Dihydroethanoanthracene derivatives reverse in vitro quinoline resistance in Plasmodium falciparum malaria.

The capacity of ten molecules for reversing resistance in Plasmodium falciparum in vitro to quinoline antimalarial drugs, such as chloroquine (CQ), quinine (QN), mefloquine (MQ) and monodesethylamodiaquine (MDAQ), was assessed against 27 Plasmodium falciparum isolates. Four of these compounds were 9,10-dihydroethanoanthracene derivatives (DEAs). These DEAs reversed 75 to 92% of the CQ resistant strains.

Inhibition of efflux of quinolines as new therapeutic strategy in malaria.

Plasmodium falciparum is one of the most lethal parasite responsible for human malaria. Until now, the only one solution to counter malaria is the use of antimalarial drugs. Unfortunately, the extensively use of drugs, such as quinolines (i.

Synthesis, biological evaluation and molecular modeling studies of arylidene-thiazolidinediones with potential hypoglycemic and hypolipidemic activities.

New arylidene-thiazolidinediones (ATZDs) were synthesized and evaluated in the alloxan-induced hyperglycemia mice model. The molecular target taken into consideration is the nuclear PPAR-gamma whose crystallographic structure is available on the PDB database as 2PRG. Thus the hypoglycemic and hypolipidemic activities of compounds were compared with the result of their docking after removal of the co-crystallized ligand present in the 2PRG structure.

Chloroquine resistance reversal agents as promising antimalarial drugs.

The development and spread of resistance to antimalarial drugs poses a severe and increasing public health threat. Failures of prophylaxis or treatment with quinolines, hydroxynaphthoquinones, sesquiterpene lactones, antifolate drugs and sulfamides are involved in a return malaria-related morbidity and mortality. Resistance is associated with a decrease in accumulation of drugs into the vacuole, which results from a reduced uptake of the drug, an increased efflux or a combination of both.

Quinoline derivatives as promising inhibitors of antibiotic efflux pump in multidrug resistant Enterobacter aerogenes isolates.

Efflux pumps protect the bacterial cell by expelling toxic compounds before they reach intracellular targets. Because this mechanism actively contributes to the resistance of a given bacterium to more than one class of antibiotics, molecules that are able to block the relevant efflux pump are of potential significance to combat drug resistance caused by efflux pumps. Different quinoline derivatives including alkoxy, alkylamino, thioalkoxy and chloroquinolines have been previously reported to make Enterobacter aerogenes resistant isolates that over express the mechanism of efflux, noticeably more susceptible to structurally unrelated antibiotics.

[In vivo study of effects of some alkyl-phenyl-pyridinium compounds after their exposure to optical UV beams].

The purpose of this paper is to study the effects of some alkyl-phenyl-pyridinium compounds (which are in fact cytostatics) on the pseudotumoral tissues after their exposure to optical UV- vis beams.

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.

Chemosensitizers in drug transport mechanisms involved in protozoan resistance.

The emergence and spread of antiparasitic drug resistance pose a severe and increasing public health threat. Failures in prophylaxis or those in treatment with quinolines, hydroxynaphtoquinones, sesquiterpenic lactones, antifolate drugs, arsenic and antimony containing drugs sulfamides induce reemergence of parasitic-related morbidity and mortality. Resistance is often associated with alteration of drug accumulation into parasites, which results from a reduced uptake of the drug, an increased efflux or, a combination of the two processes.

Inhibitors of efflux pumps in Gram-negative bacteria.

In Gram-negative bacteria, efflux complexes, consisting of an inner-membrane pump, a periplasmic adaptor protein and outer-membrane channel, provide an efficient means for the export of structurally unrelated drugs, causing the multidrug-resistance phenotype. Resistance due to this antibiotic efflux is an increasing problem worldwide. A new molecular challenge is to combat this transport by searching for new molecules to block efflux and thus restore drug susceptibility to resistant clinical strains.

Beta-lactam screening by specific residues of the OmpF eyelet.

Beta-lactams use aqueous channels of porins to penetrate Gram-negative bacteria. The L3 loop of Escherichia coli OmpF porin is a key feature that actively contributes to both channel size and electrostatic properties. Acid residues D113, E117, and D121 are responsible for the negative part of the local electrostatic field on this loop.

The interaction between resistance modifiers such as pyrido[3,2-g]quinoline, aza-oxafluorene and pregnane derivatives with DNA, plasmid DNA and tRNA.

Various resistance mechanisms such as complex formation with DNA, tRNA and MDR1 p-glycoprotein were modified in bacteria and cancer cells in presence of pregnane, pyridoquinoline, and aza-oxafluorene derivatives. Interaction between the compounds, plasmid DNA and tRNA was shown and compared to the interaction with calf thymus DNA. Complex formation with MDR1 p-glycoprotein and drug accumulation increased in cancer cells.

Synthesis of 9-acridinyl sulfur derivatives: sulfides, sulfoxides and sulfones. Comparison of their activity on tumour cells.

The synthesis of several acridine thioethers is described. These compounds were oxidized to give new sulfoxides and sulfones. Among 23 compounds prepared, 19 were tested in vitro against the human cancer cell lines panel of NCI screening.

Polymorphism in plasmodium falciparum drug transporter proteins and reversal of in vitro chloroquine resistance by a 9,10-dihydroethanoanthracene derivative.

