title: 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.affiliation: NUS Graduate School for Integrative Sciences and Engineering , