christophe Biot's Publications List

The Antimalarial Ferroquine: Role of the Metal and Intramolecular Hydrogen Bond in Activity and Resistance.

2011-02-08T09:31:07Z

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. Combinat...

Faustine Dubar, Timothy J Egan, Bruno Pradines, David Kuter, Kanyile K Ncokazi, Delphine Forge, Jean-François Paul, Christine Pierrot, Hadidjatou Kalamou, Jamal Khalife, Eric Buisine, Christophe Rogier, Hervé Vezin, Isabelle Forfar, Christian Slomianny, Xavier Trivelli, Sergey Kapishnikov, Leslie Leiserowitz, Daniel Dive, Christophe Biot (2011) ACS Chem Biol :

Novel ferrocenic steroidal drug derivatives and their bioactivities.

2011-02-08T09:31:07Z

Seven novel ferrocenic derivatives, compounds 1-7, were synthesized from steroidal drugs by Aldol condensation reaction. The derivatives were purified by chromatography, and their structures were determined on the basis of HR-ESI-MS and two-dimensional NMR spectroscopy. The purity of all derivatives was more than 95%. Compounds 1-5 demonstrated anti-proliferative activity on HeLa cell line by SRB ...

Jiradej Manosroi, Kanjana Rueanto, Korawinwich Boonpisuttinant, Worapaka Manosroi, Christophe Biot, Hiroyuki Akazawa, Toshihiro Akihisa, Witchapong Issarangporn, Aranya Manosroi (2010) J Med Chem 53: 10 3937-3943

Antimalarial versus cytotoxic properties of dual drugs derived from 4-aminoquinolines and Mannich bases: interaction with DNA.

2011-02-08T09:31:07Z

The synthesis and biological evaluation of new organic and organometallic dual drugs designed as potential antimalarial agents are reported. A series of 4-aminoquinoline-based Mannich bases with variations in the aliphatic amino side chain were prepared via a three-steps synthesis. These compounds were also tested against chloroquine-susceptible and chloroquine-resistant strains of Plasmodium falc...

Nicole I Wenzel, Natascha Chavain, Yulin Wang, Wolfgang Friebolin, Louis Maes, Bruno Pradines, Michael Lanzer, Vanessa Yardley, Reto Brun, Christel Herold-Mende, Christophe Biot, Katalin Tóth, Elisabeth Davioud-Charvet (2010) J Med Chem 53: 8 3214-3226

Organometallic complexes: new tools for chemotherapy.

2011-02-08T09:31:07Z

The importance of organometallics can be noticed by their presence in all life organisms. The most known natural organometallic molecule is vitamin B12, a porphyrin containing a cobalt atom, useful for several enzymatic transformations. Based on the remarkable properties of this class of compounds, a new area of medicinal research was developed. Gérard Jaouen was the first to introduce the term o...

N Chavain, C Biot (2010) Curr Med Chem 17: 25 2729-2745

Synthesis and antimalarial activities of rhenium bioorganometallics based on the 4-aminoquinoline structure.

2011-02-08T09:31:07Z

A bioorganometallic approach to malaria therapy led to the discovery of ferroquine (FQ, SSR97193). To assess the importance of the electronic properties of the ferrocenyl group, cyclopentadienyltricarbonylrhenium analogues related to FQ, were synthesized. The reaction of [N-(7-chloro-4-quinolinyl)-1,2-ethanodiamine] with the cyrhetrenylaldehyde complexes (η(5)-C(5)H(4)CHO)Re(CO)(3) and [η(5)-1,2...

Rodrigo Arancibia, Faustine Dubar, Bruno Pradines, Isabelle Forfar, Daniel Dive, A Hugo Klahn, Christophe Biot (2010) Bioorg Med Chem 18: 22 8085-8091

Structural analysis of an unusual bioactive N-acylated lipo-oligosaccharide LOS-IV in Mycobacterium marinum.

2011-02-08T09:31:07Z

Although lipo-oligosaccharides (LOSs) are recognized as major parietal components in many mycobacterial species, their involvement in the host-pathogen interactions have been scarcely documented. In particular, the biological implications arising from the high degree of structural species-specificity of these glycolipids remain largely unknown. Growing recognition of the Mycobacterium marinum-Dani...

