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 Pinto, L.S.R.1; Fernandes, J.T. 2; Regasini3, L.O.; Peccinini, R.G.1; Silva, M.2*; [email protected] 1Depto de Princípios Ativos Naturais e Toxicologia - Faculdade de Ciências Farmacêuticas - UNESP - Rod. Araraquara - Jaú Km 01, CEP.14801-902 - Araraquara-SP – Brasil 2Lapdesf – 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 3Instituto de Química - UNESP – Prof. Francisco Degni, CEP.14801-970 - Araraquara-SP – Brasil
Keywords: prodrug, CDS, ethambutol.
from samples in KBr pellets with a Shimadzu
Introduction
spectrophotometer. 13C and 1H spectra were collected in the Advance DPX300 spectrometer
The inefficiency of many drugs in the brain sickness
(Brüker) at 500 MHz, using 5 mm diameter
treatment results of the incapability to transport the
resonance tubes, with CDCl3, DMSO-d6. Melting-
blood-brain barrier (BBB) and maintain adequate
ranges of products were measured, without
levels of concentrations in the central nervous
correction, in an Electrothermal melting-point
system (CNS)1,2. Chemical approaches to improve
apparatus. Analytical thin-layer chromatography was
brain uptake of a therapeutic agent rely on molecular
used to monitor the purification of synthesized
First, a CDS should be sufficiently lipophilic to enter
pharmacologically active species to improve the
the central compartment. The molecule should then
deficient physicochemical properties. In designing a
undergo to an enzymatic and/or chemical conversion
chemical delivery systems (CDS)3-5 for the CNS, the
to promote retention in the CNS. It is expected that,
unique architecture of the BBB can actually be
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
Conclusions
access of tuberculostatic agent to the CNS for tuberculosis meningitis treatment, ethambutol was
The present study was intended to contribute to the
development of new anti-tuberculosis drug using
intermediate was then quaternized to generate the
CDS. The CDS approach may offer many promising
pyridinium salts and the ethambutol prodrug The
possibilities for brain delivery and targeting, like the
reactions involved in the synthesis of the ethambutol
increase brain concentrations of ethambutol and the
Acknowledgements
Authors would like to thank the Fapesp and FCFAr-
Thwaites, G. E.; Hien, T. T. Lancet Neurol., 2005,4,160.
Katti, M. K. Med. Sci. Monit., 2004, 10,215.
3Bodor, N.; Buchwald, P. Am. J. Drug Delivery, 2003, 1,13.
4Yoon, S.H., Wu, J., Bodor N. Bull. Korean Chem. Soc., 2002, 23, 761.
Bodor, N., Farag, H. H. J. Med. Chem., 1983, 26, 528.
(ethambutol prodrug) (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 wavelengths range 4000 to 400 cm-1 were obtained
4th Brazilian Symposium on Medicinal Chemistry – BrazMedChem2008
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Brazilian Chemical Society (SBQ). Division of Medicinal Chemistry. 4th Brazilian Symposium on Medicinal Chemistry