title: In vitro activity of ferroquine (SSR 97193) against Plasmodium falciparum isolates from the Thai-Burmese border.
abstract: BACKGROUND
  On the borders of Thailand, Plasmodium falciparum has become resistant to nearly all available drugs, and there is an urgent need to find new antimalarial drugs or drug combinations. Ferroquine (SSR97193) is a new 4-aminoquinoline antimalarial active against chloroquine resistant and sensitive P. falciparum strains in vivo and in vitro. This antimalarial organic iron complex (a ferrocenyl group has been associated with chloroquine) is meant to use the affinity of Plasmodium for iron to increase the probability for encountering the anti-malarial molecule.The aim of the present study was to investigate the activity of ferroquine against P. falciparum isolates from an area with a known high multi-drug resistance rate.
  
  
  METHODS
  Parasite isolates were obtained from patients with acute falciparum malaria attending the clinics of SMRU. In vitro cultures of these isolates were set-up in the SMRU-laboratory on pre-dosed drug plates, and grown in culture for 42 hours. Parasite growth was assessed by the double-site enzyme-linked pLDH immunodetection (DELI) assay.
  
  
  RESULTS
  Sixty-five P. falciparum isolates were successfully grown in culture. The ferroquine mean IC50 (95% CI) was 9.3 nM (95% C.I.: 8.7 - 10.0). The mean IC50 value for the principal metabolite of ferroquin, SR97213A, was 37.0 nM (95% C.I.: 34.3 - 39.9), which is four times less active than ferroquine. The isolates in this study were highly multi-drug resistant but ferroquine was more active than chloroquine, quinine, mefloquine and piperaquine. Only artesunate was more active than ferroquine. Weak but significant correlations were found between ferroquine and its principal metabolite (r2 = 0.4288), chloroquine (r2 = 0.1107) and lumefantrine (r2 = 0.2364).
  
  
  CONCLUSIONS
  The results presented in this study demonstrate that the new ferroquine compound SSR97193 has high anti-malarial activity in vitro against multi-drug resistant P. falciparum.
authors.affiliation: Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand. marion@shoklo-unit.com <marion@shoklo-unit.com>
authors.forename: Marion
authors.initials: M
authors.lastname: Barends
authors.forename: Anchalee
authors.initials: A
authors.lastname: Jaidee
authors.forename: Nopparat
authors.initials: N
authors.lastname: Khaohirun
authors.forename: Pratap
authors.initials: P
authors.lastname: Singhasivanon
authors.forename: François
authors.initials: F
authors.lastname: Nosten
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005296:Ferrous Compounds / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D000075163:Metallocenes; D002052:Myanmar / Q000453:epidemiology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D013785:Thailand / Q000453:epidemiology
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D005296:Ferrous Compounds; D000075163:Metallocenes; C479230:ferroquine