Yoann Rombouts, Elisabeth Elass, Christophe Biot, Emmanuel Maes, Bernadette Coddeville, Adeline Burguière, Caroline Tokarski, Eric Buisine, Xavier Trivelli, Laurent Kremer, Yann Guérardel (2010) J Am Chem Soc 132: 45 16073-16084

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

2011-02-08T09:31:07Z

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 mor...

Faustine Dubar, Guillaume Anquetin, Bruno Pradines, Daniel Dive, Jamal Khalife, Christophe Biot (2009) J Med Chem 52: 24 7954-7957

Antimalarial activities of ferroquine conjugates with either glutathione reductase inhibitors or glutathione depletors via a hydrolyzable amide linker.

2011-02-08T09:31:07Z

Based on the prodrug concept as well as the combination of two different classes of antimalarial agents, we designed and synthesized two series of ferrocenic antimalarial dual molecules consisting of a ferroquine analogue conjugated with a glutathione reductase inhibitor (or a glutathione depletor) through a cleavable amide bond in order to target two essential pathways in the malarial parasites. ...

Natascha Chavain, Elisabeth Davioud-Charvet, Xavier Trivelli, Linda Mbeki, Matthias Rottmann, Reto Brun, Christophe Biot (2009) Bioorg Med Chem 17: 23 8048-8059

Investigation of the redox behavior of ferroquine, a new antimalarial.

2011-02-08T09:31:07Z

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 o...

Natascha Chavain, Hervé Vezin, Daniel Dive, Nadia Touati, Jean-François Paul, Eric Buisine, Christophe Biot (2008) Mol Pharm 5: 5 710-716

Ferrocene conjugates of chloroquine and other antimalarials: the development of ferroquine, a new antimalarial.

2011-02-08T09:33:03Z

Daniel Dive, Christophe Biot (2008) ChemMedChem 3: 3 383-391

Ferroquine, an ingenious antimalarial drug: thoughts on the mechanism of action.

2011-02-08T09:31:07Z

Ferroquine (FQ or SR97193) is a novel antimalarial drug candidate, currently in development at Sanofi-Aventis. In contrast to conventional drugs, FQ is the first organometallic drug: a ferrocenyl group covalently flanked by a 4-aminoquinoline and a basic alkylamine. FQ is able to overcome the CQ resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative...

Faustine Dubar, Jamal Khalife, Jacques Brocard, Daniel Dive, Christophe Biot (2008) Molecules 13: 11 2900-2907

Design, synthesis, and antimalarial activity of structural chimeras of thiosemicarbazone and ferroquine analogues.

2011-02-08T09:33:03Z

The design, synthesis, and antimalarial activity of chimeras of thiosemicarbazones (TSC) and ferroquine (FQ) is reported. Key structural elements derived from FQ were coupled to fragments capable of coordinating metal ions. Biological evaluation was conducted against four strains of the malaria parasite Plasmodium falciparum and against the parasitic cysteine protease falcipain-2. To establish the...

Christophe Biot, Bruno Pradines, Marie-Hélène Sergeant, Jiri Gut, Philip J Rosenthal, Kelly Chibale (2007) Bioorg Med Chem Lett 17: 23 6434-6438

Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities.

2011-02-08T09:33:03Z

Three ferroquine (FQ) derivatives, closely mimicking the antimalarial drug hydroxychloroquine (HCQ), have been prepared. Whereas these organometallic compounds provide the expected reduced cytotoxic effects compared to FQ, they inhibit in vitro growth of Plasmodium falciparum far better than chloroquine (CQ). Moreover, this new class of bioorganometallic compounds exert antiviral effects with some...

Christophe Biot, Wassim Daher, Natascha Chavain, Thierry Fandeur, Jamal Khalife, Daniel Dive, Erik De Clercq (2006) J Med Chem 49: 9 2845-2849

Development of novel statistical potentials describing cation-pi interactions in proteins and comparison with semiempirical and quantum chemistry approaches.

2011-02-08T09:33:03Z

Novel statistical potentials derived from known protein structures are presented. They are designed to describe cation-pi and amino-pi interactions between a positively charged amino acid or an amino acid carrying a partially charged amino group and an aromatic moiety. These potentials are based on the propensity of residue types to be separated by a certain spatial distance or to have a given rel...

