecular hardness, N) were the most
bioactive against Leishmania amazonensis.
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Supplementary Information
The spectroscopic data and geometrical parameters for
the conformational minima of MBHA Ia-IVc are available
free of charge at http://jbcs.sbq.org.br as a PDF file.
Acknowledgments
The authors are grateful to Cleylton Bezerra Lopes and
Waldomiro Pinho Júnior for technical assistance and

904
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Submitted: January 26, 2012
Published online: April 17, 2012