Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases

The multifactorial nature of Alzheimer’s disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2–12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity

Morphine metabolism, transport and brain disposition

The chemical structures of morphine and its metabolites are closely related to the clinical effects of drugs (analgesia and side-effects) and to their capability to cross the Blood Brain Barrier (BBB). Morphine-6-glucuronide (M6G) and Morphine-3-glucuronide (M3G) are both highly hydrophilic, but only M6G can penetrate the BBB; accordingly, M6G is considered a more attractive analgesic than the parent drug and the M3G. Several hypotheses have been made to explain these differences. In this review we will discuss recent advances in the field, considering brain disposition of M6G, UDP-glucoronosyltransferases (UGT) involved in morphine metabolism, UGT interindividual variability and transport proteins

Development of a capillary electrophoresis method to monitor protein oxidation and antioxidant protection.

The development of a new capillary zone electrophoresis (CZE) method for the determination of protein oxidation by free radicals is described. The effects of various experimental conditions such as type of capillary. pH, buffer concentration, capillary dimensions, temperature. applied voltage, and addition of some organic solvents, were investigated. The sample injection procedure was also optimized. Target proteins investigated here (lysozyme, human serum albumin, and beta-lactoglobulin A) were effectively damaged by free radicals generated in the aqueous phase from 2,2'-azobis[2-amidinopropane] (AAPH). The new method allowed global protein fragmentation to be quantified as a function of time by monitoring the decrease in peak height of the native protein. Furthermore. the protective efficacy of antioxidants was assessed by concentration-inhibition curves against protein fragmentation. The method is thus suitable to screen compounds able to protect proteins against oxidative damag

NMR of terminal oxygen. 17. Ab initio IGLO Study of the high shielding of O (and C, N) in linear heteronuclear pi.-systems.

Linear heteronuclear pi-systems of sp character, when compared with corresponding sp(2) systems, show increased shift to higher field for all atoms concerned (O, C, N); acetylene compared with ethylene is a model case. In O-17 NMR, the molecules NO+, PhCO(+), RC=NO, N=C=O-, RN=C=O and NO,+ were examined (in addition to known CO, CO2, COS and N2O). For these molecules, C-13 and N-15 shieldings were also analysed. As had been shown before for C-13 and N-15, the increase in shielding of O-17 in linear molecules is mainly attributable to the vanishing of the deshielding component along the linear axis of the molecule (manifest also in the increase in the anisotropy of shielding Delta sigma). Ab initio IGLO calculations were executed to evaluate Delta sigma (=sigma(parallel to)-sigma(perpendicular to)). For each of the atoms concerned, the resulting calculated average values agreed well with the experimental values of isotropic shielding, sigma(iso). As in the case of C and N, the values of sigma(parallel to) Of O-17 in linear compounds are close to that of the diamagnetic shielding of the isolated O atom, sigma(d) (atom). The particular case of organic isocyanates, RNCO, which, although not completely linear, show related behaviour, is discusse

Facilitated Ion Transfer Reactions across Oil/Water Interfaces. Part I: Algebraic Development and Calculation of Cyclic Voltammetry Experiments for Successive Complex Formation.

A computational methodology to model cyclic voltammetry experiments is presented here for assisted ion transfer reactions at the interface between two immiscible electrolyte solutions. General analytical equations are given for any complexation reaction of 1:m ion-to-ligand stoichiometry, and the efficiency of the computation is demonstrated by various examples of calculated voltammograms obtained for the successive complex formation of 1:1 to 1:4 stoichiometry at the water\1,2-dichloroethane interface. The results show that the complexation reactions depend strongly on the different association constants in both phases, on the partition coefficient of the ionophore and on the initial concentrations of both the ionophore and the free metal ion. The results obtained for the formation of a unique complex are in good agreement with those performed previously by numerical simulations [Homolka et al., Electroanal. Chem., 138 (1982) 29-36 and Kakiuchi and Senda, J. Electroanal. Chem., 300 (1991) 431-445], which validates the present algebraic calculation. The methodology followed here comprises an analytical resolution of the mass balance equations at the interface. This offers the great advantage of avoiding any assumption on the phase in which the reactants are preliminarily dissolved or on the phase in which the complexation reaction occurs. Thus, the present computational method allows the analysis of any kind of assisted ion transfer reactions at an ITIES, and enables the elucidation of the mechanistic interpretation of the current waves recorded on the voltammograms. (C) 1998 Elsevier Science S.A. All rights reserve