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ABSTRACT: Amodiaquine is one of the most active anti-malarial 4-aminoquinoline but its metabolization is believed to generate hepatotoxic derivatives. Previously, we described new analogs of amodiaquine and amopyroquine, in which hydroxyl group was replaced by various amino groups and identified highly potent compounds with lower toxicity. We describe here the synthesis of new analogs that have been modified on their 4'- and 5'-positions in order to reduce their metabolization. A new synthetic strategy was developed using Buchwald coupling reaction as the key step.
European journal of medicinal chemistry 07/2011; 46(7):3052-7. · 3.27 Impact Factor
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ABSTRACT: Sigma-1 receptors are involved in numerous pathological dysfunctions and the synthesis of selective ligands is of interest. We identified a fused tetrahydroisoquinoline-hydantoin (Tic-hydantoin) structure with high affinity and selectivity for these receptors. We report here our efforts towards the pharmacomodulation of this substructure, the synthesis of 9 analogs with stereochemistry inversion, opening of isoquinoline ring, removal of isoquinoline nitrogen, replacement of isoquinoline by pyridine, of Tic-hydantoin moiety by quinazolinedione heterocycle. All these analogs provided a loss in the affinity for the sigma-1 receptor. The present work underlines the real importance of the Tic-hydantoin moiety for the obtainment of high affinity ligands.
European journal of medicinal chemistry 10/2009; 45(1):256-63. · 3.27 Impact Factor
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ABSTRACT: The prophylactic administration of amodiaquine (AQ), a 4-aminoquinoline antimalarial drug, has been associated with side effects such as agranulocytosis and liver damage. The toxicity of this drug is mediated by amodiaquine quinone-imine, an electrophilic metabolite. Replacement of the 4'-hydroxy function of AQ with various alkyl, aryl, or heteroaryl substituents would provide analogues that avoid metabolism to potentially toxic derivatives. Following a multistep procedure, 33 compounds containing hydrophobic groups at the 4'-position were synthesized using Csp(2)-Csp(2) and Csp(2)-Csp(3) Suzuki-Miyaura cross-coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)-sensitive and CQ-resistant strains of P. falciparum, with IC(50) values in the range of 7-200 nM. Alkyl analogues are more efficient than aryl or heteroaryl derivatives. All compounds were also assessed for their cytotoxicity and ability to inhibit beta-hematin formation in vitro. A detailed investigation of the structure-activity relationships for these new compounds was carried out; the 4'-methyl compound showed interesting in vivo antimalarial activity.
ChemMedChem 03/2009; 4(4):549-61. · 3.15 Impact Factor
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ABSTRACT: Activation of the newly identified sigma(1) chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the sigma(1) protein may lead to putative potent anti-cocaine agents. Here, we synthetized substituted hydantoins with high affinity for the sigma(1) protein and evaluated their behavioral efficacy. Two pure enantiomers were designed and synthesized: tetrahydroisoquinoleine-hydantoin fused compounds 3 and 4. They increased cocaine-induced locomotor stimulation or sensitization. The most active enantiomer 4, facilitated CPP acquisition but failed to substitute for cocaine. When CPP was acquired with cocaine and then extinguished, 4 provoked reactivation of CPP. These observations showed that compound 4 shows a typical profile of sigma(1) protein activator, facilitating cocaine-induced behavioral effects. Preliminary ADME properties are in favour of an optimal therapeutic development. Such Tic-hydantoin compound may serve as a new effective agonist therapy in cocaine addiction.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 03/2009; 19(7):504-15. · 3.68 Impact Factor
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ABSTRACT: In order to graft an amphiphilic polysaccharide to lipid nanocapsules, we present here a new method of dextran lipidation. The lipidation strategy is based on the formation of an oxime linkage between the amphiphilic hydroxylamine C16E20ONH2 and the reductive end of a 40 kDa dextran. This chemoselective reaction allows us to control the lipidation site and the number of lipid introduced on the dextran molecule. This new amphiphilic dextran was used to coat the surface of lipid nanocapsules. The coating efficiency was followed by dynamic light scattering and the presence of the polysaccharide was confirmed by (1)H NMR and observed by electronic microscopy.
Bioconjugate Chemistry 08/2008; 19(7):1491-5. · 4.93 Impact Factor
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ABSTRACT: In order to determine the real significance of the 4'-phenolic group in the antimalarial activity and/or cytotoxicity of amodiaquine (AQ), analogues for which this functionality was shifted or modified were synthesized. Good in vitro antimalarial activity was obtained for compounds unable to form intramolecular hydrogen bond. Among the compounds synthesized, new amino derivative 5 displayed the greatest selectivity index towards the most CQ-resistant strain tested and was active in mice infected by Plasmodium berghei.
European Journal of Medicinal Chemistry 03/2008; 43(2):252-60. · 3.35 Impact Factor
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ABSTRACT: A series of 4-anilinoquinolines bearing an amino side chain linked to the aromatic ring with a carbamate or an amide bond were synthesized and evaluated for their antimalarial activity and their cytotoxicity upon MRC-5 cells. Among the 17 compounds, a majority was found to be active in the low nanomolar range against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro with relative low cytotoxicity. Two compounds were then tested on mice infected by Plasmodium berghei and were found to exhibit reasonable in vivo activity.
