4,5-dihydropyrazoles

: novel chemistry and biological activity

Abstract

Toxoplasma gondii is an important water- or food-borne pathogen that is capable of causing severe disease in immunocompromised patients. This project aims to use synthetic chemistry to help increase our understanding of the process of host cell invasion by Toxoplasma gondii and to provide a platform that enables the identification of more potent and selective analogues. A primary high-throughput screen of 12,160 structurally diverse small molecules identified 24 noncytotoxic inhibitors invasion of Toxoplasma. For one of these inhibitors a synthetic procedure compatible with automated synthesis equipment has been developed and optimised. This procedure was then applied to the synthesis of a 96 member library. The biological data obtained (using a cell-based assay) led to the identification of compounds with increased activity.

To improve the light stability of this class of inhibitors, modification of the molecule was carried out leading to the synthesis of a 14 member dihydropyrazole library using an high-throughput compatible microwave assisted procedure. The dihydropyrazole were more light stable than the first library and in most cases the biological activity was maintained.

In addition to their relevance to the study of this biological system, we also viewed this collection of 14 analogues as a useful starting point for a study on a novel extension of Ghosez’s Diels-Alder methodology. The imino Diels-Alder reaction combined with an elimination/oxidation protocol provides rapid access to pentasubstituted pyridines. In this thesis we report our results towards this goal including a study of the dependence of this reaction on the azadiene substituents. In addition, we report the structural characterisation of the two additional products isolated in this reaction. These compounds are formed by a novel Diels-Alder/1,3-dipolar cycloaddition reaction sequence in which 7 new stereocenters are set in one pot with high diastereoselectivity.

Date of Award	30 Nov 2007
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Nicholas James Westwood (Supervisor)