title: The antimalarial ferroquine: role of the metal and intramolecular hydrogen bond in activity and resistance.
abstract: Inhibition of hemozoin biocrystallization is considered the main mechanism of action of 4-aminoquinoline antimalarials including chloroquine (CQ) but cannot fully explain the activity of ferroquine (FQ) which has been related to redox properties and intramolecular hydrogen bonding. Analogues of FQ, methylferroquine (Me-FQ), ruthenoquine (RQ), and methylruthenoquine (Me-RQ), were prepared. Combination of physicochemical and molecular modeling methods showed that FQ and RQ favor intramolecular hydrogen bonding between the 4-aminoquinoline NH group and the terminal amino group in the absence of water, suggesting that this structure may enhance its passage through the membrane. This was further supported by the use of Me-FQ and Me-RQ where the intramolecular hydrogen bond cannot be formed. Docking studies suggest that FQ can interact specifically with the {0,0,1} and {1,0,0} faces of hemozoin, blocking crystal growth. With respect to the structure-activity relationship, the antimalarial activity on 15 different P. falciparum strains showed that the activity of FQ and RQ were correlated with each other but not with CQ, confirming lack of cross resistance. Conversely, Me-FQ and Me-RQ showed significant cross-resistance with CQ. Mutations or copy number of pfcrt, pfmrp, pfmdr1, pfmdr2, or pfnhe-1 did not exhibit significant correlations with the IC(50) of FQ or RQ. We next showed that FQ and Me-FQ were able to generate hydroxyl radicals, whereas RQ and me-RQ did not. Ultrastructural studies revealed that FQ and Me-FQ but not RQ or Me-RQ break down the parasite digestive vacuole membrane, which could be related to the ability of the former to generate hydroxyl radicals.
authors.affiliation: Université de Lille, Unité de Catalyse et Chimie du Solide - UMR CNRS, ENSCL, Villeneuve d'Ascq, France.
authors.forename: Faustine
authors.initials: F
authors.lastname: Dubar
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
authors.forename: David
authors.initials: D
authors.lastname: Kuter
authors.forename: Kanyile K
authors.initials: KK
authors.lastname: Ncokazi
authors.forename: Delphine
authors.initials: D
authors.lastname: Forge
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Paul
authors.forename: Christine
authors.initials: C
authors.lastname: Pierrot
authors.forename: Hadidjatou
authors.initials: H
authors.lastname: Kalamou
authors.forename: Jamal
authors.initials: J
authors.lastname: Khalife
authors.forename: Eric
authors.initials: E
authors.lastname: Buisine
authors.forename: Christophe
authors.initials: C
authors.lastname: Rogier
authors.forename: Hervé
authors.initials: H
authors.lastname: Vezin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Forfar
authors.forename: Christian
authors.initials: C
authors.lastname: Slomianny
authors.forename: Xavier
authors.initials: X
authors.lastname: Trivelli
authors.forename: Sergey
authors.initials: S
authors.lastname: Kapishnikov
authors.forename: Leslie
authors.initials: L
authors.lastname: Leiserowitz
authors.forename: Daniel
authors.initials: D
authors.lastname: Dive
authors.forename: Christophe
authors.initials: C
authors.lastname: Biot
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004351:Drug Resistance / Q000187:drug effects; D004563:Electrochemistry; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006420:Hemeproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D017665:Hydroxyl Radical / Q000737:chemistry / Q000378:metabolism; D000075163:Metallocenes; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D005296:Ferrous Compounds; D006420:Hemeproteins; D000075163:Metallocenes; D009942:Organometallic Compounds; D017665:Hydroxyl Radical; C020753:hemozoin; D012428:Ruthenium; C479230:ferroquine