Identification of novel non-nucleoside vinyl-stilbene analogs as potent norovirus replication inhibitors with a potential host-targeting mechanism

• Published in: European journal of medicinal chemistry Vol. 184; p. 111733
• Main Authors: Harmalkar, Dipesh S., Lee, Sung-Jin, Lu, Qili, Kim, Mi Il, Park, Jaehyung, Lee, Hwayoung, Park, Minkyung, Lee, Ahrim, Lee, Choongho, Lee, Kyeong
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.12.2019; Elsevier
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; HSF-1; Humans; Inhibitors; Life Sciences & Biomedicine; Mice; Microbial Sensitivity Tests; Microsomes - drug effects; Microsomes - microbiology; Molecular Structure; Non-nucleoside; Norovirus; Norovirus - drug effects; Pharmacology & Pharmacy; RAW 264.7 Cells; RNA, Viral - drug effects; RNA, Viral - genetics; Science & Technology; Stilbenes - chemistry; Stilbenes - pharmacology; Structure-Activity Relationship; Vinyl Compounds - chemistry; Vinyl Compounds - pharmacology; Vinyl-stilbenes; Virus Replication - drug effects; Virus Replication - genetics; Non-nucleoside; HSF-1; Norovirus; Inhibitors; Vinyl-stilbenes; DIARRHEA; GASTROENTERITIS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111733

Norovirus (NV), is the most common cause of acute gastroenteritis worldwide. To date, there is no specific anti-NV drug or vaccine to treat NV infections. In this study, we evaluated the inhibitory effect of different stilbene-based analogs on RNA genome replication of human NV (HNV) using a virus replicon-bearing cell line (HG23). Initial screening of our in-house chemical library against NV led to the identification of a hit containing stilbene scaffold 5 which on initial optimization gave us a vinyl stilbene compound 16c (EC50 = 4.4 μM). Herein we report our structure-activity relationship study of the novel series of vinyl stilbene analogs that inhibits viral RNA genome replication in a human NV-specific manner. Among these newly synthesized compounds, several amide derivatives of vinyl stilbenes exhibited potent anti-NV activity with EC50 values ranging from 1 to 2 μM. A trans-vinyl stilbenoid with an appended substituted piperazine amide (18k), exhibited potent anti-NV activity and also displayed favorable metabolic stability. Compound 18k demonstrated an excellent safety profile, the highest suppressive effect, and was selective for HNV replication via a viral RNA polymerase-independent manner. Its potential host-targeting antiviral mechanism was further supported by specific activation of heat shock factor 1-dependent stress-inducible pathway by 18k. These results suggest that 18k might be a promising lead compound for developing novel NV inhibitors with the novel antiviral mechanism. [Display omitted] •A series of novel vinyl-stilbenes derivatives were designed and synthesized.•Following a structure-activity relationship study, compound 18k demonstrated an excellent therapeutic index.•Compound 18k inhibited the viral RNA genome replication in a human NV-specific manner with EC50 of 2.43 μM.•The induction of HSF-1 protein by 18k suggests involvement of HSF-1-dependent stress-inducible pathway.