Over the last decade, MDR (multidrug resistance) has increased worldwide in microbial pathogens by efflux mechanisms, leading to treatment failures in human infections. Several Gram-negative bacteria efflux pumps have been described. These proteinaceous channels are capable of expelling structurally different drugs across the envelope and conferring antibiotic resistance in various bacterial pathogens. Combating antibiotic resistance is an urgency and the blocking of efflux pumps is an attractive response to the emergence of MDR phenotypes in infectious bacteria. In the present study, various alkylaminoquinolines were tested as potential inhibitors of drug transporters. We showed that alkylaminoquinolines are capable of restoring susceptibilities to structurally unrelated antibiotics in clinical isolates of MDR Gram-negative bacteria. Antibiotic efflux studies indicated that 7-nitro-8-methyl-4-[2'-(piperidino)ethyl]aminoquinoline acts as an inhibitor of the AcrAB-TolC efflux pump and restores a high level of intracellular drug concentration. Inhibitory activity of this alkylaminoquinoline is observed on clinical isolates showing different resistance phenotypes.

The aim of this review is to give a general account on the oxidative microbial degradation of flavonols. Since now 50 years, various research groups have deciphered the way microorganisms aerobically deal with this important class of flavonoids. Flavonols such as rutin and quercetin are abundantly found in vegetal tissues and exudates, and it was thus patent that various microorganisms will bear the enzymatic machinery necessary to cope with these vegetal secondary metabolites. After initial studies focussed on the general metabolic capacity of various microorganisms towards flavonols, the so called rutin catabolic pathway was rapidly established in moulds. Enzymes of the path as well as substrates and products were known at the beginning of the seventies. Then during 30 years, only sporadic studies were focused on this pathway, before a new burst of interest at the beginning of the new century arose with structural, genomic and theoretical studies mainly conducted towards quercetinase. This is the goal of this work to relate this 50 years journey at the crossroads of microbiology, biochemistry, genetic and chemistry. Some mention of the potential usefulness of the enzymes of the path as well as micro-organisms bearing the whole rutin catabolic pathway is also discussed.

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. Of the 22 compounds under investigation, only those bearing a net positive electric charge per molecule (z) > or = 0.2 induced dye leakage. All these efficient drugs are well-known MDR-modulators: calcium-channel blockers (propranolol, verapamil, diltiazem and dipyridamole), calmodulin antagonists (clomipramine and thioridazine) and antiparasitic agents (mepacrine, thioacridine derivatives and quinine). The non-modulators tested, including antineoplastic agents and steroids, did not induce any membrane permeation. The permeation process was a co-operative one (1.1< Hill coefficient < 4.1) and the permeation doses inducing 50% dye leakage (PD50) were 1.9-11.2 mM. The permeation ability of the MDR-modulators (log(1/PD50)) increased significantly with octanol-buffer distributions per unit net electric charge ((logD)/z). The results provide evidence that a complex interplay occurs between the electric charge and the lipophilicity of the MDR-modulators when a dye leakage is induced through model membranes, and probably also when the MDR is reversed in leukaemic cells.

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Crystal data CI4HI3N3Mo Ka radiation Mr = 223.28 A = 0.71073,4, AbstractIn the title compound, (-)-cis-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid, C9HI403, carboxyl-toketone chains (catemers) are formed between screwrelated molecules spiraling along the b cell axis, with an O--H...O distance of 2.747 (3)A. The carboxyl C=:O Acta Co'stallographica Section C

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. INTRODUCTIONWithin 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. EXPERIMENTAL Synthesis, trypanocidal activity and DNA binding of new benzo [b] [ 1,8]-naphthyridones derivatives -ChemistryMelting points were determined in open capillary tubes on a Buchi-Tottoli apparatus and are given uncorrected. NMR spectra were recorded at 20.00 ± 0.1 °C, using a Bruker AM 200 spectrometer. Microanalyses were carried out using a Technicon CHN autoanalyzer.G6n6ral procedure for synthesis of compounds 1-8 (scheme 1) Procedure for compounds land 2.A mixture of freshly distilled aniline or properly substituted anilines (80 mmol), 2-chloro nicotonic acid (80 mmol), copper (0.8 g) and xylene (200 ml) is refluxed for 24 h with stirring.After filtration, the mixture is allowed to cool to room temperature. The precipitate obtained is recrystallized. Procedure for compounds 2_and_4Anthranilic acids 1 or 2 (10 mmol) are refluxed for 4 h with polyphosphoric acid in excess (more than 20 fold the weight of anthranilic acid). Then, the mixture is poured on ice and ammonia is slowly added. The precipitate obtained is recrystallized. Procedure for compounds 5 and_£A mixture of naphthyridone 2 or 4 (10 mmol), alkylating agent (15 mmol), and triethylbenzylammonium chloride hydrochloride (5 mmol), aqueous 50 % potassium hydroxide (50 ml), and toluene (100 ml) is refluxed for 24 h with stirring. Then, the organic layer is separated, washed with water, and dried with anhydrous sodium sulfate. After evaporation of solvent, crude product is recrystallized.Procedure for compound Ζ A mixture of £ (2 mmol) and 40 % hydrobromic acid (320 mmol), is refluxed for 4 h with stirring before being allowed to cool to room temperature. Solution is then neutralized with ammonia, with cooling to maintain the temperature at 0° C. The precipitate obtained is recrystallized.