Synthesis and biological evaluation of baloxavir marboxil analogs for the treatment of influenza A (H1N1) virus

Abstract The RNA‐dependent RNA polymerase (RdRp) of influenza virus, consisting of subunits of PA, PB1, and PB2 proteins, is responsible for viral mRNA transcription and vRNA replication. Cap‐dependent endonuclease (CEN) exists in PA subunit of RdRp and mediates the critical “cap‐snatching” step of viral RNA transcription, which is considered as a promising anti‐influenza target. In this manuscript, a series of novel compounds were designed, synthesized, and biologically investigated as CEN inhibitors. The cellular activities of the target compounds against influenza A/H 1 N 1 virus were investigated and the structure–activity relationship (SAR) was summarized. The results showed that some compounds were active against influenza A/H 1 N 1 virus with IC 50 values of less than 100 μM. The microsomal metabolic stabilities were carried out in human, monkey, and rat species, and the results showed that the active ingredients of compounds 32 and 40 were stable enough to be in vivo investigated. The in vivo pharmacokinetic results showed that compound 32 had acceptable biological parameters for both ig and iv administrations. Then the in vivo toxicity study of compound 32 with the doses of 100 and 50 mg/kg BID was performed in BALB/C mice. No obvious toxicity of compound 32 was observed during the experiment. Finally, the in vivo efficacy study of compound 32 in BALB/C mice showed that it was effective in alleviating influenza symptoms and showed a significant pharmacodynamic dose dependence. These results indicated that compound 32 was a promising candidate for further development.