A Drug Discovery Study: Inhibitor Design for HRV 3C Protease Based on the Scaffold of (-)-Thysanone

Abstract

This thesis is concerned with the drug development study against the common cold based on the ( )-thysanone scaffold. The common cold, majorly caused by the Human Rhinovirus, still remains one of the major causes of work-loss in industrialised countries and currently only symptomatic treatment is available to treat these viral infections. Thus, even though this illness is not life threatening, a direct anti-viral drug would be of significant benefit. ( )-Thysanone was isolated from the fungus Thysanophora penicilloides and was shown to inhibit the viral enzyme HRV 3C protease with an IC50 of 13 μg/mL (47 μM). HRV 3C protease is required for viral replication, thus inhibition of this enzyme will also inhibit the reproduction of the virus. O O O OH OH HO 7 9 (−)-thysanone This study is divided into three parts. The first part gives a brief introduction to the common cold, its major cause -the Human Rhinovirus- and attempts for drug development. The second part describes the determination of structure activity relationships (SAR) of a first generation library of inhibitors based on the ( )-thysanone scaffold and also pharmacodynamic aspects, such as the molecular mechanism of action of ( )-thysanone with HRV 3C protease, cross interactions with other important human proteases and cytotoxicity assays of our library of compounds against a human lung epithelia cell line. The third part then describes the syntheses of all analogues. Two literature known preparations of the natural product and the 7,9-dideoxy analogue were followed as well as the development of a new strategy for the synthesis of 2-carbathysanone using a Hauser-Kraus annulation as key-step and the development of a new synthetic approach for 7-deoxy analogues using an oxa-Pictet-Spengler reaction in the key step. This oxa-Pictet-Spengler approach was also used for development of a new synthetic strategy for thysanone also involving C-H activation chemistry.