Enantioselective Heck Reactions with Aryldiazonium Salts.
Challenges and Synthetic Opportunities
Caio Costa Oliveira, Ricardo Almir Angnes, Cristiane Storck Schwalm, Carlos Roque Duarte
Chemistry Institute – State University of Campinas, São Paulo – Brazil
Enantioselective catalysis has revolutionized the field of organic synthesis and has brought significant scientific and economic benefits for our society. The enantioselective arylation of olefins in particular (Heck reaction) has been a subject of intense academic and industrial interest due to its potential for providing enantiomeric enriched medicines, fragrances and new materials, which are in general more selective and less toxic than the racemic counterpart. In this context, the Pd-catalyzed coupling of arenediazonium salts to olefins (Heck-Matsuda reaction) stands as a more practical and reliable method to access structurally complex organic molecules than the conventional Heck protocols. The Heck-Matsuda arylations can be easily performed in the lab under aerobic conditions without requiring expensive and/or toxic phosphine ligands. The first examples of these reactions were described by Tsutomu Matsuda in 1977. However, in spite of the many advantages and the long-term existence of this reaction, its enantioselective version has, until recently, constituted a considerable challenge due to the intrinsic incompatibility between the ordinary phosphine ligands and the arenediazonium salts. In this lecture, the first examples of effective enantioselective Heck-Matsuda reactions will be presented using chiral bisoxazoline ligands.1 Some recent developments from our lab will also be highlighted.
up to 92.5:7.5 er
up to 95% yield
up to > 95:5 er
Intermolecular Enantioselective Heck-Matsuda Arylations. Synthesis of β–Aryl Lactones and β–
We thank the Brazilian funding agencies FAPESP, CNPq and CAPES for financial
1. a) Correia, C. R. D.; Oliveira, C. C.; Salles Jr., A. G.; and Santos, E. A. F. "The first examples of the
enantioselective Heck–Matsuda reaction: arylation of unactivated cyclic olefins using chiral
bisoxazolines" Tetrahedron Lett. 2012
, 53, 3325-3328. b) Oliveira, C. C.; Angnes, R. A. and Correia, C.
R. D. "Intermolecular Enantioselective Heck-Matsuda Arylations of Acyclic Olefins. Application to the
Synthesis of -Aryl--Lactones and -Aryl Aldehydes" J. Org. Chem
Synthesis of [Se,N]-Small Molecules: Chiral Ligands and Potentially
Antonio Luiz Braga
Departamento de Química – CFM, Universidade Federal de Santa Catarina, 88040-900, Florianópolis –
Chiral [Se,N]-Small Molecules have found growing application as ligands or catalysts in asymmetric catalysis over the past few years.1,2 The large majority of these catalysts or ligands is derived from either readily available chiral amino alcohols or other natural sources in a few high-yielding synthetic steps.2,3 Additionally, the relevance of the biological and medicinal properties of organoselenium compounds is growing in a rapid pace, mainly due to their antioxidant, antitumor, antimicrobial, and antiviral properties.4 In this context, we have developed short and efficient routes to access these type of molecules from amino acid or other natural sources, aiming to evaluate their bioactivities and/or catalytic properties. In our talk we will show our contribution in these subjects, such as the preparation of ephedrine-based diselenide (Figure 1): A promiscuous catalyst suitable to mimic the seleno-enzyme glutathione peroxidase (GPx) and to promote enantioselective C-C coupling reactions.
We are grateful to CNPq, INCT-Catálise, CAPES and FAPESC-Pronex for
financial support. References:
1. Wirth, T. Angew. Chem. Int. Ed. 2000
2. a) Braga, A. L.; Lüdtke, D. S.; Vargas, F.; Braga, R. C. Synlett 2006
, 1453. b) Braga, A. L.; Lüdtke, D.
S.; Vargas, F. Curr. Org. Chem
3. Godoi, M.; Paixão, M. W.; Braga, A. L. Dalton Trans. 2011
4. a) Nascimento, V.; Alberto, E. E.; Tondo, W. D.; Dambrowski, D.; Detty, M. R.; Nome, F.; Braga, A. L.
