Synthesis of Trifluoromethyl-alpha,beta-unsaturated Lactones and Pyrazolinones and Discovery of Influenza Virus Polymerase Inhibitors

To explore the potential biological activities of trifluoromethyl heterocycles, we recently developed a synthetic approach to access a series of alpha-trifluoromethyl-alpha,beta-unsaturated lactones and trifluoromethyl pyrazolinones. The compounds were tested for their antimicrobial activity, and we found that some compounds had anti-influenza viral activity. The beta-aryl-alpha-trifluoromethyl alpha,beta-unsaturated lactone derivatives 5 g (5-(4-chlorophenyl)-5-methyl-4-phenyl-3-(trifluoromethyl)furan-2-one), 7 b (4-(4-methoxyphenyl)-3-(trifluoromethyl)spiro[furan-5,1 '-indane]-2-one), and the trifluoromethyl pyrazolinone 12 c (1-(6-methoxy-2-naphthyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-3-one) were found to possess promising inhibitory activity against influenza virus type A, strain A/WSN/33 (H1N1). These three hit compounds were successfully optimized, and we identified that the most potent compound 5 h (5-(4-chlorophenyl)-4-(6-methoxy-2-naphthyl)-5-methyl-3-(trifluoromethyl)furan-2-one) showed inhibitory activity against various types of influenza A and B viruses in the low-micromolar range without showing cytotoxicity. Moreover, 5 h was more effective against the clinical isolate A/California/7/2009 (H1N1pdm) strain than the influenza viral polymerase inhibitor, favipiravir (T-705). We also delineated the structure-activity relationship and obtained mechanistic insight into inhibition of the viral polymerase.