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

Author:

Dantas-Pereira Luíza1ORCID,Cunha-Junior Edézio F.2ORCID,Andrade-Neto Valter V.2ORCID,Bower John F.3ORCID,Jardim Guilherme A.M.4ORCID,da Silva Júnior Eufrânio N.4ORCID,Torres-Santos Eduardo C.2ORCID,Menna-Barreto Rubem F.S.1ORCID

Affiliation:

1. Laboratorio de Biologia Celular, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil

2. Laboratorio de Bioquimica de Tripanosomatideos, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil

3. School of Chemistry, University of Bristol, Bristol, United Kingdom

4. Departamento de Quimica, Instituto de Ciencias Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

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.

Funder

Worldwide Universities Network (WUN) - Research Development Fund

Royal Society of Chemistry

Publisher

Bentham Science Publishers Ltd.

Subject

Drug Discovery,Pharmacology

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