Gérard Boyer

Strategies for bypassing the membrane barrier in multidrug resistant Gram-negative bacteria

Regarding bacterial susceptibility towards antibacterial agents, membrane permeability is part of the early bacterial defense. The bacterium manages the translocation process, influx and efflux, to control the intracellular concentration of various molecules. Antibiotics and biocides are substrates of these mechanisms and the continuing emergence of multidrug resistant isolates is a growing worldwide health concern. Different strategies could be proposed to bypass the bacterial membrane barrier, comprising influx and efflux mechanisms, in order to restore the activity of antibiotics against resistant bacteria.

Photo-inducible cytotoxic and clastogenic activities of 3,6-di-substituted acridines obtained by acylation of proflavine

The cytotoxicity and photo-enhanced cytotoxicity of a series of 18 3,6-di-substituted acridines were evaluated on both tumour CHO cells and human normal keratinocytes, and compared to their corresponding clastogenicity as assessed by the micronucleus assay. Compounds 2f tert-butyl N-[(6-tert-butoxycarbonylamino)acridin-3-yl]carbamate and 2d N-[6-(pivalamino)acridin-3-yl]pivalamide displayed a specific cytotoxicity on CHO cells. These results suggested that the two derivatives could be considered as interesting candidates for anticancer chemotherapy and hypothesized that the presence of 1,1-dimethylethyl substituents was responsible for a strong nonclastogenic cytotoxicity. Compounds 2b and 2c, on the contrary, displayed a strong clastogenicity. They indicated that the presence of nonbranched aliphatic chains on positions 3 and 6 of the acridine rings tended to induce a significant clastogenic effect. Finally, they established that most of the acridine compounds could be photo-activated by UVA-visible rays and focussed on the significant role of light irradiation on their biological properties.

Synthesis and structure of new hosts related to 9,9′-bianthryl

The molecular structures of 10,10′-biacridinyl-9,9′-dione (5), 9-(10′-bromo-9′-anthryl)carbazole (9) and 9,9′-bicarbazyl (12) have been solved by X-ray crystallography. Proton and carbon-13 NMR studies of these and related compounds, show that in solution their conformations are also ‘scissor-like’. AM1 semi-empirical calculations provide a rationale for the geometries of these compounds.

Thiazolo [5,4-α] acridines

The synthesis of thiazolo [5,4-α] acridines and acridin-9(10H)-ones by cyclisation of anthranilic acids is described. NMR (specially 1H NMR) was used to ascertain their ‘bent’ structure.

A Synthesis of 9-Methoxy-1-Methyl-1H,6H-Pyrazolo[4,3-c]Carbazole

Abstract The synthesis of 9-Methoxy-1-methyl-1H,6H-pyrazolo[4,3-c]carbazole is reported in four steps from 6-nitroindazole. Palladium acetate mediated cyclization gave only the “bent” tetracyclic derivative.

INDANE FOR SYNTHESIS OF N-ALKYL DIARYLAMINES AND N-ACYLCYCLOPENTA[4,5-b]- PHENOTHIAZINES

ABSTRACT The synthesis of new N-alkyl-N-aryl-5-indanamines is reported. 5-Aminoindane was first N-alkylated with different alkyl halides, and the resulting N-alkyl-5-indanamines were N-phenylated with organolead or organobismuth reagents to afford the corresponding diarylamines. Direct N-acylation of linear fused 1,2,3,10-tetrahydrocyclopenta-[b]phenothiazines provided the final N-acyl tetracyclic products.

Synthesis of New Substituted Pyrrolo[2,3-b]- and Pyrrolo[3,2-a]acridinone Derivatives

Abstract The synthesis of new pyrrolo [a]- and [b]acridinones by cyclization of N-arylindoles obtained using ultrasonic irradiations from nitro indole is reported.

Reduction of nitroindazoles : Preparation of new amino and chloroamino derivatives

The synthesis of chloroaminoindazoles by the reduction of the nitro group of indazoles using stannous chloride in alcoholic acid solution is reported. Using catalytic hydrogenation with palladium the expected reduction to amino-indazoles occur.

Differentiation of heterocyclic regioisomers: a combined tandem mass spectrometry and computational study of N-acridin-4-ylbenzylamide and N-acridin-2-yl-benzylamide.

Electrospray ionization (ESI) tandem mass spectrometry (MS/MS) has been used to differentiate two positional isomers of acridine derivatives, N-acridin-4-ylbenzylamide and N-acridin-2-ylbenzylamide. The study revealed that the isomeric ion structures produced by these heterocycles could be distinguished upon collision-induced dissociations (CID). In particular, the loss of a water molecule was shown to be a regiospecific reaction of the protonated N-acridin-4-ylbenzylamide, in which the location of the benzylamide substituent with respect to the acridinic nitrogen greatly assists proton migration by allowing the creation of intramolecular hydrogen bonds. To a lesser extent, the two isomers could also be distinguished by the difference in the abundance of the benzoyl cation in the MS/MS spectra of the [M+H]+ ions, as this ion is produced with a much higher rate from N-acridin-4-ylbenzylamide. Calculations based on quantum-mechanical models have been performed to evaluate the stability of the ion structures and to support mechanisms proposed for these two dissociation reactions.

Arylboronic Acid-Lead Tetraacetate-Copper Diacetate: A One-Pot System for Copper-Catalyzed N-Arylation Under Neutral Conditions

The chemistry of boronic acids continues to be a grouth area in synthetic methodology. (Pelter 1988, Schlosser 2002) Such evidence as exists indicate that they are of relatively low toxicit [bezeneboronic acid (Frankland 1859, Leibigs 1860, Frankland 1862): LD50 oral-rat: 740mg/kg] and environmental impact. Boronic acids derivatives are mild and selective arylating reagents for a wide range of functional groups. Further information on the applications of boronic acids as derivatising and protecting agents can be found in various reviews (Ferrier 1978, Brooks 1978, Duggan 2002) and monographs. (Knapp 1979, Blau 1993, Greene 1999) Selective N-arylation of amines (aliphatic, heterocyclic amines or anilines) and O-arylation of phenols and glycols can be easily realized under very mild conditions by copper-catalyzed arylation with aryl lead triacetate. As aryl boronic acid can be used for the efficient synthesis of aryllead triacetate (Morgan 1990), we decided to take advantage to develop an in situ generation of the aryllead reagent followed directly by the copper-catalysed arylation of the amine. In this paper, we describe our studies on the influence of the substituents (electron-donating or electron-withdrawing) present on the aryl moiety of the boronic acid on the arylation of various substituents of amine aniline. 2. Material and Methods We therefore decided to look for a cheap, non-toxic and easily handled combination of reagents which would lead to good to high yields of aryllead triacetate under neutral conditions. We considered that arylboronic acid should be well-swited for this purpose. We now report lead tetracetate can be easily oxidized to aryl leadtriacetate by treatment with aryl boronic acid in chloroform at room temperature. In this way, a compound (2) was prepared, in which the aryl group is substituted by electrondonating or electron-attracting groups (table1). The evolution of the reaction was monitored by t.l.c. until the lead tetracetate has completely disappeared, and the overage reaction time was 5 hours. Good yields of pure compound were obtained.