J. Am. Chem. Soc. 2012
, 138. b) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Re
Porphyrins and Related Macrocycles: Synthetic Studies and
José A. S. Cavaleiro
Department of Chemistry and QOPNA Research Unit, University of Aveiro, 3810-193 Aveiro, Portugal
Porphyrin derivatives play in Nature vital functions (e. g
., respiration, photosynthesis, drug
detoxification). Synthetic studies leading to the structural elucidation of such compounds
have been carried out during the last century. For example, the syntheses of protoporphyrin
IX (which forms the iron complex ruling respiration and detoxification processes) and of the
photosynthetic pigment chlorophyll a
have been reported, respectively, by Fisher in 1929
and Woodward in 1960.1a,b Subsequently, studies related with biosynthesis, mode of action
and catabolism of such compounds and also with processes mimicking Naturehave been
performed. As a result, "new chemical avenues" for such type of compounds were brought
up, in relation with the needs to have better synthetic procedures and knowledge about their
potential applications in several fields, mainly in Medicine.
In recent decades the Aveiro group has been involved in developing synthetic
methodologies leading to new porphyrinmacrocycles and related derivatives (chlorins,
bacteriochlorins, corroles). It has been shown that porphyrinmacrocycles can react under
cycloaddition conditions as dienes, dienophiles and dipolarophiles. A wide range of new
derivatives can be obtained in such way. Other derivatives can also be obtained by direct
functionalization of the macrocycle or by substituent transformations. Potential applications
for the new synthesized products have been considered. Studies have been carried out by
looking at the assessment to generate reactive oxygen species and at the involvement of
such species in photodynamic therapy (PDT) of cancer cells and in the photoinactivation of
microorganisms; the action of metalloporphyrins as oxidative catalysts in the oxidation of
organic substrates at CH(sp3) and C(sp2) centers, using hydrogen peroxide as the oxygen
donor, has also been evaluated.2a-d This lecture will consider the main features of such work
performed at the University of Aveiro. Acknowledgements:
Thanks are due to all students and colleagues involved in the work. Thanks are
also due to the University of Aveiro and to all portuguese funding institutions (INIC, JNICT, FCT) for
funding and PhD/Postdoc awarded grants. Nowadays thanks are due to Fundação para a Ciência e a
Tecnologia (FCT), European Union, QREN, FEDER and COMPETE for funding the QOPNA research
unit (project PEst-C/QUI/UI0062/2011) and the National NMR Network.
1. a) Fisher H.; Zeile K. Liebigs Ann. Chem.
, 98. b) Woodward R. B. J. Am. Chem. Soc
2. a) Silva A. M. G.; Cavaleiro J. A. S.; Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions,
Progress in Heterocyclic Chemistry, 2008
, 44, Gribble G. W.; Joule J. A.,(Eds.), Elsevier, Amsterdam.
b) Cavaleiro J. A. S.; Tomé J. P. C.; Faustino M. A. F.; Synthesis of Glycoporphyrins, Top.
, 179, E. S. H. El-Ashry, (Ed.), Heterocycles from Carbohydrate Precursors,
Springer. c) Cavaleiro J. A. S.; Faustino M. A. F.; Tomé J. P. C.; Porphyrinyl-type sugar derivatives:
synthesis and biological evaluations,Specialist Periodical Reports, CarbohydateChemistry--
Biological Approaches, 2009
, 199; Rauter A. P.; Lindhorst T. K., (Eds.), Royal Society of Chemistry,
London. d) Cavaleiro J. A. S.; Tomé A. C.; Neves M. G. P. M. S.; meso
New Synthetic Methodologies, Handbook of Porphyrin Science
(With Applications to Chemistry, Physics,
Materials Science, Engineering, Biology and Medicine), 2010
, 193; Kadish K. M, Smith K. M., Guilard
R., (Eds.), World Scientific Publishing Co., Singapore.
