Screening and pharmacodynamic evaluation of the antirespiratory syncytial virus activity of steroidal pyridine compounds in vitro and in vivo

Abstract

Respiratory syncytial virus (RSV) causes serious lower respiratory tract infections and there are currently no safer or more effective drugs available. It is important to find novel medications for RSV infection. A series of steroidal pyridines were synthesized for screening and evaluation of their antiviral activity and investigation of their antiviral mechanism of action. Compound 3l had the highest antiviral activity, with a half‐maximal effective concentration (EC50) of 3.13 μM. Compound 3l was explored for its effects in vitro on RSV 2 h before infection (pretreatment), at the time of infection (competition), and 2 h after infection (postinfection). Toll‐like receptor (TLR)‐3, retinoic acid‐inducible gene (RIG)‐I, interleukin (IL)‐6, and interferon (IFN)‐β were suppressed at the cellular level. Mouse lung tissue was subjected to hematoxylin and eosin (HE) staining and immunohistochemistry, which showed that RSV antigen and M gene expression could be reduced by compound 3l. Decreased expression of TLR‐3, RIG‐I, IL‐6, IFN‐β, and IL‐10 was also found in vivo. The results indicated that compound 3l exerted its antiviral effects mainly through inhibition of viral replication and downregulation of inflammatory factors.

Recent Progress toward the Discovery of Small Molecules as Novel Anti-Respiratory Syncytial Virus Agents

“…149 In 2020, Wang et al reported on a series of 17-pregnenolone cyanopyridine derivatives as anti-RSV agents. 152 The best compound 62 (Figure 19) exhibited an EC 50 of 3.13 μM by CPE on HEp-2 cells infected with RSV Long strain (VR-26) coupled with a CC 50 of 538.65 μM. Investigations of the MoA highlighted that 62 had antiviral activity at a postentry stage and downregulated TLR-3, IL-6, and RIG-I expression, which was confirmed in vivo.…”

“…In 2020, Wang et al reported on a series of 17-pregnenolone cyanopyridine derivatives as anti-RSV agents . The best compound 62 (Figure ) exhibited an EC 50 of 3.13 μM by CPE on HEp-2 cells infected with RSV Long strain (VR-26) coupled with a CC 50 of 538.65 μM.…”

“…After 6 days, lung tissue damage and viral replication were reduced compared to the control group. 152 In 2020, Hou et al reported that ephedrannin B (63, Figure 19), a proanthocyanidine isolated from the roots of Ephedra sinica Stapf and known for its anti-inflammatory properties, 153 reduced RSV A2 replication in BEAS-2B cells at 5 and 10 μM by PRA without showing cytotoxicity (toxicity was observed at ≥20 μM). 154 63 also reduced mRNA expression levels of IL-6, IL-8, IL-1β, and TNF-α, as well as protein levels of MAPK signalingrelated molecules.…”

Synthesis, biological activities, and future perspectives of steroidal monocyclic pyridines

“…Wang et al 76 reported the synthesis of 17-pregnenolone cyanopyridines 113a–l through a simple procedure in moderate-to-good yields. First, pregnenolone reacted with acetic anhydride under catalyzed conditions to give the acetylated product 112 .…”

“…Wang et al 76 reported the evaluation of pyridinyl steroids 113a-l (Fig. 4) as antiviral agents against respiratory syncytial virus (RSV).…”