title: Dihydroethanoanthracene derivatives reverse in vitro quinoline resistance in Plasmodium falciparum malaria.
abstract: The capacity of ten molecules for reversing resistance in Plasmodium falciparum in vitro to quinoline antimalarial drugs, such as chloroquine (CQ), quinine (QN), mefloquine (MQ) and monodesethylamodiaquine (MDAQ), was assessed against 27 Plasmodium falciparum isolates. Four of these compounds were 9,10-dihydroethanoanthracene derivatives (DEAs). These DEAs reversed 75 to 92% of the CQ resistant strains. These synthetic compounds were more effective in combination with CQ than verapamil, ketotifen, chlorpromazine, reserpine or nicardipine, which reversed less than 50% of the CQ resistant strains. DEAs significantly reversed 67 to 100% of MDAQ resistant parasites. These compounds were more effective in combination with MDAQ than ketotifen (60% of reversal), chlorpromazine (45%), verapamil (33%), reserpine (30%) or nicardipine (9%). The reversal activity of MQ resistance was less pronounced, regardless of the molecule tested, and was homogeneous with a rate ranging from 42% for ketotifen to 58% for reserpine, nicardipine, verapamil and cyproheptadine. The four DEAs significantly reversed 50 to 55% of the parasites resistant to MQ. Fifty-six to 78 % of the QN resistant parasites were reversed by the synthetic DEAs. There were few differences in the rate of reversal activity on QN resistant strains between the ten compounds, with rates ranging between 56 to 78% for the ten chemosensitizers. The use of DEAs in combination with quinoline seems to be thus a promising strategy for limiting the development of drug resistant strains and for treating patients in drug resistant areas.
authors.affiliation: Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Boulevard Charles Livon, Parc le Pharo, BP 46, 13998 Marseille Armées, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Henry
authors.forename: Sandrine
authors.initials: S
authors.lastname: Alibert
authors.forename: Meili
authors.initials: M
authors.lastname: Baragatti
authors.forename: Joel
authors.initials: J
authors.lastname: Mosnier
authors.forename: Eric
authors.initials: E
authors.lastname: Baret
authors.forename: Rémy
authors.initials: R
authors.lastname: Amalvict
authors.forename: Eric
authors.initials: E
authors.lastname: Legrand
authors.forename: Thierry
authors.initials: T
authors.lastname: Fusai
authors.forename: Jacques
authors.initials: J
authors.lastname: Barbe
authors.forename: Christophe
authors.initials: C
authors.lastname: Rogier
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Pagès
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology / Q000627:therapeutic use*; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D004351:Drug Resistance; D006801:Humans; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D000873:Anthracenes; D000962:Antimalarials; D011804:Quinolines