Discovery of novel favipiravir derivatives with improved pharmacokinetic properties as anti-SFTSV agents

Favipiravir is a nucleobase analogue that exhibits antiviral activities against a variety of RNA viruses. Due to the lack of antivirals to combat SFTS, an emerging tickborne epidemic caused by a RNA virus belonging to the Phenuividae family within Bunyavirales, Favipiravir has been put brand new attention as optimal SFTS clinical candidate. We here disclose chemical synthesis of novel derivatives of Favipiravir. All derivatives showed favorable inhibitory effect on SFTSV replication in vitro . The 50 % effective concentration (EC 50 ) of the most active compound H3 was 12.06 μM, better than that of Favipiravir (15.51 μM). Most importantly, compared with the clinical candidate Favipiravir, pharmacokinetic studies conducted on rats demonstrated enhanced pharmacokinetic properties for H2 and H3 including parameters of T 1/2 , C max and AUC. These combined attributes identified novel promising drug candidates for the treatment of SFTSV infection. • First time report medicinal chemistry based on SFTS clinical candidate. • Novel Favipiravir derivatives were designed and synthesized. • Compound H2 and H3 showed higher anti-SFTSV activity than Favipiravir. • H2 's dose normalized i.v. AUC last 97 % higher than that of Favipiravir in SD rats.