Monday , 27 February 2017

N-[4-[Benzyloxy] benzyl]-benzenemethaneamines with High Biological Activity against Intracellular Trypanosoma cruzi and Leishmania infantum Amastigotes

Gabrielle Frizzo Souza1, Simon Bernhard Cämmerer1*, Caio Haddad Franco2, Laura Maria Alcantara2, Carolina Borsoi Moraes2, Lucio Holanda Freitas-Junior2*
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.
2Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Rua Giuseppe Maximo Scolfaro. 10.000 – Polo II de Alta Tecnologia Campina –São Paulo, Brasil.

Chagas disease and Leishmaniasis, caused respectively by Trypanosoma cruzi and Leishmania spp., are neglected tropical diseases for which only unsatisfactory chemotherapeutic options are available. Therefore, there is still an urgent need to develop novel and improved pharmaceuticals for the treatment of these diseases. Inhibition of sterol biosynthesis has been proposed as a strategy for chemotherapy of Trypanosoma spp. and Leishmania spp., because they mainly depend on endogenous ergosterol. Benzyl farnesyl amine has been proven to exhibit high inhibition of human squalene synthase (SQS), a key enzyme of cholesterol biosynthesis in man. Isosteric replacement of the farnesyl chain for benzyloxybenzyl substituent has been demonstrated to result in derivatives with stronger inhibition of human SQS and higher metabolic stability. These mimetics of benzyl farnesyl amine have never been tested for biological activity against Trypanosoma cruzi and Leishmania infantum. In this study, a small library of substituted N-[4-[benzyloxy] benzyl]-benzenemethaneamines was prepared by chemical synthesis and tested for biological activity against these pathogenic tropical protozoa. All compounds exhibited high activity against intra cellular amastigotes of Trypanosoma cruzi and Leishmaniainfantum. N-[[4-[3´,4´-Dimethoxy]- benzyloxy] benzyl]-benzenemethaneamine hydrochloride 6c showed, with EC50: 2.8 mM, thehighestpotencyagainst Trypanosoma cruzi, comparabletotheactivityofthe positive controlbenznidazole (EC50: 3.0 mM), whereas(S)-a-methyl- N-[4-[benzyloxy]benzyl]-benzenemethaneaminehydrochloride6 f presentedthemostpotentactivityagainst Leishmania infantum, with EC50: 7.7 mM. The compoundspresented a high selectivitytowardsL. infantumamastigotes. Thisfinding demonstrates that structurally simple SQS inhibitors have a high potential in anti-Chagas and anti-Leishmaniasis drug design. It is of great importance for the development of novel, low cost antitrypanosomial and antileishmanial drugs in emerging countries. 

Keywords: Benzyl Farnesyl Amine Mimetics, Trypanosoma cruzi, Leishmania infantum, Neglected Tropical Infectious Diseases Drug Discovery

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