Jacques Brocard

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.

Synthesis and antifungal activity of a ferrocene-fluconazole analogue.

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.

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.

Trioxaferroquines as new hybrid antimalarial drugs.

The synthesis, characterization, and antimalarial evaluation of a new series of potential antimalarial molecules, named trioxaferroquines, are reported. Trioxaferroquines are hybrid antimalarial drugs containing a 1,2,4-trioxane covalently linked to ferroquine (Fq), a synthetic ferrocenylquinoline derivative currently under clinical development. The aim was to combine, within a single structure, an iron(II) species, a 1,2,4-trioxane, as in artemisinin, and a substituted quinoline, as in chloroquine.

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.

A novel and convenient method for palladium-catalysed alkoxycarbonylation of aryl and vinyl halides using HCO2R/NaOR system

Abstract Aryl iodides, vinyl bromides and tricarbonyl(chloroarene)chromium complexes react under mild conditions with sodium alkoxides and alkyl formates as source of carbon monoxide in the presence of dichlorobis(triphenylphosphine)-palladium as catalyst to give the corresponding carboxylic esters in high yields.

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

BackgroundFerroquine (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 patients, the potential for resistance to this drug was evaluated.MethodsThe relationship between CQ-resistant transporter gene genotype and susceptibility to FQ were studied in 33 Cambodian P. falciparum field isolates previously studied for their in vitro response to CQ. In parallel, the ability of the CQ-resistant strain W2, to become resistant to FQ under drug pressure was assessed.ResultsThe IC50 values for FQ in field isolates were found to be unrelated to mutations occurring in the P. falciparum chloroquine resistance transporter (PfCRT) or to the level of expression of the corresponding mRNA. In vitro, under a drug pressure of 100 nM of FQ, transient survival was observed in only one of two experiments.ConclusionField isolates studies and experimental drug pressure experiments showed that FQ overcomes CQ resistance, which reinforces the potential of this compound as a new antimalarial drug.

Synthesis and application in enantioselective hydrogenation of new free and chromium complexed aminophosphine–phosphinite ligands

Abstract A straightforward synthesis of new free and Cr(CO) 3 complexed AMPP ligands ( 4 – 7 ) is described starting from ( S )-indoline-2-carboxylic acid. The ligands were applied successfully in the asymmetric hydrogenation of α-functionalized ketones i.e. a ketolactone 8 , a ketoamide 9 and an aminoketone 10 leading to the corresponding optically active alcohols in 99, 97, and 99% ee respectively.

Palladium-catalysed alkoxycarbonylation of tricarbonyl(η6-mono and dichloroarene)chromium complexes under mild conditions using HCO2R/MOR system

Alkoxycarbonylation competes with nucleophilic aromatic substitution and palladium-catalysed reduction during treatment of Cr(CO)3-complexed chloroarenes with HCO2R / MOR / PdCl2(PPh3)2. The influence of the nature of the HCO2R / MOR system and of stereoelectronic factors in dichlorobenzene complexes are discussed.