الفهرس 
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Abstract
HCV infection is considered as the most challenging public health problem in Egypt where the prevalence is the highest in the world. In the recent therapeutical development of new anti-HCV drugs, a variety of active protease inhibitors have been already approved for treatment of HCV in some countries (e.g. asunaprevir, paritaprevir and grazoprevir). These members of the ”previr” family display a common structure based on a tripeptide featuring a central 4-heteroarylproline unit. Method: Our PhD work involves the attempts to prepare two new series of anti-protease analogs as novel anti-HCV agents. These analogs involve isosteric replacement of pyrrolidine ring by isoxazolidine ring and introduction of either a heteroaryloxy to afford isoxazolidine-O-analogs or a heteroaryl-CH2- appendage at the C4 position to afford isoxazolidine-CH2-analogs. The oxaproline precursors have been de novo synthetized using an asymmetric 1,3-dipolar cycloaddition (1,3-DC) strategy, that involves the reaction between a vinyloxy / allyl (iso)quinoline and a carbalkoxynitrone. Results: We succeeded only to obtain the tripeptide analogs in cis form, since they resulted from a carboxylic acid precursor that was equally obtained as a cis compound after saponification whatever the stereochemistry of the starting dipeptidic ethyl ester, as established by HPLC. This cis relationship was proved using NOESY measurements. Conclusion: All the synthesized tripeptides analogs had been tested as anti-HCV agents in both biochemical and replicon assays. Although none of them showed better activity than asunaprevir, one analogue of them cisI-72b exhibits promising antiviral activity. That encourages us to keep our trials to obtain trans analogs of them.