Design and synthesis of phenolic acid analogues as inhibitors of fatty acid metabolism

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Inflammation is a normal defence mechanism protecting the host from infections by the initiation of pathogen killing and tissue repair processes. However, many common conditions and diseases occur when the inflammatory response becomes excessive, and pathological states characterised by elevated levels of inflammatory metabolites can occur. Amongst these metabolites are lipid mediators of inflammation that are derived from fatty acids. Fatty acid metabolism influences inflammation through a variety of mechanisms. Elucidating the mode of action by which compounds inhibit enzymes that metabolize fatty acids is a promising strategy to understand these mechanisms. Phenolic acids, which are widely distributed natural compounds, will be used as building blocks to construct specific and efficient inhibitors of these enzymes. The observed action of some phenolic acid based compounds as reported by the applicant's laboratory led him to propose the creation and optimization of molecular diversity from these simple and naturally available compounds. The proposed program involves methodology in synthesis and medicinal chemistry while including molecular modeling and collaborations with biochemists. For the next five years, 4 graduate and 10 undergraduate students will receive high quality training in the art of organic and medicinal chemistry, and other research related skills. In addition to imparting intensive HQP training, this program will expand the number of approaches available for the synthesis of biologically relevant analogues of phenolic acids where molecular diversity is in great demand. The medicinal chemistry community working on the development of phenolic acid based compounds and the population will benefit from the outcome of this aspect of the proposed research.