Piperazine derivatives as iron chelators: a potential application in neurobiology.

Polysubstituted piperazine derivatives, designed as new iron chelators, were synthesized and fully characterized by nuclear magnetic resonance and mass spectroscopy. Their potential to prevent iron-induced neurotoxicity was assessed using a cellular model of Parkinson disease. We demonstrated their ability to provide sustained neuroprotection to dopaminergic neurons that are vulnerable in this pathology. The iron chelating properties of the new compounds were determined by spectrophotometric titration illustrating that high affinity for iron is not associated with important neuroprotective effects.

Design and synthesis of 3-isoxazolidone derivatives as new Chlamydia trachomatis inhibitors.

Chlamydia trachomatis (Ct) is a bacterial human pathogen responsible for the development of trachoma, the worldwide infection leading to blindness, and is also a major cause of sexually transmitted diseases. As iron is an essential metabolite for this bacterium, iron depletion presents a promising strategy to limit Ct proliferation. The aim of this study is to synthesize 3-isoxazolidone derivatives bearing known chelating moieties in an attempt to develop new bactericidal anti-Chlamydiaceae molecules. We have investigated the paths by which these new compounds affect Ct serovar L2 development in HeLa cells, in the presence or absence of exogenously added iron. The iron-chelating properties of these molecules were also determined. Our data reveal important bactericidal effects which are distinguishable from those due to iron chelation.

E-assay concept: detection of bisphenol A with a label-free electrochemical competitive immunoassay.

A label-free electrochemical immunosensor was developed by electropolymerization of N-(3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)propyl) 3-(5-hydroxy-1,4-dihydro-1,4-dioxonaphthalen-2(3)-yl)propionamide (JugBPA). By combination with an antibody directed to bisphenol A (αBPA), this conducting polymer-based biosensor can detect BPA directly with a limit of detection of 2pgmL(-1). Square wave voltammetry shows that the polymer film presents a current decrease upon anti-BPA binding and an opposite current increase upon BPA addition in solution. This electrochemical immunosensor (E-assay) also shows high selectivity towards closely related compounds (bisphenol A dimethacrylate, and dibutyl phthalate). The E-assay concept described here could be a promising tool for simple, low-cost and reagentless on-site environmental monitoring.

A label-free electrochemical immunosensor for direct, signal-on and sensitive pesticide detection.

A new electropolymerizable monomer, [N-(6-(4-hydroxy-6-isopropylamino-1,3,5-triazin-2-ylamino)hexyl) 5-hydroxy-1,4-naphthoquinone-3-propionamide], has been designed for use in a label-free electrochemical immunosensor when polymerized on an electrode and coupled with a monoclonal anti-atrazine antibody. This monomer contains three functional groups: hydroxyl group for electropolymerization, quinone group for its transduction capability, and hydroxyatrazine as bioreceptor element. Square wave voltammetry shows that the polymer film, poly[N-(6-(4-hydroxy-6-isopropylamino-1,3,5-triazin-2-ylamino)hexyl) 5-hydroxy-1,4-naphthoquinone-3-propionamide], presents negative current change following anti-atrazine antibody complexation and positive current change after atrazine addition in solution. This constitutes a direct, label-free and signal-on electrochemical immunosensor, with a very low detection limit of ca. 1 pM, i.e. 0.2 ng L(-1), one of the lowest reported for such immunosensors. This is far lower than the detection limit required by the European Union directives for drinkable water and food samples (0.1 µg L(-1)). The strategy described has great promise for the development of simple, cost-effective and reagentless on-site environmental monitors.

Docking and 3D-QSAR studies of BMS-806 analogs as HIV-1 gp120 entry inhibitors.

BMS-378806 (BMS-806) is a small molecule that blocks the binding of host-cell CD4 with viral gp120 protein and therefore inhibits the first steps of HIV-1 infection. Recently, 36 analogs compounds of BMS-806 were synthesized and their biological activity evaluated. Based on these compounds, a molecular docking was firstly performed with BMS-806 to the gp120 cavity in order to get a representative ligand conformation for the 3D-QSAR process. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were then conducted for these 36 compounds. CoMFA and CoMSIA models give reliable correlative and predictive abilities but the CoMFA model performance was slightly better than CoMSIA. CoMFA contours were analysed and have been correlated to the gp120 viral protein. The discussion indicates several key fragment positions on the ligands and their implications on the gp120 protein binding. The computational approach used in this paper provides reliable clues for further design of small molecules gp120/CD4 inhibitors based on the BMS-806.

PMS-601, a new platelet-activating factor receptor antagonist that inhibits human immunodeficiency virus replication and potentiates zidovudine activity in macrophages.

We assessed the anti-human immunodeficiency virus (anti-HIV) activity in vitro of new platelet-activating factor (PAF) receptor antagonists, as PAF and viral replication are thought to be involved in HIV neuropathogenesis. We found that PMS-601 inhibited proinflammatory cytokine synthesis and HIV replication in macrophages and potentiated the antiretroviral activity of zidovudine. These results suggest that PMS-601 is of potential value as an adjuvant treatment for HIV infection.

[Antiretroviral ant anti-inflammatory properties of a novel platelet activation factor antagonist, PMS-601]. / Propriétés antirétrovirales et anti-inflammatoires d'un nouvel antagoniste du facteur d'activation des plaquettes, la PMS-601.

The platelet-activating factor (PAF) plays a major role in neuropathogenesis associated with human immunodeficiency virus (HIV) infection by enhancing the inflammatory syndrome and viral replication, particularly in cells of the macrophage lineage, and its neurotoxic properties. We therefore evaluated the ability of PAF-R antagonists to inhibit HIV-1 replication and down-modulate the synthesis of pro-inflammatory mediators in healthy or HIV-1-infected macrophages. PMS-601 demonstrated the highest anti-HIV activity. Considering its mode of action and anti-inflammatory properties, PMS-601 interferes with early and late steps of the HIV biological cycle and decreases the synthesis of PAF, TNF-alpha, MIP-1 alpha, MIP-1 beta and RANTES. Altogether, these results suggest that PAF-receptor antagonists, and particularly PMS-601, could be of potential value as treatment adjuvants in HIV infection.

Structure-activity relationships in platelet-activating factor (PAF). 10. From PAF antagonism to inhibition of HIV-1 replication.

Excessive levels of PAF and cells of macrophage lineage appear to play an important role in neuronal cell injury, inflammatory syndrome, and HIV replication in CNS resulting in AIDS dementia complex (ADC). The beneficial effects of PAF receptor antagonists are evident and give rise to expected therapeutic strategies for neurotrauma. Piperazine derivatives bearing a "cache-oreilles" (ear-muff) electronic distribution are able to inhibit in vitro PAF effects and, thus, could be used in pathologies where this mediator is involved. Therefore, their potential anti-HIV activity was investigated, and we find that (i) these PAF antagonists are effectively active in HIV-infected monocyte-derived macrophages (MDM) but there is no correlation between both anti-HIV and anti-PAF activities; (ii) the presence of a carbamate function (compounds 1a-d) is favorable to the antiviral activity; (iii) the lipophilicity of the substituent on the piperazinic cycle seems to be less important for the anti-PAF activity than for the antiviral one. Our leading compound, PMS 601 (compound 1a), presents a dual activity with IC(50) of 8 and 11 microM for anti-PAF and anti-HIV activity, respectively, without cytotoxic events at 1000 microM in MDM. Although its mode of action is not clearly defined, these data suggest that PMS 601, which displays no effect on acellular reverse transcriptase or protease tests, deserves further investigation in the treatment of HIV-1-associated dementia.