The mechanism and pharmacodynamics of 2-((1H-indol-3-yl)thio/sulfinyl)-N-pheny acetamide derivative as a novel inhibitor against human respiratory syncytial virus.

Human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection worldwide. Until now, there are no licenced vaccines or effective antiviral drugs against RSV infections. In our previous work, we found 2-((1H-indol-3-yl)thio/sulfinyl)-N-pheny acetamide derivatives (4-49 C and 1-HB-63) being a novel inhibitor against RSV in vitro. Here, we explored the underlying mechanism of 2-((1H-indol-3-yl)thio/sulfinyl)-N-pheny acetamide derivatives to inhibit RSV replication in vitro and disclosed that 4-49 C worked as the inhibitor of membrane fusion and 1-HB-63 functioned at the stage of RSV genome replication/transcription. Yet, both of them could not inhibit RSV infection of BALB/c mice by using RSV-Luc, in vivo imaging and RT-qPCR analyses, for which it may be due to the fast metabolism in vivo. Our work suggests that further structural modification and optimisation of 2-((1H-indol-3-yl) thio/sulfinyl)-N-pheny acetamide derivative are needed to obtain drug candidates with effective anti-RSV activities in vivo.

Design and synthesis of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides as novel dual inhibitors of respiratory syncytial virus and influenza virus A.

Respiratory syncytial virus (RSV) and influenza A virus (IAV) are two of the most common viruses that cause substantial morbidity and mortality in infants, young children, elderly persons, and immunocompromised individuals worldwide. Currently, there are no licensed vaccines or selective antiviral drugs against RSV infections and most IAV strains become resistant to clinical anti-influenza drug. Here, we described the discovery of a series of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamide as novel and potent RSV and IAV dual inhibitors. Thirty-five derivatives were designed, prepared, and evaluated for their anti-RSV and anti-IAV activities. Among the tested compounds, 14'c, 14'e, 14'f, 14'h, and 14'i exhibited excellent activity against both RSV and IAV, which showed low micromolar to sub-micromolar EC50 values. Further, compounds 14'c and 14'e were identified as the most promising dual inhibitors with lesser cytotoxicity than the clinical drug, ribavirin. These findings may contribute to the development of a lead compound for the treatment of RSV and/or IAV infections.

High-throughput screening of active compounds against human respiratory syncytial virus.

Human respiratory syncytial virus (RSV) is one of the predominant pathogens causing lower respiratory tract infection in infants and young children worldwide, whereas there is so far no vaccine or drug against RSV infection for clinical use. In this work, we developed and validated a fluorescence-based high-throughput screening (HTS) assay to identify compounds active against RSV, using RSV-mGFP, a recombinant RSV encoding enhanced green fluorescent protein (EGFP). Thereafter, among 54,800 compounds used for our screen, we obtained 62 compounds active against RSV. Among these hits, azathioprine (AZA) and 6-mercaptopurine (6-MP) were identified as RSV inhibitors with half maximal inhibitory concentration (IC50) values of 6.69 ±â€¯1.41 and 3.13 ±â€¯0.98 µM, respectively. Further experiments revealed that they functioned by targeting virus transcription or/and genome replication. In conclusion, the established HTS assay is suitable to screen anti-RSV compounds, and the screened two hits of AZA and 6-MP, as potential anti-RSV agents targeting RSV genome replication/transcription, are worthy of further investigation on their anti-RSV activity in vivo.