Title:Design and Synthesis of Amino Acid Tethered Thiazolones to Screen for Hepatitis C NS5B Polymerase Inhibitors
VOLUME: 14 ISSUE: 12
Author(s):Yili Ding*, Kenneth L. Smith and Chamakura V.N.S. Varaprasad
Affiliation:Life Science Department, Foshan University, Guangdong, Foshan, Valeant Pharmaceuticals International, Drug Discovery, 3300 Hyland Avenue Costa Mesa, CA 92626, Das Pharma, Turangi P.O., Kakinada, Andhra Pradesh 533016
Keywords:Amino acid, tethered thiazolone, library, hepatitis C, NS5B polymerase inhibitors, liver failure.
Abstract:Background: Hepatitis C Virus (HCV) infection is one of the causes for liver cirrhosis
and hepatocellular carcinoma leading to liver failure. An estimated 2-3% of the world population is
chronically infected with HCV. HCV is a positive single stranded RNA virus encoding for a single
polypeptide, which cleaves into structural and non-structural proteins. The non-structural (NS) proteins
play critical roles in viral replication and have become the targets for HCV chemotherapy. The
current treatment involves pegylated interferon-α/ribavirin-based treatment and a combination of
direct-acting antivirals. NS5B is a critical enzyme for the replication of HCV RNA and is an interesting
target for the screening and design of small molecule inhibitors to interfere in the HCV viral
replication.
Methods: Screening of a library of compounds in a replicon assay, a thiazolone derivative was
identified as a NS5B enzyme inhibitor (IC50: 11 µM). Based on the structure of this lead compound,
few libraries of compounds were designed and synthesized following a fragment based approach.
Structural features of both peptide-based and non-peptide-based protease inhibitors such as lopinavir
and tipranavir were considered while designing novel compounds.
Results: Several novel protease inhibitors were designed and synthesized based on the structural
fragments of lopinavir and tipranavir. This resulted in identification of compounds with thiazolone
scaffold as having good anti-HCV NS5B enzyme activity.
However, to improve their cellular activity, the thiazolone scaffold was then tethered with several
amino acids and then screened for their anti-HCV activity which led to finding a tethered thiazolone
as novel hepatitis C NS5B polymerase inhibitor with good cellular potency (EC50 = 1.2 µM).
Conclusion: Systematic modification of lead compound (EC50 = 35 µM) from an enzyme assay and
by tethering with a suitable amino acid improved the cellular potency of the lead compound. This
resulted in a compound 18c with nearly 30 fold (EC50 = 1.2 µM) potent compound in cellular assay
than the original lead compound. It's believed that this improvement was possible because of better
transport of the active compound into the cell due to its amino acid tether.