Dimitri Gilis, Christophe Biot, Eric Buisine, Yves Dehouck, Marianne Rooman (2006) J Chem Inf Model 46: 2 884-893

Novel approaches to antimalarial drug discovery.

2011-02-08T09:33:03Z

Major advances in our understanding of malaria parasite biology have been made. Coupled with the completion of the malaria genome, this has presented exciting opportunities for target-based antimalarial drug discovery. However, the unraveling of more validated biological targets will not necessarily translate into the identification of new chemical entities that are effective against drug resistan...

Christophe Biot, Kelly Chibale (2006) Infect Disord Drug Targets 6: 2 173-204

Solvent-induced effects: self-association of positively charged pi systems.

2011-02-08T09:33:03Z

Antimalarial cationic drugs, such as chloroquine (CQ) and ferroquine (FQ), form stable dimer structures not only in the solid state but also in solution. The short distances (3.3-3.5 A) observed between the positively charged quinolinium rings suggest that this self-association process is driven by pi/pi stacking interactions. Nevertheless, the strength of these dispersive forces is likely not suf...

Eric Buisine, Katherine de Villiers, Timothy J Egan, Christophe Biot (2006) J Am Chem Soc 128: 37 12122-12128

Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193) in field isolates and in W2 strain under pressure.

2011-02-08T09:33:03Z

Ferroquine (FQ), or SSR97193, is a novel antimalarial drug currently in phase I clinical trials. FQ is a unique organometallic compound designed to overcome the chloroquine (CQ) resistance problem. FQ revealed to be equally active on CQ-sensitive and CQ-resistant Plasmodium falciparum laboratory strains and field isolates. FQ is also curative on rodent malaria parasites. As FQ will be tested in pa...

Wassim Daher, Christophe Biot, Thierry Fandeur, Helene Jouin, Lydie Pelinski, Eric Viscogliosi, Laurent Fraisse, Bruno Pradines, Jacques Brocard, Jamal Khalife, Daniel Dive (2006) Malar J 5:

Probing the role of the covalent linkage of ferrocene into a chloroquine template.

2011-02-08T09:33:03Z

A new therapeutic approach to malaria led to the discovery of ferroquine (FQ, SR97276). To assess the importance of the linkage of the ferrocenyl group to a 4-aminoquinoline scaffold, two series of 4-aminoquinolines, structurally related to FQ, were synthesized. Evaluation of antimalarial activity, physicochemical parameters, and the beta-hematin inhibition property indicate that the ferrocene moi...

Christophe Biot, Wassim Daher, Cheikh M Ndiaye, Patricia Melnyk, Bruno Pradines, Natascha Chavain, Alain Pellet, Laurent Fraisse, Lydie Pelinski, Christian Jarry, Jacques Brocard, Jamal Khalife, Isabelle Forfar-Bares, Daniel Dive (2006) J Med Chem 49: 15 4707-4714

In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

2011-02-08T09:33:03Z

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono...

Wassim Daher, Lydie Pelinski, Sylvie Klieber, Freddy Sadoun, Viviane Meunier, Martine Bourrié, Christophe Biot, François Guillou, Gérard Fabre, Jacques Brocard, Laurent Fraisse, Jean-Pierre Maffrand, Jamal Khalife, Daniel Dive (2006) Drug Metab Dispos 34: 4 667-682

Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity.

2011-02-08T09:33:03Z

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 ...

Christophe Biot, Donatella Taramelli, Isabelle Forfar-Bares, Lucien A Maciejewski, Mlandzeni Boyce, Guy Nowogrocki, Jacques S Brocard, Nicoletta Basilico, Piero Olliaro, Timothy J Egan (2005) Mol Pharm 2: 3 185-193

Stair motifs at protein-DNA interfaces: nonadditivity of H-bond, stacking, and cation-pi interactions.

2011-02-08T09:34:13Z

At the interface between protein and double-stranded DNA, stair motifs simultaneously involve three different types of pairwise interactions: aromatic base stacking, hydrogen bonding, and cation-pi. The relative importance of these interactions is studied in the stair motif occurring in the 1TC3 crystal structure, which involves an arginine and two stacked guanines, by means of Hartree-Fock (HF) a...

Christophe Biot, René Wintjens, Marianne Rooman (2004) J Am Chem Soc 126: 20 6220-6221

5-substituted tetrazoles as bioisosteres of carboxylic acids. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials.

