Synthesis of prodrug with therapeutic potential for

Brazilian Chemical Society (SBQ). Division of Medicinal Chemistry. 4th Brazilian Symposium on Medicinal Chemistry
Synthesis of prodrug with therapeutic potential for tuberculosis
meningitis using CDS
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Pinto, L.S.R. ; Fernandes, J.T. ; Regasini , L.O.; Peccinini, R.G. ; Silva, M. *; [email protected]
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Depto de Princípios Ativos Naturais e Toxicologia - Faculdade de Ciências Farmacêuticas - UNESP - Rod. Araraquara
- Jaú Km 01, CEP.14801-902 - Araraquara-SP – Brasil
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Lapdesf – Lab. de Pesquisa e Desenvolvimento de Fármacos - Depto de Fármacos e Medicamentos - Faculdade de
Ciências Farmacêuticas - UNESP - Rod. Araraquara - Jaú Km 01, CEP.14801-902 - Araraquara-SP – Brasil
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Instituto de Química - UNESP – Prof. Francisco Degni, CEP.14801-970 - Araraquara-SP – Brasil
Keywords: prodrug, CDS, ethambutol.
Introduction
The inefficiency of many drugs in the brain sickness
treatment results of the incapability to transport the
blood-brain barrier (BBB) and maintain adequate
levels of concentrations in the central nervous
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system (CNS) . Chemical approaches to improve
brain uptake of a therapeutic agent rely on molecular
manipulations. Prodrug formation involves a
transient
chemical
modification
of
the
pharmacologically active species to improve the
deficient physicochemical properties. In designing a
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chemical delivery systems (CDS) for the CNS, the
unique architecture of the BBB can actually be
turned to an advantage.
from samples in KBr pellets with a Shimadzu
13
1
spectrophotometer.
C and H spectra were
collected in the Advance DPX300 spectrometer
(Brüker) at 500 MHz, using 5 mm diameter
resonance tubes, with CDCl3, DMSO-d6. Meltingranges of products were measured, without
correction, in an Electrothermal melting-point
apparatus. Analytical thin-layer chromatography was
used to monitor the purification of synthesized
derivatives and bound drug.
First, a CDS should be sufficiently lipophilic to enter
the central compartment. The molecule should then
undergo to an enzymatic and/or chemical conversion
to promote retention in the CNS. It is expected that,
at the same time, peripheral elimination of the entity
is accelerated due to facile conversion of the CDS in
the body.
Results and Discussion
In this work, to obtain a redox CDS and improve the
access of tuberculostatic agent to the CNS for
tuberculosis meningitis treatment, ethambutol was
covalently linked to nicotinic acid. These
intermediate was then quaternized to generate the
pyridinium salts and the ethambutol prodrug The
reactions involved in the synthesis of the ethambutol
prodrug are outlined in Figure 1.
OH
H3C
DCC
NH
CH3
+
Acknowledgements
H3C
NH
NH
O
CH3
O
N
HO
(EBM)
The present study was intended to contribute to the
development of new anti-tuberculosis drug using
CDS. The CDS approach may offer many promising
possibilities for brain delivery and targeting, like the
increase brain concentrations of ethambutol and the
decrease of adverse effects.
OH
OH
NH
Conclusions
(NA)
(NEB)
O
Authors would like to thank the Fapesp and FCFArUNESP.
N
CH3I
OH
____________________
OH
H3C
H3C
NH
NH
CH3
Na2S2O4
NH
NH
CH3
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Thwaites, G. E.; Hien, T. T. Lancet Neurol., 2005,4,160.
Katti, M. K. Med. Sci. Monit., 2004, 10,215.
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Bodor, N.; Buchwald, P. Am. J. Drug Delivery, 2003, 1,13.
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Yoon, S.H., Wu, J., Bodor N. Bull. Korean Chem. Soc., 2002, 23, 761.
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Bodor, N., Farag, H. H. J. Med. Chem., 1983, 26, 528.
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O
O
O
O
N
CH3
(ethambutol prodrug)
N
+ ICH3
(pyridinium ethambutol salt)
Figure 1. Synthesis of ethambutol prodrug.
(EBM - ethambutol, NA - nicotinic acid, NEB nicotinoylethambutol).
The compounds were structurally characterized and
identified: infrared absorption spectra in the
-1
wavelengths range 4000 to 400 cm were obtained
4th Brazilian Symposium on Medicinal Chemistry – BrazMedChem2008