title: Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity.
abstract: Ferroquine (FQ) is a 4-aminoquinoline antimalarial which contains a quinoline nucleus similar to chloroquine, but a novel ferrocenic group in its side chain. Previous work has demonstrated that this compound has excellent activity against malaria parasites, both in vitro and in vivo, with especially good activity against chloroquine-resistant parasites, but details of its mechanism of action have not previously been reported. In this study, we have investigated the physicochemical properties of FQ for comparison with chloroquine (CQ). Like CQ, FQ forms complexes with hematin in solution (log K = 4.95 +/- 0.05). FQ is an even stronger inhibitor of beta-hematin formation than CQ (IC(50) = 0.78 equiv relative to hematin for FQ vs 1.9 for CQ). These data suggest that the mechanism of action of FQ is likely to be similar to that of CQ and probably involves hematin as the drug target and inhibition of hemozoin formation. However, both the basicity and lipophilicity of FQ are significantly different from those of CQ. The lipophilicity of FQ and CQ are similar when protonated at the putative food vacuole pH of 5.2 (log D = -0.77 and -1.2 respectively), but differ markedly at pH 7.4 (log D = 2.95 and 0.85 respectively). In addition, the pK(a) values of FQ are lower (pK(a1) = 8.19 and pK(a2) = 6.99) than those of CQ (10.03 and 7.94, respectively). This suggests that there will be somewhat less vacuolar accumulation of FQ compared with CQ. Single crystal structure determination of FQ shows the presence of a strong internal hydrogen bond between the 4-amino group and the terminal N atom. This, together with the electron donating properties of the ferrocene moiety, probably explains the decreased pK(a). Interestingly, the decreased accumulation arising from the less basic behavior of this compound is partly compensated for by its stronger beta-hematin inhibition. Increased lipophilicity, differences in geometric and electronic structure, and changes in the N-N distances in FQ compared to CQ probably explain its activity against CQ-resistant parasites.
authors.affiliation: Laboratoire de Catalyse de Lille-UMR CNRS 8010, ENSCL, Bâtiment C7, Université des Sciences et Technologies, B.P. 90108, 59652, Villeneuve d'Ascq cedex, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Biot
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Isabelle
authors.initials: I
authors.lastname: Forfar-Bares
authors.forename: Lucien A
authors.initials: LA
authors.lastname: Maciejewski
authors.forename: Mlandzeni
authors.initials: M
authors.lastname: Boyce
authors.forename: Guy
authors.initials: G
authors.lastname: Nowogrocki
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Brocard
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
mesh_terms: D000634:Aminoquinolines; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D005296:Ferrous Compounds / Q000737:chemistry / Q000494:pharmacology*; D006427:Hemin / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D000075163:Metallocenes; D008958:Models, Molecular; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D005296:Ferrous Compounds; D000075163:Metallocenes; D011804:Quinolines; D006427:Hemin; D002738:Chloroquine; C479230:ferroquine