Prodrugs of N-dicarboximide derivatives of the rat selective toxicant norbormide

Norbormide [5-(alpha-hydroxy-alpha-2-pyridylbenzyl)-7-(alpha-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either its unpleasant 'taste' or rapid onset of effects. A series of NRB-derived prodrugs were prepared in an effort to 'mask' this acute response. Their synthesis and biological evaluation (in vitro vasoconstrictory activity, in vitro hydrolytic and enzymatic stability and lethality/palatability in vivo) is described. Prodrug 2 displayed the most promising profile with respect to a delay in the onset of symptoms and was subsequently demonstrated to be significantly more palatable to rats. Moreover, prodrug 25 was found to be largely accepted by rats in a choice trial, resulting in high mortality. (C) 2013 Elsevier Ltd. All rights reserved

A new precursor for conducting polymer-based brush interfaces with electroactivity in aqueous solution

We present the synthesis of a novel conducting polymer (CP) incorporating both pyrrole and thiophene units in its monomer, which is also substituted with an initiator for grafting of sidechains by atom-transfer radical polymerisation (ATRP). The precursor monomer for the CP macroinitiator, 2-(2,5-di(pyrrol-2-yl)thiophen-3-yl)ethyl 2-bromopropanoate) (PyThon) is very readily electropolymerised at low monomer concentrations and low applied potentials. Density functional theory (DFT) predictions of ionisation potentials and spin-charge distribution for PyThon are in good agreement with these experimental results. We present also the grafting of sidechains from electropolymerised PolyPyThon (PPyThon) to yield surface-confined polymer brushes. Functionalisation with polystyrene (PS), poly(2,3,4,5,6-pentafluorostyrene) (PFS) and poly(ethylene glycol) methyl ether acrylate (PEGMEA) is demonstrated and confirmed by FT-IR and water contact angle measurements. These PPyThon-based molecular brushes are electroactive in both water and acetonitrile, and show evidence of changes in surface conformation related to the redox state of the CP. The growth of human fibroblasts on PPyThon films is also demonstrated, indicating good biocompatibility of the polymer. We conceive PPyThon-based molecular brushes as a substrate for electrical stimuli-responsive surfaces with application particularly in the biomedical field

Fatty Acid-Derived Pro-Toxicants of the Rat Selective Toxicant Norbormide

Norbormide [5-(\u3b1-hydroxy-\u3b1-2-pyridylbenzyl)-7-(\u3b1-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, as an acute vasoactive, NRB has a rapid onset of action which makes it relatively unpalatable to rats, often leading to sublethal uptake and accompanying bait shyness. A series of NRB-derived pro-toxicants (3a \u2013 i, 4a \u2013 i, and 5a \u2013 i) were prepared in an effort to \u2018mask\u2019 this acute response and improve both palatability and efficacy. Their synthesis, in vitro biological evaluation (vasocontractile response in rat vasculature, stability in selected rat media) and palatability/efficacy in Sprague\u2013Dawley, wild Norway, and wild ship rats is described. Most notably, pro-toxicant 3d was revealed to be free of all pre-cleavage vasoconstrictory activity in rat caudal artery and was subsequently demonstrated to release NRB in the presence of rat blood, liver, and pancreatic enzymes. Moreover, it consistently displayed a high level of acceptance by rats in a two-choice bait-palatability and efficacy trial, with accompanying high mortality. On this evidence, fatty acid ester prodrugs would appear to offer a promising platform for the further development of NRB-derived toxicants with enhanced palatability and efficacy profiles

Grafting from Poly(3,4-ethylenedioxythiophene): A Simple Route to Versatile Electrically Addressable Surfaces

We demonstrate a simple route to versatile electrically addressable conductive polymer graft copolymer systems. The monomer of poly­(3,4-ethylenedioxythiophene), one of the commercially most important conductive polymers, was modified by the addition of an ATRP-initiating site to grow brushes from. The modified monomer is easily accessible by a one-step synthesis from the commercially available 2,3-dihydrothieno­[3,4-<i>b</i>]­[1,4]­dioxin-2-yl)­methanol. The modified monomer is subsequently electropolymerized onto large area gold-coated electrodes and utilized as a backbone for grafting pH-responsive poly­(acrylic acid) brushes from