SAG br Transparency declaration br Acknowledgements

Transparency declaration
Acknowledgements
Hepatitis C Virus (HCV) infection represents a disease of significant global impact that afflicts around 170 million people worldwide., A small proportion of infected people clear the virus naturally, whilst the majority develop chronic hepatitis C (CHC) which can lead to a spectrum of liver diseases from mild SAG to extensive liver fibrosis and cirrhosis, conferring significant morbidity and mortality to affected individuals. The world health organization (WHO) estimates that globally around 200 million people are chronically infected with HCV, with 3–4 million new infections occurring every year. The standard therapy for HCV infection has been based for more than a decade on the use of pegylated interferon alpha (PEG-IFNα) and the antiviral nucleoside analogue ribavirin (RBV). Since 2011, a number of directly acting antivirals (DAAs), such as the protease inhibitors (PIs) telaprevir, boceprevir and simeprevir, and the viral RNA-dependent RNA polymerase inhibitor sofosbuvir,, have been licensed for use as part of combination therapies for HCV and CHC infections. These innovative treatment regimens have revolutionized the field of HCV medicine and provided optimism to find a cure in HCV patients. However, the fight against HCV infections is not fully over yet, because of the high costs associated with the therapies as well as the emergence of mutant strains resistant to DAA drugs., , We recently reported the design and discovery of new amidinourea HCV inhibitors with structure (), as analogues of the antiviral drug moroxydine. As a continuation of this work, the synthesis and biological evaluation of a new series of amidinourea derivatives with general structure was planned. Since the natural polyamines spermine, spermidine and putrescine were recently reported to possess inhibitory activity against HCV, we became intrigued by the possibility to merge both the amidinourea and the polyamine moieties into a hybrid structure. This resulted in the design of a series of amidinourea-polyamine hybrids with general structure (). In connective tissue work, the synthesis, biological evaluation and mode of action studies of new polyamine amidinourea as inhibitors of HCV is described. The synthesis of a set of amidinourea compounds derived from the diamines putrescine and 1,8-diaminooctane was first planned. The diamines – were reacted with ′-di-Boc-S-methylisothiourea in DCM at room temperature affording the Boc-guanidines –. The latters were reacted with an appropriate amine (allylamine, benzylamine and -Cl-aniline) and then treated with HCl/AcOEt solution to afford the corresponding amindinoureas –. . Putrescine was also converted into the monoguanidine derivative which in turn led the amidinoureas and through reaction with allylamine, benzoyl chloride and Boc deprotection as shown in . The choice of an allyl substituent on the amidinourea moiety arose from preliminary data and previous work on similar amidinourea derivatives endowed with antimicrobial activity., Amidinoureas – bearing a spermine and spermidine backbone respectively were synthesised in a similar way as reported in . The guanylated intermediates –, obtained via guanylation of the appropriate polyamine, were reacted with allyamine in refluxing THF affording, after Boc deprotection, the derivatives –. The secondary amine groups in were also converted into tertiary amines via reductive amination reaction leading to , in order to explore the importance of an NH moiety for the antiviral activity. The reaction of with allyl amine and Boc-deprotection led to amidinourea . Finally, a set of guanidine derivatives – and – were synthesised as described in with the aim to evaluate a correlation between the presence of an amidinourea moiety on a polyamine backbone with the antiviral activity. The alkylated S-methylisothiourea derivatives – were synthesised via Mitsunobu reaction according to previously reported procedures. Reaction of – with 1,8-diaminooctane and the triamine , followed by Boc cleavage with HCl/AcOEt led to guanidine derivatives – and –.