BG958 reverses resistance in chloroquine-resistant isolates from different countries. Five mutations in the Plasmodium falciparum crt (pfcrt) gene resulting in the amino acid changes K76T, M74I, N75E, A220S, and R371I are systematically identified in resistance-reversed Asian, African, and Brazilian parasites which possess the pfcrt (CIET) haplotype. In combination with BG958, the activity of chloroquine is increased in parasites with the N86Y mutation in pfmdr1.

Arylsulfonyl acridinyl derivatives acting on Plasmodium falciparum.

Several arylacridinyl sulfones have been synthesized and their antimalarial action was tested on Plasmodium falciparum. PABA (para-aminobenzoic acid) has no antagonistic effect with these compounds as opposed to the observed effect with dapsone and sulfonamides previously studied. A possible relationship between the ability of cleavage of the S-9C acridinic bond and activity is suggested.

Dihydroethanoanthracene derivatives as in vitro malarial chloroquine resistance reversal agents.

The ability of four 9,10-dihydroethanoanthracene derivatives (BG920, BG932, BG958, and BG996), as well as verapamil and promethazine, to reverse chloroquine resistance was assessed against 24 chloroquine-resistant and 10 chloroquine-susceptible strains of Plasmodium falciparum from different countries. The 9,10-dihydroethanoanthracene derivatives clearly increase chloroquine susceptibility only in chloroquine-resistant isolates.

Inhibitors of antibiotic efflux in resistant Enterobacter aerogenes and Klebsiella pneumoniae strains.

In Enterobacter aerogenes and Klebsiella pneumoniae, efflux provides efficient extrusion of antibiotics and contributes to the multidrug resistance phenotype. One of the alkoxyquinoline derivatives studied here, 2,8-dimethyl-4-(2'-pyrrolidinoethyl)-oxyquinoline, restores noticeable drug susceptibility to resistant clinical strains. Analyses of energy-dependent chloramphenicol efflux indicate that this compound inhibits the efflux pump mechanism and improves the activity of structurally unrelated antibiotics on multidrug-resistant E.

4-alkoxy and 4-thioalkoxyquinoline derivatives as chemosensitizers for the chloramphenicol-resistant clinical Enterobacter aerogenes 27 strain.

Enterobacter aerogenes is a Gram-negative bacteria frequently responsible for nosocomial respiratory tract infections. Strains resistant to chloramphenicol are frequently isolated. Alkoxy and thio-alkoxyquinolines have a potential to act as chemosensitizers that would render multi-drug-resistant (MDR) bacterial infections susceptible to antibiotics to which they were originally resistant.

Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates.

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.

Synthesis of 4-octyl-2H-1,4-benzo-thiazin-3-ones.

Synthesis, physical and analytical properties of 6-alkylacylamino-4-octyl-2H-1,4-benzo-thiazin-3-ones derivatives are described. These new compounds were prepared by acylation and/or alkylation of the amino group under phase transfer catalysis conditions. Acid hydrolysis of the alkylacylamino-2H-1,4-benzo-thiazin-3-ones afforded N-alkylamino-benzothiazin-3-ones.

Effects of a series of dihydroanthracene derivatives on drug efflux in multidrug resistant cancer cells.

A set of 9,10-dihydro-9,10-ethano and ethenoanthracene derivatives was tested with the aim to quantify the effect observed on drug efflux. Structure activity relationships and molecular modeling studies allowed to define topological display of pharmacophoric groups for these reversal agents.

Synthesis of aza mono, bi and tricyclic compounds. Evaluation of their anti MDR activity.

Anti MDR activity of a series of acridine, pyridoquinoline, quinoline and pyridine analogous amines was evaluated. Interesting activity is displayed by tricyclic compounds. Besides ring size, influence of the side chain was studied.

In vitro reversal of chloroquine resistance in Plasmodium falciparum with dihydroethanoanthracene derivatives.

The effects of combining four dihydroethanoanthracenic (DEA) derivatives and chloroquine were assessed in vitro against Plasmodium falciparum chloroquine resistant parasites W2, Palo Alto, FCR3, and Bres1. Like verapamil or promethazine, the four dihydroethanoanthracenic derivatives tested can be added to the growing list of agents that show capability in enhancing the activity of chloroquine against resistant parasites. The structurally related tricyclic antihistaminic compounds examined in this study exerted different intrinsic antimalarial activity, but the same chloroquine-potentiating activity as verapamil or promethazine.

Benzo[b]-1,8-naphthyridine derivatives: synthesis and reversal activity on multidrug resistance.

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.

Synthesis and effects on chloroquine susceptibility in Plasmodium falciparum of a series of new dihydroanthracene derivatives.

To suggest a mechanism of action for drugs capable to reverse the chloroquine resistance, a new set of 9,10-dihydro-9,10-ethano and ethenoanthracene derivatives was synthesized and compounds were tested with the aim to assess their effect on chloroquine susceptibility in Plasmodium falciparum resistant strains. With respect to this, reversal of resistance and change in drug accumulation were compared. Structure-activity relationship and molecular modeling studies made it possible to define a pharmacophoric moiety for reversal agents and to propose a putative model of interaction with some selected amino acids.

Computer simulation of spermine-porin channel interactions.

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,.