Solubility enhancement of mefenamic acid by inclusion complex with ß-cyclodextrin: in silico modelling, formulation, characterisation, and in vitro studies.

The aim of this study was to prepare and characterise inclusion complexes of a low water-soluble drug, mefenamic acid (MA), with ß-cyclodextrin (ß-CD). First, the phase solubility diagram of MA in ß-CD was drawn from 0 to 21 × 10-3 M of ß-CD concentration. A job's plot experiment was used to determine the stoichiometry of the MA:ß-CD complex (2:1). The stability of this complex was confirmed by molecular modelling simulation. Three methods, namely solvent co-evaporation (CE), kneading (KN), and physical mixture (PM), were used to prepare the (2:1) MA:ß-CD complexes. All complexes were fully characterised. The drug dissolution tests were established in simulated liquid gastric and the MA water solubility at pH 1.2 from complexes was significantly improved. The mechanism of MA released from the ß-CD complexes was illustrated through a mathematical treatment. Finally, two in vitro experiments confirmed the interest to use a (2:1) MA:ß-CD complex.

Biologically active carbazole derivatives: focus on oxazinocarbazoles and related compounds.

Four series of carbazole derivatives, including N-substituted-hydroxycarbazoles, oxazinocarbazoles, isoxazolocarbazolequinones, and pyridocarbazolequinones, were studied using diverse biological test methods such as a CE-based assay for CK2 activity measurement, a cytotoxicity assay with IPC-81 cell line, determination of MIC of carbazole derivatives as antibacterial agents, a Plasmodium falciparum susceptibility assay, and an ABCG2-mediated mitoxantrone assay. Two oxazinocarbazoles Ib and Ig showed CK2 inhibition with IC50 = 8.7 and 14.0 µM, respectively. Further chemical syntheses were realized and the 7-isopropyl oxazinocarbazole derivative 2 displayed a stronger activity against CK2 (IC50 = 1.40 µM). Oxazinocarbazoles Ib, Ig, and 2 were then tested against IPC-81 leukemia cells and showed the ability to induce leukemia cell death with IC50 values between 57 and 62 µM. Further investigations were also reported on antibacterial and antiplasmodial activities. No significant inhibitory activity on ABCG2 efflux pump was detected.

Conception of Cellulose/Alginate/Mesalazine microspheres by solvent evaporation technique for drug release: Experimental and theoretical investigations.

Preparation of microspheres containing Mesalazine referred to as 5-aminosalicylic acid (5-ASA) for colon targeting drug was carried out using the emulsion solvent evaporation technique. The formulation was based on 5-ASA as the active agent, sodium Alginate (SA) andEthylcellulose (EC) as encapsulating agents, with polyvinyl alcohol (PVA) as emulsifier. The effects ofthe following processing parameters, 5-ASA %, EC:SA ratio and stirring rate on the properties of the resulting products in the form microspheres were considered. The samples were characterized using Optical microscopy, SEM, PXRD, FTIR, TGA, and DTG. In vitro release of 5-ASA from the different batches of microspheres was tested in biologically simulated fluids, (gastric; SGF, pH 1.2 for 2 h), then (intestinal fluid SIF, pH 7.4for 12 h) at 37 °C. The release kinetic results have been treated mathematically relaying on Higuchi's and Korsmeyer-Peppas' models for drug liberation. DOE study was performed to evaluate the interactive effects of variables on the drug entrapment and microparticle sizes. Molecular chemical interactions in structures were optimized using DFT analysis.

An alkylaminoquinazoline restores antibiotic activity in Gram-negative resistant isolates.

To date, various bacterial drug efflux pump inhibitors (EPIs) have been described. They exhibit variability in their activity spectrum with respect to antibiotic structural class and bacterial species. Among the various 4-alkylaminoquinazoline derivatives synthesized and studied in this work, one molecule, 1167, increased the susceptibility of important human-pathogenic, resistant, Gram-negative bacteria towards different antibiotic classes. This 4-(3-morpholinopropylamino)-quinazoline induced an increase in the activity of chloramphenicol, nalidixic acid, norfloxacin and sparfloxacin, which are substrates of the AcrAB-TolC and MexAB-OprM efflux pumps that act in these multidrug-resistant isolates. In addition, 1167 increased the intracellular concentration of chloramphenicol in efflux pump-overproducing strains. The rate of restoration depended on the structure of the antibiotic, suggesting that different sites in the efflux pumps may be involved. A molecule exhibiting a morpholine functional group and a propyl extension of the side chain was more active.

Chloroquinolines block antibiotic efflux pumps in antibiotic-resistant Enterobacter aerogenes isolates.

Efflux mechanisms protect bacterial cells by pumping out toxic compounds and actively contribute to bacterial multidrug resistance. Agents inhibiting efflux pumps are of interest for the control of multidrug-resistant bacterial infections. Herein we report the effects of new chloroquinoline derivatives that render resistant Enterobacter aerogenes isolates noticeably more susceptible to structurally unrelated antibiotics. In addition, some of these chloroquinolines increase the intracellular concentration of chloramphenicol. Some of the molecules tested in this work are able to inhibit the main efflux pump (AcrAB-TolC), which is involved in E. aerogenes antibiotic resistance.

Quinazoline derivatives are efficient chemosensitizers of antibiotic activity in Enterobacter aerogenes, Klebsiella pneumoniae and Pseudomonas aeruginosa resistant strains.

Amongst the three series of quinazoline derivatives synthesised and studied in this work, some molecules increase the antibiotic susceptibility of Gram-negative bacteria presenting multidrug-resistant phenotypes. N-alkyl compounds induced an increase in the activity of chloramphenicol, nalidixic acid and sparfloxacin, which are substrates of the AcrAB-TolC and MexAB-OprM efflux pumps in clinical isolates. These molecules are able to increase the intracellular concentration of chloramphenicol in efflux pump-overproducing strains. Their activity depends on the antibiotic structure, suggesting that different sites may be involved for the recognition of substrates by a given efflux pump. Quinazoline molecules exhibiting a nitro functional group are more active, and structure-activity relationship studies may be undertaken to identify the pharmacophoric group involved in the AcrB and MexB affinity sites.