Sunday , 23 July 2017

Synthesis of Chiral 3-[[(Aryl) methyl] amino]- and 3-[[(Heteroaryl)-methyl]-amino]-quinuclidines with High Biological Activity against Intracellular Trypansoma cruzi Amastigotes

Bruna Fereira de Souza1, Mayara Roncaglia dos Santos1, Renan Pimentel de Souza1, Simon Bernhard Cämmerer1*, Natália Aimée d´Angelo2, Caio Haddad Franco3, Carolina Borsoi Moraes3 Lúcio H. Freitas-Junior3*

1Instituto de Química, Universidade Estadual de Campinas, Rua Monteiro Lobato S/N, Cidade Universitaria Zeferino Vaz, Barão Geraldo, CP 6154, CEP 13083-970, Campinas, São Paulo, Brasil.
2Instituto de Ciências da Saúde – ICS, Universidade Paulista. Avenida Comendador Enzo Ferrari, 280– Swift -CEP 13043-900, Campinas – São Paulo, Brasil
3Chemical Biology and Screening Platform, Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Rua Giuseppe Maximo Scolfaro, 10.000 – Polo II de Alta Tecnologia Campinas, Brasil.

A B S T R A C T
Inhibition of the sterol biosynthesis is a highly attractive strategy for chemotherapy of Trypanosoma cruzi, because this protozoa mainly depends on endogenous ergosterol. Various racemic, but only a few chiral quinuclidines were proven to be strong inhibitors of ergosterol biosynthesis in protozoa and fungi. In this study we describe the preparation of chiral 3-[[(aryl-) methyl] amino]- and 3-[[(heteroaryl)methyl]-amino]quinuclidines and their evaluation as inhibitors of intracellular Trypanosoma cruzi amastigotes with the aim to explore their potential for the development of new drugs against the Chagas disease. Main objective was to study the influence of the absolute configuration of the stereo center at C-3 on the biological activity on Trypanosoma cruzi. Most compounds showed a high biological activity against growth of intracellular Trypanosoma cruzi amastigotes. This is the first study comparing the biological activity of enantiomers of selected chiral 3-[[(aryl) methyl] amino]- and 3-[[(heteroaryl)methyl]amino]quinuclidines on Trypanosoma cruzi intracellular amastigotes. (S)-enantiomers exhibited a higher biological activity against this pathogenic protozoa as (R)-enantiomers. All compounds were highly selective towards the parasite and showed low cytotoxicity to host cells.
Keywords: Chiral Arylquinuclidines, Trypanosoma cruzi, Intracellular Amastigotes.

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