Hepatitis C virus (HCV) infection is a major health problem worldwide. Approximately, 170-200 million individuals are chronically infected worldwide and a quarter of these patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma and even liver failure. A complete eradication of the virus is one of the most important treatment goals for antiviral research. In 2011, the first-generation protease inhibitors boceprevir (BOC) telaprevir (TVR) were approved by FDA as the direct-acting antiviral agents. A number of promising new direct-acting antiviral agents (DAAs) have been developed in the past few years. Due to their increased efficacy, safety, and tolerability, interferon-free oral therapies with DAAs are in use for patients with chronic HCV and cirrhosis patients. In this review, we will discuss the results of clinical trials of several DAAs and the approved combinations, including NS3/4A protease inhibitors, NS5A inhibitors, and NS5B inhibitors. A number of drugs, including Sovaldi®, Harvoni® Viekira Pak®, Epclusa®, Zepatier® have been approved by FDA in the past two-three years. The latest advancement of DAA therapy and related side effects due to the therapy are also discussed.
Background:
The era of drug discovery suggested the designing of “hybrid drugs,” which acquired the
recognition in the field of medicinal chemistry due to it’s influential role in preserving different health challenges.
Objective:
A new series of chalcone derivatives 4a-4i, bearing isoxazole moieties, were designed and synthesized with
microwave irradiation, which were biologically evaluated for their activity on NCI-60 cell-lines to check efficacy in anticytotoxic effect.
Methods:
The required diverse acetophenone molecule was prepared by chloro-amine coupling using lansoprazole (lanso
chloro) drug intermediate, i.e., 4-(2,2,2-trifluoroethoxy)-2-(chloromethyl)-3-methylpyridine engaged in the reaction with
various aryl aldehydes (2a-2i) in the primary media gave fluoro contained chalcone (3a-3i). The desired isoxazoles (4a-4i)
were synthesized by MW (microwave irradiation) based reaction using hydroxylamine for cyclization purposes.
Results:
The espoused scheme resulted in good yields of a new set of isoxazole-chalcone conjugates with potent cytotoxic
activity were found in compounds 4h and 4i against Leukemia RPMI-8226 (With GI50 Values ≈ -10 µg/ml) cancer cell line
and Non-Small Cell Lung Cancer HOP-92 (With GI50 Values ≈ -25 µg/ml) cancer cell line.
Conclusion:
The optimization of the reaction indicated that the MW based reaction progress was an efficient and timesaving process for the course of isoxazole synthesis. An anticancer study shows that compounds 4h demonstrated significant
anti-cancer activity.
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