New Chemical Tools to Study the Biology of Malaria
iMed.UL, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa,
Antimalarial drugs currently in use engage a reduced number of validated targets, and their
efficacy is being undermined by the spread of parasite resistance. In addition, chemical
diversity among these drugs is limited, which also contributes to the emergence of cross-
resistance. Antimalarial drug discovery has traditionally focused on the optimization of
known lead compounds to achieve efficacious drug exposures with the lowest possible
dose. Recently, ligand- and structure-based design approaches complemented by cell-
based screening have been developed to identify innovative and readily synthesizable hit
and lead compounds. Here, we review how chimeric compounds (e.g. 1
) have been
designed and synthesized to engage different molecular targets in malaria parasites,
enabling efficient elimination of parasites both in vitro and in vivo.1-4 In addition, we will
report how structure-based design and target agnostic cell-based screening led to the
discovery of novel small molecules that will help to overcome our limited understanding of
We thank the Fundação para a Ciência e Tecnologia for financial support (PEst-
OE/SAU/UI4013/2011 and REDE/1501/REM/2005)
1. Capela R., Oliveira R., Moreira R., Gonçalves L., Domingos A., Gut J., Rosenthal P. J., Lopes F.
Bioorg. Med. Chem. Lett., 2009
, 19, 3229. 2. Verissimo E., Gibbons P., Araujo N., Cristiano M. L. S.,
Rosenthal P. J., Gut J., Moreira R., Guedes R. C., O'Neill P. M., J. Med. Chem., 2010
, 53, 8202. 3.
Capela R., Cabal G. G., Rosenthal P. J., Gut J., Mota M. M., Moreira R., Lopes F., Prudêncio M.
Antimicrob. Agents Chemother., 2011
, 55, 4698. 4. Oliveira R., Newton A. S., Guedes R. C., Miranda D.,
Amewu R. K., Srivastava A., Gut J., Rosenthal P. J., O'Neill P. M., Ward S. A., Lopes F., Moreira R.,
, in press. 5. Lavrado J., Cabal G., Prudêncio M., Mota M. M., Gut J., Rosenthal P.
J., Diaz C., Guedes R., Santos D. dos, Bichenkova E., Douglas K. T., Moreira R., Paulo A. J. Med.
, 54, 734. 6. Rodrigues T., Moreira R., Gut J., Rosenthal P. J., O'Neill P. M., Biagini G. A.,
Lopes F., dos Santos D. J. V. A., Guedes R. C. Bioorg. Med. Chem., 2011
, 19, 6302-6308. 7. Rodrigues
T., da Cruz F. P., Prudêncio M., Lafuente-Monasterio M., Gonçalves D., Sitoe A. R., Bronze M. R., Gut
J., Rosenthal P. J., Javier Gamo F.-, Mota M. M., Lopes F., Moreira R., J. Med. Chem., 2013
, in press.
Heterocycles via Pericyclic Reactions of Aza- and Diazafulvenium
Teresa M. V. D. Pinho e Melo
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
Aza- and diazafulvenium methide systems 1
are versatile building blocks for the synthesis
of pyrroles and pyrazoles.1 These extended dipoles participate in sigmatropic [1,8]H shifts
and 1,7-electrocyclizations giving vinyl pyrroles and pyrazoles. Under flash vacuum
pyrolysis conditions these heterocycles undergo interesting rearrangements. Aza- and
diazafulvenium methides can be intercepted by dipolarophiles. The 4,5-dimethoxycarbonyl
act exclusively as 1,7-dipoles affording products resulting from the
addition across the 1,7-positions. These 1,7-cycloadducts include chlorin and
bacteriochlorin type macrocycles (e.g. 5
) as well as steroidal analogues (e.g. 6
with relevance in medicinal chemistry. In contrast with this chemical behavior, 5-
trifluoromethylazafulvenium methides 3
can participate in both 1,7- and 1,3-dipolar
cycloadditions. Recently, the generation and reactivity of benzodiazafulveniummethides4
has also been described (Scheme 1
). In this lecture, details of our contribution to the
chemistry of these "higher-order" azomethine ylides and azomethine imines will be
X = CR Azafulvenium Methides
X = N Diazafulvenium Methides
Generation and reactivity of aza- and diazafulvenium methides.
Thanks are due to FCT (PEst-C/QUI/UI0313/2011), FEDER, COMPETE and
QREN for financial support.
1. a) Pinho e Melo, T. M. V. D.; Soares, M. I. L.; Gonsalves, A. M. d'A. R.; Paixão, J. A., Beja, A. M.;
Silva, M. R. J. Org. Chem., 2005
, 6629-6638. b) Pinho e Melo, T. M. V. D.; Nunes, C. M.; Soares, M.
