Daniel Dive

Ferrocene Conjugates of Chloroquine and other Antimalarials: the Development of Ferroquine, a New Antimalarial

A convenient approach to antimalarial drug discovery is the use of the organic scaffold of a known antimalarial drug and an organometallic moiety to alter its unwanted properties and/or to optimize its initial effects. This minireview focuses mainly on the discovery of ferroquine, which has emerged from a collaborative French discovery project, and efforts to understand its mechanism of action and resistance.WILEY-VCHThis article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

The antimalarial ferroquine: role of the metal and intramolecular hydrogen bond in activity and resistance.

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.

The antimalarial ferroquine: from bench to clinic

Ferroquine (FQ, SSR97193) is currently the most advanced organometallic drug candidate and about to complete phase II clinical trials as a treatment for uncomplicated malaria. This ferrocenecontaining compound is active against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum and P. vivax strains and/or isolates. This article focuses on the discovery of FQ, its antimalarial activity, the hypothesis of its mode of action, the current absence of resistance in vitro and recent clinical trials.

Synthesis and antimalarial activity in vitro of potential metabolites of ferrochloroquine and related compounds.

In man, the two major metabolites of the antimalarial drug chloroquine (CQ) are monodesethylchloroquine (DECQ) and didesethylchloroquine (di-DECQ). By analogy with CQ, the synthesis and the in vitro tests of some amino derivatives of ferrochloroquine (FQ), a ferrocenic analogue of CQ which are presumed to be the oxidative metabolites of FQ, are reported. Desmethylferrochloroquine 1a and didesmethylferrochloroquine 2 would be more potent against schizontocides than CQ in vitro against two strains (HB3 and Dd2) of Plasmodium falciparum. Other secondary amino derivatives have been prepared and proved to be active as antimalarial agents in vitro, too.

Novel metallocenic compounds as antimalarial agents. Study of the position of ferrocene in chloroquine

Abstract The synthesis, characterization and antimalarial activity of two new ferrocene–chloroquine compounds are reported. One of them, 7-chloro-4- N -[(4- N′ -ethyl- N′ -ferrocenylmethyl)ammonio-1-methylbutylamino]quinolin-1-ium bi-tartrate ( 2 ) showed very promising antimalarial activity in vivo on mice infected with Plasmodium berghei N. and Plasmodium yoelii NS. and in vitro against chloroquine resistant-strains of Plasmodium falciparum .

Synthesis of ferroquine enantiomers: first investigation of effects of metallocenic chirality upon antimalarial activity and cytotoxicity.

Ferroquine (FQ) is a new antimalarial agent with a high blood schizotoncidal activity. Previous studies on this compound were done with racemate mixtures. As FQ possesses planar chirality, pure enantiomers were obtained by enzymatic resolution in order to compare their antimalarial activities and cytotoxicities. (+)‐FQ and (−)‐FQ were equally active in vitro, at nanomolar concentrations. Both enantiomers were slightly less active than the racemate in vivo; cytotoxicities were similar. Actually, the racemate represents the optimal formulation. To the best of our knowledge, this is the first investigation of biological activities of compounds with metallocenic chirality.

Investigation of the Redox Behavior of Ferroquine, a New Antimalarial

Ferroquine (FQ or SR97193) is a unique ferrocene antimalarial drug candidate which just entered phase IIb clinical trials in autumn 2007. FQ is able to overcome the chloroquine (CQ) resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. However, as for other therapeutic agents such as chloroquine (CQ) and artemisin, its mechanism of action remains partially unknown. Most investigations have so far focused on comparing the activity of FQ to that of CQ in order to understand how the ferrocene core contributes to a stronger antiplasmodial activity. Studies have already shown that the ferrocene altered the shape, volume, lipophilicity, basicity and also electronic profile of the parent molecule and, hence, its pharmacodynamic behavior. However, few investigations have been undertaken to probe the real contribution of redox properties of the ferrocene (iron(II))/ferricinium (iron(III)) system in FQ as reported in this article. In our experimental and theoretical approach, we considered the redox profile of the ferrocene core of FQ in the specific conditions (acidic and oxidizing) of the parasitic digestive vacuole as a possible discriminating property from CQ in the antimalarial activity.

Novel ferrocenic artemisinin derivatives: synthesis, in vitro antimalarial activity and affinity of binding with ferroprotoporphyrin IX

Following our search for novel compounds with high antimalarial activity, a series of artemisinin (QHS) derivatives containing a ferrocenic nucleus was prepared and tested in vitro against Plasmodium falciparum strains. Two new metallocenic derivatives (1 and 3) were found as potent as QHS. All compounds showed a capacity to bind with ferroprotoporphyrin IX. A decrease in the Soret band absorbance of ferroprotoporphyrin IX, resulting from the addition of different drugs concentrations, was shown. The association stoichiometry of compounds to ferroprotoporphyrin IX appears to be 1:2 at equilibrium, with an intermediate 1:1 complexation. These results appear to strengthen the role of adducts between artemisinin derivatives and heme in generation of artemisinin radicals. Such interaction of artemisinin ferrocenyl derivatives with ferroprotoporphyrin IX and its biological significance could form a basis in future drug development.

Enhancement of the antimalarial activity of ciprofloxacin using a double prodrug/bioorganometallic approach.

The derivatization of the fluoroquinolone ciprofloxacin greatly increases its antimalarial activity by combining bioorganometallic chemistry and the prodrug approach. Two new achiral compounds 2 and 4 were found to be 10- to 100-fold more active than ciprofloxacin against Plasmodium falciparum chloroquine-susceptible and chloroquine-resistant strains. These achiral derivatives killed parasites more rapidly than did ciprofloxacin. Compounds 2 and 4 were revealed to be promising leads, creating a new family of antimalarial agents.

The Ferroquine Antimalarial Conundrum: Redox Activation and Reinvasion Inhibition†

Metal health: Ferroquine is a ferrocene-based analogue of the antimalarial drug chloroquine. In addition to the primary mechanism of quinoline action, fluorescent probe studies in infected red blood cells show another mechanism is at work. It is based on the production of HO(·) in the acidic and oxidizing environment of the digestive vacuole of the malaria parasite and implies that, with ferroquine, reinvasion can be inhibited.