Trisubstituted Thieno[3,2-b]pyrrole 5-Carboxamides as Potent Inhibitors of Alphaviruses.

Abstract

Chikungunya virus (CHIKV) is a re-emerging vector-borne alphavirus and is transmitted to humans by Aedes mosquitoes. Despite the re-emergence of CHIKV as an epidemic threat, there is no approved effective antiviral treatment currently available for CHIKV. Herein, we report the synthesis and structure-activity relationship studies of a class of thieno[3,2-b]pyrroles and the discovery of a trisubstituted thieno[3,2-b]pyrrole 5-carboxamide 15c that exhibits potent inhibitory activity against in vitro CHIKV infection. Compound 15c displayed low micromolar activity (EC50 value of ca. 2 μM) and limited cytotoxic liability (CC50 > 100 μM) therefore furnishing a selectivity index of greater than 32. Notably, 15c not only controlled viral RNA production, but efficiently inhibited the expression of CHIKV nsP1, nsP3, capsid, and E2 proteins at a concentration as low as 2.5 μM. More importantly, 15c also demonstrated broad spectrum antiviral activity against other clinically important alphaviruses such as O'nyong-nyong virus and Sindbis virus.

• Authors: Kuan-Chieh Ching, Yiu-Wing Kam, Andres Merits, Lisa F P Ng, Christina L L Chai
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 23 Pg. 9196-213 (Dec 10 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26540338 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Nucleic Acid Synthesis Inhibitors
• Pyrroles
• RNA, Viral
• Viral Proteins
• thienopyrrole

Topics

• Antiviral Agents (chemistry, pharmacology)
• Chikungunya Fever (drug therapy, virology)
• Chikungunya virus (drug effects, genetics)
• HEK293 Cells
• Humans
• Nucleic Acid Synthesis Inhibitors (chemistry, pharmacology)
• Protein Biosynthesis (drug effects)
• Pyrroles (chemistry, pharmacology)
• RNA, Viral (genetics)
• Structure-Activity Relationship
• Viral Proteins (genetics)