Design and Synthesis of Enzyme Inhibitors Against Infectious Diseases Targeting Hepatitis C Virus NS3 Protease and Mycobacterium tuberculosis Ribonucleotide Reductase

Detta är en avhandling från Uppsala : Acta Universitatis Upsaliensis

Sammanfattning: Infectious diseases, including hepatitis C and tuberculosis, claim the lives of over 15 million people each year. Hepatitis C is caused by the hepatitis C virus (HCV) which infects the liver and can ultimately result in liver transplantation. HCV is very adaptive as a result of its high mutation rate. Thus, there is a potential high risk for the development of drug resistance and also a possible cross-resistance due to a structural similarity between many of the HCV NS3 protease inhibitors currently in clinical trial and on the market, that all are based on a P2-proline or a proline mimic. Thus, part of the research behind this thesis was to explore a new structural P3-P2 unit for the NS3 protease inhibitors, a 2(1H)-pyrazinone moiety. A microwave-assisted protocol was developed, and the 2(1H)-pyrazinone core was synthesized in only 2 × 10 min. A series of optimization steps resulted in several submicromolar 2(1H)-pyrazinone-containing NS3 protease inhibitors that performed well against drug-resistant NS3 protease variants. The key modifications were: exchanging the unstable carbamate P3 capping group for a stable urea functionality, transferring the P2 group from the amino acid residue to the pyrazinone ring and elongating the substituent, and using an aromatic acyl sulfonamide in the P1-P1' position.The causative agent of tuberculosis is Mycobacterium tuberculosis (Mtb), which currently infects one third of the world's population. No new TB drugs have been approved in nearly 50 years and drug resistance has been observed for all of the current first-line drugs. Because of the importance of identifying novel drug targets, the ribonucleotide reductase (RNR) enzyme was investigated. The RNR enzyme consists of two R1 and two R2 subunits and is essential for Mtb replication. Starting from hits identified in a virtual screening program, a small library of low molecular weight inhibitors of the association between the R1 and R2 subunits was designed and synthesized. The compounds with the strongest affinity for the R1 subunit of RNR were further evaluated in an orthogonal activity assay. Two RNR inhibitors with promising antimycobacterial effects were identified, which can serve as leads in the further optimization of this class of compounds.