European Journal of Medicinal Chemistry 12/2007; 43(10):2045-55. · 3.35 Impact Factor
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ABSTRACT: Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of PrP(Sc), a pathogenic misfolded isoform of the normal cellular prion protein (PrP(C)). Until now, no pharmacological options exist for these novel pathogens. Here we describe the screening of a series of polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The most active molecule, named 42, had a half-effective concentration (EC50) for antiprion activity of 50 nM. In a library of quinoline derivatives we were able to identify several structure-activity relationships (SAR). Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria, particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion and antimalarial substances overlap.
Journal of Medicinal Chemistry 09/2006; 49(17):5300-8. · 5.25 Impact Factor
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ABSTRACT: A library of acylhydrazone iron chelators was synthesized and tested for its ability to inhibit the growth of a chloroquine-resistant strain of Plasmodium falciparum. Some of these new compounds are significantly more active than desferrioxamine DFO, the iron chelator in widespread clinical use and also than the most effective chelators.
Bioorganic & Medicinal Chemistry Letters 02/2006; 16(1):31-5. · 2.55 Impact Factor
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Christophe Biot,
Wassim Daher,
Cheikh M Ndiaye, Patricia Melnyk,
Bruno Pradines,
Natascha Leleu-Chavain,
Alain Pellet,
Laurent Fraisse,
Lydie Pelinski,
Christian Jarry,
Jacques Brocard,
Jamal Khalife,
Isabelle Forfar-Bares,
Daniel Dive
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ABSTRACT: 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 â-hematin inhibition property indicate that the ferrocene moiety has
to be covalently flanked by a 4-aminoquinoline and an alkylamine. Current data reinforced our choice of
FQ as a drug candidate.
Journal of Medicinal Chemistry 01/2006; 49:4707. · 5.25 Impact Factor
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ABSTRACT: Herein is described a new class of selective sigma1 ligands consisting of tetrahydroisoquinoline-hydantoin (Tic-hydantoin) derivatives. Compound 1a has high affinity (IC50 = 16 nM) for sigma1 receptor and is selective in a large panel of therapeutic targets. This study presents structural changes on the side chain of the Tic-hydantoin core. Analogs of higher affinity could be identified (IC50 approximately 2-3 nM).
Bioorganic & Medicinal Chemistry Letters 12/2005; 15(21):4828-32. · 2.55 Impact Factor
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ABSTRACT: Herein is described a new class of selective sigma1 ligands consisting of tetrahydroisoquinoline-hydantoin (Tic-hydantoin) derivatives. Compound 3a has high affinity (IC50 = 16 nM) for the sigma1 receptor and is selective in a large panel of therapeutic targets. This first study presents structural changes around the Tic-hydantoin core, leading to a Tic-hydantoin analogue with a higher sigma1 affinity (IC50 approximately 1 nM).
Bioorganic & Medicinal Chemistry Letters 12/2005; 15(21):4833-7. · 2.55 Impact Factor
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ABSTRACT: The purpose of this review is to provide an update on our work based on the 1,4-bis(3-aminopropyl)piperazine skeleton and how it allowed our group to validate a new target. After a brief introduction where we will relate the way this substructure was introduced in our 4-aminoquinolinyl derivatives, we will present first the different libraries synthesized around this moiety: (1) libraries of sulfonamides, amides and amines derived from 4-aminoquinolines and, (2) libraries where the 4-aminoquinoline nucleus is replaced. High throughput evaluation of biological activity and physicochemical parameters will be presented. The evaluation of the anti-malarial activity of the compounds will be discussed in the light of a chloroquine-like mechanism (accumulation in the acidic food vacuole and inhibition of beta-hematin formation). In a second part we will present active 1,4-bis(3-aminopropyl)piperazine as tools for identification and/or validation of new antimalarial targets. Fluorescence assays on some derivatives show that they are surprisingly localized outside the food vacuole, suggesting the existence of other target(s). Secondly, we will present a library of 1,4-bis(3-aminopropyl)piperazine as inhibitors of the cytosolic aminopeptidase Pfa-M1, a new potential target for antimalarials.
Combinatorial Chemistry & High Throughput Screening 03/2005; 8(1):39-48. · 1.78 Impact Factor
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ABSTRACT: Synthesis and evaluation of the activity of new N(1)-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives against a chloroquine-resistant strain of Plasmodium falciparum are described. Selectivity indices were improved for two compounds versus the lead 1, the bis-cyclopropylmethyl derivative, thus increasing the therapeutic interest of our family. As our previous studies conducted on the mode of action of our compounds made us hypothesize the existence of original mechanisms and/or original targets, terminal amino derivatives can be considered as promising tools further mechanistical studies, as probes for affinity chromatography.
Bioorganic & Medicinal Chemistry Letters 02/2005; 15(2):297-302. · 2.55 Impact Factor
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Tetrahedron Letters 37(24):4145-4148. · 2.68 Impact Factor