I. L.; Paixão, J. A., Beja, A. M.; Silva, M. R. J. Org. Chem., 2007
, 4406-4415. c) Pereira, N. A. M.;
Fonseca, S. M.; Serra, A. C.; Pinho e Melo, T. M. V. D.; Burrows, H. D. Eur. J. Org. Chem. 2011,
3979. d) Peláez, W. J.; Pinho e Melo, T.M. V. D. Tetrahedron 2013
, 3646-3655. e) Soares, M. I. L.;
Nunes, C. M.; Gomes, C. S. B.; Pinho e Melo, T. M. V. D. J. Org. Chem. 2013
2,4,5-Tri(hetero)arylimidazoles: Design, Synthesis and
Characterization as Novel TPA Chromophores and Optical
M. Manuela M. Raposo
Centre of Chemistry, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal
2,4,5-Tri(hetero)aryl-imidazoles are a versatile class of compounds with a wide range of
applications in diverse areas such as medicinal or materials chemistry due to their biological
activity, as well their optoelectronic properties. Our earlier studies showed that the optical
and thermal properties of these derivatives could be tuned by substitution of aryl groups at
positions 2, 4 and 5 by 5-membered heterocycles such as thiophene and furan. This raises
the potential for several innovative applications of these -conjugated systems in nonlinear
second harmonic generators (SHG)), chemosensors, OLEDs and DNA
Recent results from our research group concerning the design, synthesis and
characterization of novel 2,4,5-tri(hetero)aryl-imidazoles 1
), as two-photon
absorption (TPA) chromophores and/or as optical chemosensors will be presented and
R1 = H, MeO, N,N
-dialkylamino, CN, NO2
X = N-alkyl, O, S
Structure of novel 2,4,5-tri(hetero)aryl-imidazoles.
Thank are due to Fundação para a Ciência e Tecnologia
(Portugal) and FEDER-
COMPETE for financial support through Centro de Química (PEst-C/QUI/UI0686/2011 (F-COMP-01-
0124-FEDER-022716)) and Centro de Física - Universidade do Minho (Project PTDC/CTM/105597/2008
(FCOMP-01-0124-FEDER-009457)), a PhD grant to R.C.M. Ferreira (SFRH/BD/86408/2012) and a a
post-doctoral grant to R.M.F. Batista (SFRH/BPD/79333/2011). The NMR spectrometer Bruker Avance III
400 is part of the National NMR Network and was purchased with funds from FCT and FEDER. References:
1. a) Batista R. M. F.; Oliveira E.; Costa S. P. G.; Lodeiro C.; Raposo M. M. M. Org. Lett. 2007
b) Costa S. P. G.; Belsley M.; Lodeiro C.; Raposo M. M. M. Tetrahedron 2008
, 9230. c) Batista R. M.
F.; Costa S. P. G.; Belsley M.; Raposo M. M. M. Dyes Pigments 2009
, 329. d) Pina J.; Seixas de
Melo J.; Batista R. M. F.; Costa S. P. G.; Raposo M. M. M. J. Phys. Chem B 2010
, 4964. e) Oliveira
E.; Batista R. M. F.; Costa S. P. G.; Raposo M. M. M.;
Lodeiro C. Inorg. Chem
, 10847. f)
Pedras B.; Batista R. M. F.; Tormo L.; Costa S. P. G.; Raposo M. M. M.;
Orellana G.; Capelo J. L.;
Lodeiro C. Inorg. Chim
. Acta 2012
, 95. g) Batista R. M. F.; Costa S. P. G.; Raposo M. M. M. J.