2011-02-08T09:34:13Z

Plasmodium parasites are exposed to elevated fluxes of reactive oxygen species during intraerythrocytic life. The most important antioxidative systems are based on the glutathione reductases of the malarial parasite Plasmodium falciparum and the host erythrocyte. The development of menadione chemistry has led to the selection of the carboxylic acid 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl] hexanoic...

Christophe Biot, Holger Bauer, R Heiner Schirmer, Elisabeth Davioud-Charvet (2004) J Med Chem 47: 24 5972-5983

Free-energy calculations of protein-ligand cation-pi and amino-pi interactions: from vacuum to proteinlike environments.

2011-02-08T09:34:13Z

To probe the role of cation-pi and amino-pi interactions in the context of protein-ligand interactions, the stability of 55 X-ray cation/amino-pi motifs involving the Ade moieties of cofactor molecules and Arg, Lys, Asn, or Gln side chains of their host protein was evaluated using quantum chemistry calculations. The conjunction of vacuum interaction energies, vibrational entropy, and solvation con...

Christophe Biot, Eric Buisine, Marianne Rooman (2003) J Am Chem Soc 125: 46 13988-13994

Sequence-structure signals of 3D domain swapping in proteins.

2011-02-08T09:34:13Z

Three-dimensional domain swapping occurs when two or more identical proteins exchange identical parts of their structure to generate an oligomeric unit. It affects proteins with diverse sequences and structures, and is expected to play important roles in evolution, functional regulation and even conformational diseases. Here, we search for traces of domain swapping in the protein sequence, by mean...

Yves Dehouck, Christophe Biot, Dimitri Gilis, Jean Marc Kwasigroch, Marianne Rooman (2003) J Mol Biol 330: 5 1215-1225

Double-drug development against antioxidant enzymes from Plasmodium falciparum.

2011-02-08T09:34:13Z

New drugs against malaria are urgently and continuously needed. Plasmodium parasites are exposed to higher fluxes of reactive oxygen species and need high activities of intracellular antioxidant systems. A most important antioxidative system consists of (di)thiols which are recycled by disulfide reductases (DR), namely both glutathione reductases (GR) of the malarial parasite Plasmodium falciparum...

Christophe Biot, Jean Dessolin, Philippe Grellier, Elisabeth Davioud-Charvet (2003) Redox Rep 8: 5 280-283

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

2011-02-08T09:34:13Z

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 enan...

Laurence Delhaes, Christophe Biot, Laurence Berry, Philippe Delcourt, Lucien A Maciejewski, Daniel Camus, Jacques S Brocard, Daniel Dive (2002) Chembiochem 3: 5 418-423

Probing the energetic and structural role of amino acid/nucleobase cation-pi interactions in protein-ligand complexes.

2011-02-08T09:34:13Z

X-ray structures of proteins bound to ligand molecules containing a nucleic acid base were systematically searched for cation-pi interactions between the base and a positively charged or partially charged side chain group located above it, using geometric criteria. Such interactions were found in 38% of the complexes and are thus even more frequent than pi-pi stacking interactions. They are moreov...

Christophe Biot, Eric Buisine, Jean-Marc Kwasigroch, René Wintjens, Marianne Rooman (2002) J Biol Chem 277: 43 40816-40822

What is paradoxical about Levinthal paradox?

2011-02-08T09:34:13Z

We would be tempted to state that there has never been a Levinthal paradox. Indeed, Levinthal raised an interesting problem about protein folding, as he realized that proteins have no time to explore exhaustively their conformational space on the way to their native structure. He did not seem to find this paradoxical and immediately proposed a straightforward solution, which has essentially never ...

Marianne Rooman, Yves Dehouck, Jean Marc Kwasigroch, Christophe Biot, Dimitri Gilis (2002) J Biomol Struct Dyn 20: 3 327-329

Bromination studies of the 2,3-dimethylnaphthazarin core allowing easy access to naphthazarin derivatives.

2011-02-08T09:35:06Z

J Dessolin, C Biot, E Davioud-Charvet (2001) J Org Chem 66: 16 5616-5619

In vitro and in vivo antimalarial activity of ferrochloroquine, a ferrocenyl analogue of chloroquine against chloroquine-resistant malaria parasites.

