Abstract:
Rats (Rattus spp.) are among the world's most invasive pest animals, causing global economic, environmental and epidemiological damage. Most current rodenticides exhibit distinct disadvantages, including a lack of species selectivity, risks of environmental contamination, accumulation of residues in the food chain and a general lack of humaneness. Within this study, a dual approach was implemented towards the development of two independent classes of rodenticide: (1) organic carbon monoxide releasing molecules (CORMs); and (2) the rat-selective toxicant, norbormide (NRB). Carbon monoxide (CO) is a potent gaseous poison which induces its toxic effects through binding to the central metal component of biologically important metalloproteins. To exploit the toxicity of CO, a series of 11 novel organic CORMs built on a putative intramolecular base-induced CO-release mechanism were synthesised. In vitro analysis successfully demonstrated CORM-induced carboxyhaemoglobin formation in rat blood, albeit at levels insufficient to be a viable rodenticide. For the second approach, the influence of the stereochemistry of norbormide (NRB) on its palatability and efficacy in rats was investigated. Previously, the individual isomers of NRB have only been isolated in low (<0.01%) yields. Similarly, the stereoselective synthesis of NRB has not been reported. Within this study, it has been demonstrated that the stereochemistry of the key 2-fulvenylmethanol intermediate can be subtly tailored through the use of chiral ligand-Lewis acid complexes during its synthesis. Moreover, the stereochemical outcome of the Diels-Alder cyclisation of the 2-fulvenylmethanol product and maleimide was found to be highly sensitive to both reaction medium and Lewis acid. In the presence of InCl3, the highest levels of stereoselectivity were observed, affording exclusively endo-erythro products; however, the individual isomers were not attainable via this method. Instead, each of the isomers were successfully isolated (>50% recovery) using a novel N-dicarboximide derivatisation approach built on literature protecting group chemistry. In vivo evaluation of the NRB isomers did not reveal any clear trends with respect to isomer-specific palatability. However, a final investigation into the physical properties (namely particle size and shape) of various NRB batches suggested that a pharmaceutic phenomenon (i.e. the rate of dissolution and toxicant bioavailability) may be significantly impacting NRB palatability and efficacy.