Photochem. Photobiol. Chem. 2013
Sugar-based surfactants as selective antimicrobial agents: a
Alice Martins,a Vasco Cachatra,a C. Dias,a J. Pais,a Patrícia Serra,a M. S. Santos,b Amélia P.
aCarbohydrate Chemistry Group, Center of Chemistry and Biochemistry, Faculdade de Ciências da
Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal;
bStructure and Reactivity Group, Center of Chemistry and Biochemistry, Faculdade de Ciências da
Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
Antibiotics resistance is a global threat that encourages research on new antimicrobial
molecular entities with new mechanisms of action. In this work we present the synthesis of
new antimicrobial glycosides which structure differs in both glycon and aglycon
components. Our previous studies on alkyl deoxy hexopyranosides of the D and L series in
their α- and β-anomeric configuration have shown that high surface activity is a pre-requisite
for their antimicrobial properties, and their selectivity appeared to be linked to the anomeric
configuration of the sugar and to its deoxygenation pattern.1 Hence, chemical approaches to
glycon deoxygenation and structurally diverse aglycons will be presented, based on a
simple but efficient methodology comprising the reaction of glycals with alcohols or their
heteroanalogues, catalysed by triphenylphosphane hydrobromide. D- and L-glycosides with
aglycons exhibiting alkyl chains of different size, their fluorinated or branched chain
analogues, and those chains with an internal or terminal amide functionality as well as
thioglycosides were synthesized. The surface activity of the aqueous solutions of several
glycosides was evaluated in terms of adsorption and aggregation parameters. Compounds'
bioactivity towards Bacillus anthracis
and their acute cytotoxicity will be disclosed, revealing
promising structures in view of efficacy and also of low toxicity, when compared to that of
chloramphenicol. An overview of the key structural features regarding glycon and aglycon
chemical composition and glycon configuration for this new family of antibiotics will be
presented, highlighting the correlation of their aggregation and adsorption physical data with
the antibacterial activity. Acknowledgements:
We thank QREN for financial support of the Project QREN-SI I&DT co-promotion
FACIB – Project nr. 21547, and Fundação para a Ciência e a Tecnologia for financial support of PEST-
OE/QUI/UI0612/2013 and of Alice Martins post-Doc grant SFRH/BPD/42567/2007. References:
1. Martins A.; Santos M. S.; Dias C; Serra P.; Cachatra V.; Pais J.; Caio, J.; Teixeira, V. H.; Machuqueiro,
M.; Silva, M. S.; Pelerito A.; Justino J.; Goulart M.; Silva, F. V.; Rauter A. P. Eur. J. Org. Chem. 2013
1448 and references cited therein.
Sulfur reloaded: New S(IV)-mediated transformations
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Sulfur ylides occupy a prominent place among so-called "textbook reagents" in organic chemistry.1 Recently, they have also garnered interest as potential carbene donors for metal complexes.2 Nevertheless, the standard syntheses of sulfur ylides are still multi(≥ 2)step procedures and applications in transition metal catalysis remain limited.1 We have developed a new concept of "ylide transfer" for the direct, one-step synthesis of sulfur ylides 2 from carbonyl and heteroaromatic compounds 1 (Scheme 1).3
In this communication, results from those studies will be presented, as well as interesting applications of the ylide products in transition metal catalysis. Furthermore, an intriguing alternative pathway that results in a powerful direct arylation of carbonyl compounds (Scheme 2), as well as other recent developments, shall be discussed.4,5
We thank the Max-Planck-Society, the Deutsche Forschungsgemeinschaft (MA
4861/4-1 and 4-2) and the Max-Planck-Institut für Kohlenforschung for support.
1. a) M. B. Smith, J. March, Advanced Organic Chemistry
; Wiley: New York, 2001
2. See, e.g.
: a) P. Müller, D. Fernandez, P. Nury, J.-C. Rossier, Helv. Chim. Acta 1999
, 935. b) M.
Gandelman, B. Rybtchinski, N. Ashkenazi, R. M. Gauvin, D. Milstein, J. Am. Chem. Soc. 2001
5372. c) I. K. Mangion, I. K. Nwamba, M. Shevlin, M. A. Huffan, Org. Lett. 2009
3. X. Huang, R. Goddard, N. Maulide, Angew. Chem. Int. Ed. 2010
4. a) X. Huang, N. Maulide, J. Am. Chem. Soc. 2011
, 8510; b) X. Huang, M. Patil. C. Farès, W.
Thiel, N. Maulide, J. Am. Chem. Soc. 2013
5. a) X. Huang, S. Klimczyk, N. Maulide, Chem. Sci. 2013
, 1105; b) X. Huang, B. Peng, M. Luparia, L.
