Pierre Brouant

Membrane permeation by multidrug-resistance-modulators and non-modulators: effects of hydrophobicity and electric charge.

This study was designed to test the hypothesis that lipophilic cationic drugs with only roughly similar structures mediate the reversal of multidrug‐resistance (MDR) by interacting with membrane phospholipids. The permeation properties of MDR‐modulators and non‐modulators were studied by quantifying their ability to induce the leakage of Sulphan blue through the membrane of negatively charged unilamellar liposomes.

Antimicrobial activity of 9-oxo and 9-thio acridines: Correlation with intercalation into DNA and effects on macromolecular biosynthesis

The antimicrobial activity of several new 9-acridinones and 9-thioalkylacridines towards Escherichia coli, Staphylococcus aureus, Mycobacterium smegmatis and Candida albicans was investigated. Minimal inhibitory, bactericidal and fungicidal concentrations were determined using a microplate assay which enabled inhibitory, bactericidal and fungicidal indices to be calculated. These indices facilitated structure/activity relationship studies. DNA-intercalating capability and DNA supercoiling inhibitory effects as well as inhibitory effects on macromolecular synthesis were determined. Results showed that intercalation into DNA, which is the mechanism of action usually postulated for acridines, cannot be correlated with the properties examined. However, inhibition of RNA synthesis may be involved in the antimicrobial activity of the drugs.

Structure and conformational analysis of 5,11-dibenzyldibenzo[b,f][1,5]diazocine-6,12-dione. A novel approach for new chemosensitizers

Abstract On the basis of structural similarities between various calcium channel antagonists (Verapamil or Diltiazem) a novel series of derivatives belonging to the dibenzodiazocinedione family were designed and synthesised to obtain drugs able to revert multidrug resistance (MDR). X-ray structure studies and conformational analysis of 5,11-dibenzyldibenzo[b,f][1,5]diazocine-6,12-dione were performed. Molecular modelling results have shown that observed reversal activity of this new derivative could refer to a thermodynamically limited concentration in a peculiar (extended) conformation.

A Potential Antiprotozoal Drug Containing Acridine and Thiadiazole Moieties

The title compound, 3-(6-chloro-2-methoxy-9-acridinyl)-5-[2-(diethylamino)ethylthio]-1,3,4-thiadiazol-2(3H)-one, C 22 H 23 ClN 4 OS 3 , belongs to a series of new potential antiprotozoal drugs containing the acridine and thiadiazole systems. These two quasi-planar moieties are bonded together and are almost perpendicular to one another because of steric hindrance.

SYNTHESIS, TRYPANOCIDAL ACTIVITY AND DNA BINDING OF NEW BENZO[b][1,8]- NAPHTHYRIDONES DERIVATIVES

A novel set of N-alkyl naphthyridone compounds has been prepared and characterized. These compounds have been compared to analogous 9-acridinones for a possible trypanocidal activity. With reference to this, naphthyridones seem to be more promising compounds than the 9-acridinone ones. INTRODUCTION Within the scope of the search of new trypanocidal agents (1-3) we have recently prepared and tested some 1,4-dimethoxy-9-(10H)-acridinone derivatives (4). As the naphtyridine nucleus is structurally related to the acridine one, we were also interested in preparing and investigating antiparasitic activity of some new benzo [b][1,8]-5-naphthyridone derivatives, substituted similarly as acridinones already tested.

IMPROVEMENT OF THE ULLMANN'S CONDENSATION METHOD FOR THE SYNTHESIS OF 2-ANILINONICOTINIC ACIDS

Several 2-anilinonicotinic acid derivatives were prepared under the UUmanns reaction conditions by condensation of 2chloronicotinic acid and various substituted anilines. Improvement of the procedure based on the effect of the catalyst and that of the solvent on the reaction yields is reported.

