Synthesis, Cytotoxicity and In Vitro Antileishmanial Activity of Naphthothiazoles

Autor(es)

de Toledo, Juliano S. ^[1] ; Junior, Paulo E. S. ^[2] ; Manfrim, Viviane ^[2] ; Pinzan, Camila F. ^[1] ; de Araujo, Alexandre S. ^[3] ; Cruz, Angela K. ^[1] ; Emery, Flavio S. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Biol Celular & Mol & Bioagentes Patogen, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Ciencias Farmaceut, BR-14040903 Ribeirao Preto, SP - Brazil

^[3] Univ Estadual Paulista, Dept Fis, Inst Biociencias Letras & Ciencias Exatas Sao Jos, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CHEMICAL BIOLOGY & DRUG DESIGN; v. 81, n. 6, p. 749-756, JUN 2013.
• Citações Web of Science: 4

Resumo

The leishmaniasis is a spectral disease caused by the protozoan Leishmania spp., which threatens millions of people worldwide. Current treatments exhibit high toxicity, and there is no vaccine available. The need for new lead compounds with leishmanicidal activity is urgent. Considering that many lead leishmanicidal compounds contain a quinoidal scaffold and the thiazole heterocyclic ring is found in a number of antimicrobial drugs, we proposed a hybridization approach to generate a diverse set of semi-synthetic heterocycles with antileishmanial activity. We found that almost all synthesized compounds demonstrated potent activity against promastigotes of Leishmania (Viannia) braziliensis and reduced the survival index of Leishmania amastigotes in mammalian macrophages. Furthermore, the compounds were not cytotoxic to macrophages at fivefold higher concentrations than the EC50 for promastigotes. All molecules fulfilled Lipinski's Rule of Five, which predicts efficient orally absorption and permeation through biological membranes, the in silico pharmacokinetic profile confirmed these characteristics. The potent and selective activity of semi-synthetic naphthothiazoles against promastigotes and amastigotes reveals that the 2-amino-naphthothiazole ring may represent a scaffold for the design of compounds with leishmanicidal properties and encourage the development of drug formulation and new compounds for further studies in vivo. (AU)

• Processo FAPESP: 09/51812-0 - Desenvolvimento de uma plataforma para o estudo do metabolismo in vivo e in vitro de produtos naturais, uma necessidade para o sistema de ensaios pré-clínicos
• Beneficiário: Norberto Peporine Lopes
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático
• Processo FAPESP: 09/14184-0 - Agentes anti-infecciosos: congregando a química medicinal e síntese orgânica na busca de protótipos antiparasitários
• Beneficiário: Flavio da Silva Emery
• Modalidade de apoio: Auxílio à Pesquisa - Regular