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.

Several 2-anilinonicotinic acid derivatives were prepared under the Ullmann's reaction conditions by condensation of 2-chloronicotinic 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.

Porin channels play a prominent role during fluoroquinolone uptake and spermine strongly alters the diffusion rate of norfloxacine. Consequently the interactions between spermine and bacterial porin were studied by computer simulation. The results indicate that various residues (E62, D 113, E 117,...) closely located in the internal eyelet region of the OmpF channel are potential binding sites. Among them, the D 113 residue, seems to play an important role in the association channel-spermine. This interaction introduces several changes in the internal morphology of the channel which are responsible for the inhibition of antibiotic uptake using the porin route.

A series of benzo[b]-1,8-naphthyridine derivatives branched with various side-chains and substituents were prepared with the aim of being investigated as multidrug resistance (MDR) modulators. The syntheses were achieved from 2-halonicotinic acid and suitable aryl-amines according to a three-step procedure. All the derivatives were tested in vitro on mouse T-Lymphoma cell line L5178 transfected by MDR1 gene and the chemosensitizing properties of the compounds were compared to those of verapamil and propranolol, as well as to several other tricyclic derivatives like phenothiazines and acridines. Most of the compounds tested reversed the MDR of tumour cells more effectively than the reference drugs did and they showed more potent chemosensitizing activity than phenothiazine and acridine derivatives have.

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.

Phenothiazine derivatives containing two linearly condensed phenothiazine moieties, 16H,18H-dibenzo[c,l]-7,9-dithia-16,18-diazapentacene (I), dibenzo[c,l]-16,18-diacetyl-7,9-dithia-16,18-diazapentacene (II) dibenzo[c,l]-16,18-dibenzoyl-7,9-dithia-16,18-diazapentacene (III), and 16H,18H-dibenzo[c,l]-7,9-dithia-16,18-diazapentacene-7,7,9,9-bis-dioxide (IV), strongly adsorb on spectrographic graphite resulting in modified electrodes with electrocatalytic activity for NADH oxidation. From cyclic voltammetry measurements, performed in aqueous buffer solutions at different potential scan rates and pH values, the rate constants of the heterogeneous electron transfer and the transfer coefficients were estimated. The linear dependence between the peak current and the potential scan rate, corroborated with the slope of the formal standard potential versus pH linear regression, pointed out to a quasi-reversible, surface confined redox process involving 1e−/1H+. The electrocatalytical efficiency, evaluated from cyclic voltammetry, and the second order electrocatalytical rate constant (k1), calculated from rotating disk electrode experiments, revealed the same sequence of the activity decrease: III>II>IV>I. Compound III-modified electrodes were characterized by the highest k1 (1.8×103 M−1 s−1, at pH 7.0) as well as by the highest stability, expressed by the lowest rate of the surface coverage depleting under continuous potential cycling.

The preparation of novel alkyl monobridged 2,3-dimethyl-5-amino-benzo[b][1,8]naphthyiridine and benzo[b][1,8]naphthyridone derivatives by phase transfer catalysis is reported.

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.

The synthesis of several acridinic thioethers is described. Compounds prepared were tested in vitro as potential drugs against the opportunistic infection known as cryptosporidiosis. With a view to predict activity, the quantitative structure-activity relationships were investigated. Correlations between experimental data and either log P or pKa are discussed.

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.

A new method using solid-liquid PTC for preparing 9-cyanoacridine derivatives in high yields under mild conditions is described.

We studied the effect of thioacridine derivatives on the function of P-glycoprotein in MDR mouse T-lymphoma cell line L5178 and in MDR human leukemia cell line K562/ADR by rhodamine 123 uptake assay. The effect of some selected thioacridines was also investigated on the expression of the mdr1 gene. Expression was analysed by RT-PCR. Two compounds: 3-amino-9-thio-(4'-nitrobenzyl)acridinone and 2,7-dimethoxy-9-thio-(2'-diethylaminoethyl) acridinone were able to block the function of the P-gp, and also to decrease significantly mdr1 gene expression. Because these two derivatives exert their positive effects as reversing agents they could be potential candidate anticancer agents for further investigation. The thioacridines, which do not affect P-gp function, do not affect or increase the expression of mdr1 gene. Our results showed the structure-activity relationships of these compounds, providing a direction for the development of new, more active compounds.

The title compound, C14H13N3, is an intermediate in the synthesis of the corresponding 5-aminobenzo[b][1,8]-naphthyridine. Problems of isomerism occur with this series. According to the crystal structure, conformational features do not appear to be involved either in the mechanism of the reaction or in determination of the isomers obtained.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The title compound, 3-(6-chloro-2-methoxy-9-acridinyl)5-[2-(diethylamino)ethylthio]-1,3,4-thiadiazol-2(3H)-one, C22H23ClN4OS3. belongs to a series of new potential 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.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

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.