15 th Brazilian Meeting on Organic Synthesis – 15 th BMOS – November 10-13, 2013 - Campos do Jordão, Brazil Synthesis and evaluation against Trypanosoma cruzi of naphthoquinone-containing triazoles Emilay B. T. Diogo, a Gleiston G. Dias, a Wagner O. Valença, b Celso A. Camara, b Mauro G. da Silva, b Ronaldo N. de Oliveira, b Rubem F. S. Menna-Barreto, c Solange L. de Castro c and Eufrânio N. da Silva Júnior a* a Instituto de Ciências Exatas, Departamento de Química, UFMG, MG, Brazil; b Departamento de Ciências Moleculares, UFRPE, PE, Brazil; c Laboratório de Biologia Celular, IOC, FIOCRUZ, RJ, Brazil. *eufranio@ufmg.br Keywords: Lapachol, β-Lapachone, Quinone, Chagas disease, Click chemistry. INTRODUCTION Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, affects approximately eight million individuals in Latin America. 1 CD is characterized by a short acute phase defined by patent parasitemia and a long and progressive chronic phase. Up to 40%-50% of chronically infected patients develop progressive cardiomyopathy and/or motility disturbances of the esophagus and colon. The available chemotherapy for CD is not satisfactory depending on two heterocyclic agents, nifurtimox and benznidazole. 2 Naphthoquinones are considered privileged structures in medicinal chemistry due to their structural properties and biological activities. Recently, we have described the synthesis, trypanocidal and leishmanicidal activity of lapachone-based 1,2,3-triazoles. 3 In this context, herein we describe the synthesis and evaluation against T. cruzi of 1,2,3-triazole substituted para- and ortho- naphthoquinones. RESULTS AND DISCUSSION Compounds 1-10, N-phthalimidoalkyl-azides, and 11-12 were initially synthesized and used in a click chemistry reaction with substituted 2-(prop-2- yn-1-ylamine)-naphthoquinone to obtain the respective triazole compounds in high yields (Scheme 1). Scheme 1. Obtention of para-quinones 1-12. Ortho-quinones were synthesized from the intermediate azide 13 previously described. 3 To prepare the novel derivatives 14-16, naphthoquinones substituted by a terminal alkyne were obtained and used in the click chemistry reaction (Scheme 2). Nor-β-lapachone derivatives 14-16 were isolated in moderate yields. Scheme 2. Obtention of ortho-quinones 14-15. The substances 1-12 were not active against T. cruzi with IC 50 /24h > 4000 μM. Compounds 14-15 was planned in order to obtain ortho-quinone- coupled to para-quinoidal structure (Scheme 2). Our strategy was effective and the substances 14-16 presented IC 50 /24 h values = 80.8, 6.8 and 8.2 μM, respectively. When compared with benznidazole, the standard drug used against T. cruzi, compounds 15 and 16 were fifteen and twelve times more active than anti-T. cruzi drug benznidazole. CONCLUSION We synthesized and evaluated fifteen substances and three potent trypanocidal compounds were identified, more active than the anti-T. cruzi drug benznidazole, the standard anti-T. cruzi drug. Compound 15 was fifteen times more active than benznidazole and this substance is a promising candidate for further investigations. ACKNOWLEDGEMENTS This research was supported by grants from the CNPq, CAPES, FAPEMIG, FAPEAL, FACEPE- PRONEM, Fiocruz and UFMG. REFERENCES 1 Rassi Júnior, A.; Rassi, A.; Rezende, J. M. Infect. Dis. Clin. North Am. 2012, 26, 275. 2 Soeiro, M. N. C.; de Castro, S. L. Open Med. Chem. J. 2011, 5, 21. 3 Guimarães, T. T.; Pinto, M. C. F. R.; Lanza, J. S.; Melo, M. N.; do Monte- Neto, R. L.; de Melo, I. M. M.; Diogo, E. B. T.; Ferreira, V. F.; Camara, C. A.; Valença, W. O.; de Oliveira, R. N.; Frézard, F.; da Silva Júnior, E. N. Eur. J. Med. Chem. 2013, 63, 523.