118 research outputs found

    Antikinetoplastid SAR study in 3-nitroimidazopyridine series: identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

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    To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

    Two distinct patterns of treatment resistance:clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses

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    BACKGROUND: Clozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated. METHOD: This is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010. We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not. RESULTS: Seventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25-4.94] compared to those with non-TR. The relationship between an early age of first contact (years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44-9.56); and patients of male gender (OR 3.13 95% CI 1.35-7.23). CONCLUSIONS: For the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine

    Surface enhanced infrared spectral investigation of 2,3-bis(chloromethyl)anthracene-1,4,9,10-tetraone on silver nanoparticles

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    International audienceThe size effect of silver nanoparticles on photophysical properties of 2,3-bis(chloromethyl)anthracene-1,4,9,10-tetraone (BCMAT) has been investigated using an IR technique. Silver colloids of different sizes have been prepared by two different methods. Mechanisms for adsorption and complex formation have been elucidated from surface-enhanced infrared absorption spectra. The observation shows that BCMAT is adsorbed on silver nanoparticles through a C = O group and that its orientation is stand-on. Surface enhancement factors have been calculated. As the particles decrease in size their total surface area grows, which leads to the gain in the enhancement factor

    Ground and excited state preferential solvation behaviour of 1,4-dihydroxy-3-methylanthracene-9,10-dione in DMF + CCl4 binary system

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    International audiencePreferential solvation of 1,4-dihydroxy-3-methylanthracene-9,10-dione (DHMAD) has been investigated using optical absorption and fluorescence emission techniques. Optical absorption spectra of DHMAD in different solvents show the intra molecular charge transfer band in the region 400-550 nm. The preferential solvation parameter shows that in dimethyl formamide (DMF)+carbon tetrachloride (CCl4) mixture, the DHMAD is preferentially solvated by DMF in the ground state and in the excited state DHMAD is preferentially solvated by CCl4 in DMF rich region and by DMF in CCl4 rich region. (C) 2011 Elsevier B.V. All rights reserved

    ELECTRON TRANSFER REACTIONS IN 5-NITROISOQUINOLINES

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