Abstract EN:

Hepatitis C virus (HCV) infection is considered the most challenging public health problem in Egypt where the prevalence is the highest in the world. Recent survey known as the Egyptian Health Issues Survey (EHIS) reported a prevalence of 10% HCV infection. 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 (asunaprevir, paritaprevir, grazoprevir). These members of the "previr" family display a common structure based on a tripeptide featuring a central 4-heteroarylproline unit. Our PhD work involves the attempts to prepare two new series of anti-protease analogues as novel anti-HCV agents. These analogues involve isosteric replacement of proline ring by isoxazolidine ring and introduction of either a heteroaryloxy or a heteroaryl-CH2- appendage at the C4 position. 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 quinoline and a carbalkoxynitrone. The obtained oxaproline unit have been subjected to sequential deprotection of N- and CO2H groups, and amide couplings to afford the target tripeptide analogues. Our work includes two domains of methodologic research in organic chemistry: (i) the access of highly functional isoxazolidines by 1,3-DC with the difficulty of diastereocontrol with aldonitrones and the acid sensitivity of these compounds (ii) the synthesis and the coupling of optically active non-natural and «difficult to make» amino acid derivatives. Both biochemical and cell-based assays have been done for the formed analogues.