Gomes, L. F. Veiros, N. Maulide, Angew. Chem. Int. Ed. 2012
6. a) González S. D.-; Marion N.; Nolan S. P. Chem. Rev. 2009
, 3621. b) Hahn F. E. Angew. Chem.
Int. Ed. 2006
7. Nair V.; Menon R. S.; Biju A. T.; Sinu C.R.; Paul R. R.; Jose A.; Sreekumar V. Chem. Soc. Rev. 2011
α,β-Unsaturated Diazoketones as Useful Platforms in the Synthesis
of Pyrrolidine, Piperidine and Indolizidine Alkaloids
Antonio C. B. Burtoloso
Instituto de Química de São Carlos, Universidade de São Paulo, 13560-970, São Carlos, SP, Brazil
Diazocompounds are a very interesting class of compounds that can promote a wide range of reactions, such as cyclopropanations, insertion reactions, ylide formation, dimerization, and elimination and formation of ketenes by the Wolff rearrangement, among others. An interesting class of these diazocompounds is the α,β-unsaturated diazoketones,1 which has received little attention when compared to the saturated ones due to the difficulty of its preparation by the usual existing methods. Herein, we would like to describe two new methodologies for the preparation of α,β-unsaturated diazoketones with E
geometry and their use as efficient platforms in the synthesis of pyrrolidines,1 indolizidines2,3 and piperidines (Scheme 1).
α,β-unsaturated diazoketones as platforms in the synthesis of alkaloids.
We thank FAPESP and CNPq for financial support.
1) Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2011
2) Pinho, V. D.; Burtoloso, A. C. B. Tetrahedron Lett. 2012
3) Bernardim, B.; Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2012
Dual-acting Antimalarial Triterpenoids from an African Medicinal
M. J. U. Ferreira
iMed.UL, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa,
Despite the efforts to eradicate malaria during the last decade, it remains a major global
health problem, particularly in many of the poorest countries in the world. The increasing
prevalence of drug-resistant Plasmodium falciparum
strains is one of the greatest
challenges in malaria control. In order to overcome drug-resistance, new antimalarial drugs
are urgently needed.
Natural product-derived compounds have played a major role in drug discovery and
development. In case of malaria drug discovery, the great significance of plant-derived
drugs for the treatment of the disease is highlighted by quinine, artemisinin and their
derivatives, which are currently the mainstay of the antimalarial therapy.
As part of our search for bioactive compounds from medicinal African plants, we have
carried out a preliminary screening of different plants species for their antimalarial activity. Momordica balsamina
L. (Cucurbitaceae) was found to be the most active plant. M.
also referred to as the balsam apple, or African pumpkin, is an extensively
cultivated vegetable consumed in many tropical and subtropical regions of the world. It has
also been widely used in traditional medicine in Africa to treat various diseases, mostly
diabetes, and malaria symptoms.
Bioassay-guided fractionation of the methanol extract of the aerial parts of Momordica
led to the isolation of several cucurbitane-type triterpenoids. These compounds
and acylated derivatives were evaluated for their antimalarial activity against the erythrocytic
stages of the Plasmodium falciparum
chloroquine-sensitive strain 3D7 and the chloroquine-
resistant clone Dd2.1
Evaluation of the activity of some compounds against the liver stage of P. berghei
carried out2, measuring the luminescence intensity in Huh-7 cells infected with a firefly
luciferase-expressing P. berghei
GFP-Luccon. Toxicity of compounds was assessed
on the same cell line through the fluorescence measurement of cell confluency. Moreover,
toxicity towards human cells of compounds was also investigated in the MCF-7 breast
cancer cell line, showing that most of them were not toxic or exhibited weak toxicity. In
blood stages of P. falciparum,
several compounds displayed antimalarial activity, revealing
some alkanoyl ester derivatives the highest antiplasmodial effects, with IC50 values in the
nanomolar range. The highest antiplasmodial activity against the liver stages of P. berghei
was also displayed by ester derivatives,
with high inhibitory activity and no toxicity.
