title: Identification of specific reversal agents for Leishmania ABCI4-mediated antimony resistance by flavonoid and trolox derivative screening.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Manzano
authors.forename: Florine
authors.initials: F
authors.lastname: Lecerf-Schmidt
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Lespinasse
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
mesh_terms: D000965:Antimony / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D002839:Chromans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D007891:Leishmania / Q000187:drug effects*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D002839:Chromans; D004791:Enzyme Inhibitors; D005419:Flavonoids; D026901:Membrane Transport Proteins; D000965:Antimony; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
keywords: ABC transporters; drug efflux; flavonoid derivatives; trolox derivatives