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Identification of specific reversal agents for Leishmania ABCI4-mediated antimony resistance by flavonoid and trolox derivative screening.
Manzano, José Ignacio; Lecerf-Schmidt, Florine; Lespinasse, Marie-Ange; Di Pietro, Attilio; Castanys, Santiago; Boumendjel, Ahcène; Gamarro, Francisco.
Afiliação
  • Manzano JI; Instituto de Parasitología y Biomedicina 'López-Neyra', IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain.
J Antimicrob Chemother ; 69(3): 664-72, 2014 Mar.
Article em En | MEDLINE | ID: mdl-24126793
ABSTRACT

OBJECTIVES:

To identify reversal agents for the Leishmania ABCI4 transporter that confers resistance to antimony.

METHODS:

Selective ABCI4 inhibitors among a series of 15 flavonoid and trolox derivatives or analogues were investigated by evaluating their ability to reverse antimony resistance in Leishmania parasites overexpressing ABCI4. Among the compounds screened, N-ethyltrolox carboxamide (compound D2) produced the highest reversal activity. In order to optimize the activity of D2, we synthesized a series of 10 derivatives by condensation of various amines with trolox.

RESULTS:

Analysis of antimony resistance reversal activity showed that N-propyltrolox carboxamide (compound D4) was the most potent ABCI4 inhibitor, with reversal activity being maintained in the intracellular amastigote stage. In addition, trolox derivatives significantly reverted the resistance to zinc protoporphyrin. The mechanism of action of these active derivatives was found to be related to significant reversion of Sb(III) and zinc protoporphyrin accumulation and to a decrease in drug efflux.

CONCLUSIONS:

Our findings suggest that trolox derivatives D2 and D4 could be considered to be specific reversal agents targeting the Leishmania ABCI4 transporter. The structure-activity relationship obtained in the present study highlights the importance of the size and length of the alkyl substituent linked to trolox. Furthermore, the structural data obtained provide valuable information for the further development of new, even more specific and potent Leishmania ABCI4 reversal agents.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Membrana Transportadoras / Flavonoides / Cromanos / Avaliação Pré-Clínica de Medicamentos / Leishmania / Antimônio / Antiprotozoários Tipo de estudo: Diagnostic_studies / Prognostic_studies / Screening_studies Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Membrana Transportadoras / Flavonoides / Cromanos / Avaliação Pré-Clínica de Medicamentos / Leishmania / Antimônio / Antiprotozoários Tipo de estudo: Diagnostic_studies / Prognostic_studies / Screening_studies Idioma: En Ano de publicação: 2014 Tipo de documento: Article