Intramolecular F‚‚‚H hydrogen bonding in 2-fluorophenol, 2,6-difluorophenol, and 2,3,5,6-tetrafluorohydroquinone has been studied by ab initio molecular orbital calculations. Geometry optimizations at the MP2/6-31G** level resulted in two planar local minima on the potential energy surface, characterized by different orientations of the hydroxy hydrogen. In the conformers where the hydroxy hydrogen points toward a fluorine, the computations suggest weak intramolecular F‚‚‚H hydrogen bonding interactions. Characteristic changes in the geometrical parameters upon hydrogen bonding are manifested in the lengthening of the C-F bond involved in the interaction by 0.01 Å, in the lengthening of the O-H bond by 0.003 Å, in the decrease of the C-O-H bond angle by 1°, and in a tilt of the C-F and C-O bonds toward each other, as compared with the geometries of the parent molecules. The hydrogen bonds shorten in the order 2-fluorophenol > 2,6-difluorophenol > 2,3,5,6-tetrafluorohydroquinone (C 2h ) > 2,3,5,6-tetrafluorohydroquinone (C 2V ), implying strengthening of hydrogen bonds in the opposite direction. The strength of hydrogen bonding and its overall consequences in the rest of the molecule are less pronounced in systems where the hydrogen bond occurs in five-membered rings than when it is part of a six-membered system.

Various alkyl derivatives of 1-(trimethylsilanyl)but-3-en-2-ol acetate (1a−e) undergo regioselective palladium-catalyzed nucleophilic substitution via β-silyl-substituted (η3-allyl)palladium intermediates. With external nucleophiles, such as malonates and enolates, the nucleophilic substitution occurs with complete allylic rearrangement, providing functionalized allylsilanes as building blocks of high synthetic potential. Internal nucleophiles, such as disilanes and NaBPh4, afford bisallylic disilanes and (allylsilyl)benzene derivatives with good regioselectivity. For both types of nucleophiles, the double bond geometry of the resulting allylsilane is selectively trans. The β-silyl-substituted (η3-allyl)palladium intermediates of the reaction were also isolated. The 1H NMR studies indicate selective formation of the syn-isomer of the key (η3-allyl)palladium intermediates, which explains the high trans-selectivity of the double bond formation in the allylsilane products. According to the 13C NMR studies, the β-silyl functionality exerts deshielding effects on the nearest allylic terminal carbon (C3), which can be ascribed to hyperconjugative interactions between the silyl functionality and the allylpalladium moiety. It was concluded that, together with the steric effects of the silyl group, these electronic interactions are responsible for the high regioselectivity of the nucleophilic attack in the catalytic process.

The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure-activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.

ABSTRACT:Recently, we described a series of phenyl methyl-isoxazole derivatives as novel, potent, and selective inhibitors of the voltage-gated sodium channel type 1.7 (Bioorg Med Chem Lett 21:3871-3876, 2011). The lead compound, 2-chloro-6-fluorobenzyl [3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbamate, showed unprecedented GSH and cysteine reactivity associated with NADPH-dependent metabolism in trapping studies using human liver microsomes. Additional trapping experiments with close analogs and mass spectra and NMR analyses suggested that the conjugates were attached directly to the 5-methyl on the isoxazole moiety. We propose a mechanism of bioactivation via an initial oxidation of the 5-methyl generating a stabilized enimine intermediate and a subsequent GSH attack on the 5-methylene. Efforts to ameliorate reactive metabolite generation were undertaken to minimize the potential risk of toxicity. Formation of reactive metabolites could be significantly reduced or prevented by removing the 5-methyl, by N-methylation of the carbamate; by replacing the nitrogen with a carbon or removing the nitrogen to obtain a carboxylate; or by inserting an isomeric 5-methyl isoxazole. The effectiveness of these various chemical modifications in reducing GSH adduct formation is in line with the proposed mechanism. In conclusion, we have identified a novel mechanism of bioactivation of phenyl 5-methylisoxazol-4-yl-amines. The reactivity was attenuated by several modifications aimed to prevent the emergence of an enimine intermediate. Whether 5-methyl isoxazoles should be considered a structural alert for potential formation of reactive metabolites is dependent on their context, i.e., 4-nitrogen.