Synthesis of prodrug with therapeutic potential for
Transcrição
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 1 2 3 1 2 Pinto, L.S.R. ; Fernandes, J.T. ; Regasini , L.O.; Peccinini, R.G. ; Silva, M. *; [email protected] 1 Depto de Princípios Ativos Naturais e Toxicologia - Faculdade de Ciências Farmacêuticas - UNESP - Rod. Araraquara - Jaú Km 01, CEP.14801-902 - Araraquara-SP – Brasil 2 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 3 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 1,2 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 3-5 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 1 Thwaites, G. E.; Hien, T. T. Lancet Neurol., 2005,4,160. Katti, M. K. Med. Sci. Monit., 2004, 10,215. 3 Bodor, N.; Buchwald, P. Am. J. Drug Delivery, 2003, 1,13. 4 Yoon, S.H., Wu, J., Bodor N. Bull. Korean Chem. Soc., 2002, 23, 761. 5 Bodor, N., Farag, H. H. J. Med. Chem., 1983, 26, 528. 2 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