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Naphthoquinones and Derivatives for Chemotherapy: Perspectives and Limitations of their Anti-trypanosomatids Activities

[ Vol. 27 , Issue. 15 ]

Author(s):

Luíza Dantas-Pereira, Edézio F. Cunha-Junior, Valter V. Andrade-Neto, John F. Bower, Guilherme A.M. Jardim, Eufrânio N. da Silva Júnior, Eduardo C. Torres-Santos and Rubem F.S. Menna-Barreto*   Pages 1807 - 1824 ( 18 )

Abstract:


Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited, and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo is essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

Keywords:

T. cruzi, Leishmania spp., T. brucei, Chagas disease, Leishmaniasis, sleeping sickness, chemotherapy, naphthoquinones, naphthoimidazoles.

Affiliation:

Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, School of Chemistry, University of Bristol, Bristol, Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro



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