MICROWAVE ACTION ON 2-(ARYLAMINO)-NICOTINlC ACID DERIVATIVES

Microwave action on adsorbed 2-(arylamino)-nicotinic acid derivatives allows to obtain, depending on the pH of the substrate, the corresponding N-amino substituted pyridines by decarboxylation or the naphthyridone derivatives by cyclization reaction. INTRODUCTION Benzo[b]-l,8-naphthyridine-5-ones have been synthesized with a view to obtain new anticancer agents. These compounds can be prepared by cyclization of the corresponding 2-(arylamino)-nicotinic acid derivatives (1). Due to the fact that reaction conditions are generally tedious, e.g. the reaction takes place in the presence of polyphosphoric acid or phosphorus oxychloride, and yields are not very high, we tried to improve the cyclization reaction using dry medium procedure under microwave activation. Bentonite clay was previously used for performing acid-catalysed cyclodehydration of benzoylbenzoic acids (2) and that of 2-carboxylic acid-diphenylamines (3). Results obtained in doing so, led us to extend this procedure to the cyclization reaction of 2-(arylamino)-nicotinic acid derivatives. Substrates were absorbed on bentonite with various pH values or on p-toluenesulfonic acid, taking advantage of the well known dehydration catalytic activities of this compound, before to be subjected to the action of microwaves.

Un sel de Maprotiline (Ludiomil), Médicament Psychotrope, C20H24N+.C21H22NO2−.0,5H2O

Maprotiline (ludiomil) is a tetracyclic antidepressant drug which crystallized in DMF as the salt [3-(9,10-dihydro-9,10-ethano-9-anthracenyl)propyl]methylammonium N-[3-(9,10-dihydro-9,10-ethano-9-anthracenyl)propyl]-N-methylcarbamate hemihydrate. The asymmetric unit contains a C 20 H 24 N + cation and a C 21 H 22 NO 2 − anion. The dihedral angle between the planes of the benzene rings is 117.8 (3)° in the cation and 121.5 (3)° in the anion. Conformational paramaters were calculated and compared to those of similar compounds and tricyclic antidepressant drugs

APPLICATION OF PHASE TRANSFER CATALYSIS IN THE ACRIDINE SERIES. VII (1). SYNTHESIS OF 9-CYANOACRIDINE DERIVATIVES

A new method using solid-liquid PTC for preparing 9-cyanoacridine derivatives in high yields under mild conditions is described. Some procedures for the synthesis of 9-cyanoacndine derivatives have been developed which use reactions of acridine (2,3,9), 9-choloroacridine (4,5,7,10), 9-methoxyacridine hydrate (6) or 3,9-dichloroacridine with sodium or potassium cyanide (2-9) or anhydrous hydrogen cyanide in the absence (6) or presence of benzoylchloride (7). When 9-chloroacndine is used as starting material, reaction conditions are rather hard (heating in a sealed tube for 4 hours at 160-170°C with potassium and cuprous cyanine) except when the reaction takes place in the presence of p-toluene sulfinate or methane sulfinate as catalyst (10). For this reason, we propose to prepare 9-cyanoacndine derivatives starting from the corresponding 9-chloroacridines and using sodium cyanide under liquid-solid phase transfer catalysis conditions.

Étude structurale d'une imidazolylcétone l'isopropyl-1-phényl-2-diaza-1,3-one-6-bicyclo[3,3,0]octène-2

The solid state configuration of 1-isopropyl-2-phenyl-1,3-diaza-6-one-bicyclo[3.3.0]oct-2-ene was determined from X-ray diffraction data (a = 10.039(3) A; b = 8.683(3) A; c = 15.505(6) A; β = 90.72(9)°; P21/c;R = 0.047). This structure is compared to those of three other related (Δ-2)-imidazolines. Molecular structure in solution was investigated by 1H nuclear magnetic resonance spectroscopy. Results clearly indicate that the title compound has the same structure in the solid state as in solution. On the contrary, this configuration differs appreciably from those of other (Δ-2)-imidazolines considered in this report. Keywords: (Δ-2)-imidazolines, crystal structure, NMR, conformations.