2011-02-08T09:35:06Z

Previous studies have shown that ferrochloroquine (FQ) exhibited an antimalarial activity against Plasmodium spp. The present work confirmed this activity, described the curative effect on P. vinckei and investigated the FQ toxicity in vitro and in vivo. The in vitro and in vivo growth inhibition of P. falciparum and P. berghei N, respectively, showed that FQ antimalarial activity was 1.5-10 times...

L Delhaes, H Abessolo, C Biot, L Berry, P Delcourt, L Maciejewski, J Brocard, D Camus, D Dive (2001) Parasitol Res 87: 3 239-244

A prodrug form of a Plasmodium falciparum glutathione reductase inhibitor conjugated with a 4-anilinoquinoline.

2011-02-08T09:34:13Z

Glutathione (GSH), which is known to guard Plasmodium falciparum from oxidative damage, may have an additional protective role by promoting heme catabolism. An elevation of GSH content in parasites leads to increased resistance to chloroquine (CQ), while GSH depletion in resistant P. falciparum strains is expected to restore the sensitivity to CQ. High intracellular GSH levels depend inter alia on...

E Davioud-Charvet, S Delarue, C Biot, B Schwöbel, C C Boehme, A Müssigbrodt, L Maes, C Sergheraert, P Grellier, R H Schirmer, K Becker (2001) J Med Chem 44: 24 4268-4276

Synthesis and antifungal activity of a ferrocene-fluconazole analogue.

2011-02-08T09:35:06Z

A novel ferrocene fluconazole analogue was synthesized and its antifungal properties investigated against yeast strains of medical importance, including those intrinsically resistant to fluconazole. In vitro tests revealed a slight increase in fungal growth and a reversal of the effect of fluconazole at minimal inhibitory concentrations.

C Biot, N François, L Maciejewski, J Brocard, D Poulain (2000) Bioorg Med Chem Lett 10: 8 839-841

Synthetic ferrocenic mefloquine and quinine analoguesas potential antimalarial agents.

2011-02-08T09:35:06Z

A few years ago we proposed a strategy for the synthesis of new ferrocene-chloroquine analogues replacing the carbon chain of chloroquine by hydrophobic ferrocenyl moieties. Now, this strategy has been applied to the antimalarial amino-alcohols class to afford new potentially active analogues of mefloquine and quinine bearing a substituted ferrocenic group. The pathway used for the synthesis of th...

C Biot, L Delhaes, L A Maciejewski, M Mortuaire, D Camus, D Dive, J S Brocard (2000) Eur J Med Chem 35: 7-8 707-714

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

2011-02-08T09:35:06Z

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 didesmethy...

C Biot, L Delhaes, C M N'Diaye, L A Maciejewski, D Camus, D Dive, J S Brocard (1999) Bioorg Med Chem 7: 12 2843-2847

In vitro antimalarial activity of a new organometallic analog, ferrocene-chloroquine.

2011-02-08T09:35:06Z

The in vitro activities of new organometallic chloroquine analogs, based on 4-amino-quinoleine compounds bound to a molecule of ferrocene, were evaluated against chloroquine-susceptible, chloroquine-intermediate, and chloroquine-resistant, culture-adapted Plasmodium falciparum lineages by a proliferation test. One of the ferrocene analogs totally restored the activity of chloroquine against chloro...

O Domarle, G Blampain, H Agnaniet, T Nzadiyabi, J Lebibi, J Brocard, L Maciejewski, C Biot, A J Georges, P Millet (1998) Antimicrob Agents Chemother 42: 3 540-544

Synthesis and antimalarial activity in vitro and in vivo of a new ferrocene-chloroquine analogue.

2011-02-08T09:35:06Z

The antimalarial activities of ferrocenic compounds mimicking chloroquine and active upon chloroquine-resistant strains of Plasmodium falciparum were evaluated. Four 7-chloro-4-[[[2-[(N,N-substituted amino)methyl]ferrocenyl]methyl]amino]quinoline derivatives have been synthesized; one of them, 1a, showed high potent antimalarial activity in vivo on mice infected with Plasmodium berghei N. and Plas...

C Biot, G Glorian, L A Maciejewski, J S Brocard (1997) J Med Chem 40: 23 3715-3718