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A new protocol is developed for the synthesis of N-substituted thioamides, employing arenes and isothiocyanates in 1-butyl-3-methylimidazolium chloroaluminate ionic liquid, [bmim]Cl*2Al[Cl.sup.3], as a homogenous Lewis acid catalyst and solvent. The effect of Lewis acidity and the stoichiometry of the ionic liquid on the extent of product formation is studied. Studies reveal that a progressive increase in yields was observed with increasing Lewis acidity, and two equivalents of [bmim]Cl*2Al[Cl.sup.3] was the optimal amount for the reaction. A distinct para selectivity for the incoming thioamido group on activated arenes was observed under ambient conditions. Key words: arenes, isothiocyanates, Friedel-Crafts, ionic liquids, thioamides.

Research has been conducted on the Friedel-Crafts sulfonylation reaction of benzene and substituted benzenes with the 4-methyl benzenesulfonyl chloride. The use of the 1-butyl-3-methylimidazolium chloroaluminate ionic liquids as a reaction media and as Lewis acid catalyst for the Friedel-Crafts sulfonylation reaction is described and the details are reported.

A convenient approach is described for 3-pyridinols and 5-pyrimidinols via a two-step Cu-catalyzed benzyloxylation/catalytic hydrogenation sequence. The radical-scavenging ability has revealed that the increased acidities of the pyridinols and pyrimidinols have rendered them susceptible to more significant kinetic solvent effects when compared to phenols.

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans., (Copyright © 2016 The Author(s).)