1. a) Ramalhete C.; Lopes D., Mulhovo S.; Molnár J., Rosário V.E.; Ferreira M.J.U. Bioorg. Med. Chem
5254. b) Ramalhete C.; Lopes D., Mulhovo S.; Molnár J., Rosário V.E.; Ferreira M.J.U. Bioorg.
, 19, 330.
2. Ramalhete C.; da Cruz F.P., Lopes D.; Mulhovo S.; Rosário V. E.; Prudêncio M.; Ferreira M.J.U. Bioorg. Med. Chem
, 19, 7474.
Straightforward organic chemistry against an intricate infectious
disease: new chloroquine and quinacrine analogues as dual-stage
B. Pérez,a C. Teixeira,b A. Gomes,a J. R. B. Gomes,b P. Gomesa
aCIQ-UP, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-
007 Porto, Portugal; bCICECO, Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro,
A child dies every minute from malaria. Despite this intricate infectious disease is known for
millennia, and associated deaths have decreased by about 30% in Africa since 2006,
eradication is far from being achieved in the near future.1 There are well identified obstacles
to malaria eradication, namely, the complexity of the malaria parasite's life cycle,
widespread resistance to cheaper and most popular antimalarial drugs, and lack of efficient
vaccines or multi-stage antimalarials, able to efficiently deplete liver- and blood-stage forms
parasites from the human body. Another drawback in malaria therapy is the
high cost of first-line drugs, which instigates traffic of fake antimalarials.2
For over a decade, we have been working on the chemical modification of known drugs by
means of simple and inexpensive synthetic organic chemistry, aiming at the low-cost
improvement of their therapeutic properties.3 In this connection, we have recently focused
our research towards development of potential dual-action antimalarials, obtained by
conjugation of cinnamic acids to aminoquinoline or acridine cores from classical antimalarial
drugs (Scheme 1
).This led to discovery of novel chloroquine and quinacrine analogues as
dual-stage antimalarial leads.4
Synthetic route towards N
-cinnamoylated analogues of the classic antimalarials chloroquine
This work is supported by FEDER through the COMPETE program (ref. FCOMP-
01-0124-FEDER-020963) andby Portuguese National Funds through FCT –Fundação para a Ciência e a
Tecnologia (ref. PTDC/QUI-QUI/116864/2010). BP and CT thank FCT for their doctoral
(SRFH/BD/86166/2012) and post-doctoral (SFRH/BPD/62967/2009) grants, respectively.
1. World Malaria Report
, World Health Organization 2012
, ISBN 978 92 4 156453 3.
2. a) Reddy, D.; Bannerji, J.Lancet Infect. Dis. 2012
, 829; b) http://www.fakedrugskill.org/ (accessed
on May 28th, 2013).
3. a) Vale, N.et al. J. Med. Chem. 2009
, 7800; b) Matos, J. et al. Antimicrob. Agents Chem other.
, 1564; c) Pérez, B.et al. Eur. J. Med. Chem. 2012
4. a) Pérez, B. et al. ChemMedChem 2012
, 1537; b) Pérez, B. et al. Med. Chem. Commun. 2012
1170; c) Pérez, B. et al. J. Med. Chem. 2013
, 556; d) Pérez, B. et al. Bioorg. Med. Chem. Lett. 2013
, 610; e) Gomes, A. et al.
A Brief Saga into the Electrophilic Aromatic Substitution
Pierre Mothé Esteves
Instituto de Química, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos, 149, CT,
Bl.A-622, Cid. Univ., Rio de Janeiro, 21941-909
A discussion about the aromatic substitution mechanism, based on internal single electron
transfer between the reagents and its consequences for developing new electrophilic
reactions will be presented. An mechanistic continuum is proposed for explaining different
reactivity and observations. This investigation lead to the development new methods for
halogenation and nitration of aromatic compounds.
We thank the CNPq and FAPERJ for financial support. References:
1. Esteves, P. M.; Barboza, A. G. H., Carneiro, J. W. M., Laali, K. K., Prakash, G. K. S., Olah, G. A.,
Rasul, Golam, Cardoso, S. P. J. Am. Chem. Soc. 2003
2. Esteves, P. M.; Queiroz, J.F.; Carneiro, J.W.M; Sabino, A. A.; Sparapan, R.; M. N. J. Org. Chem
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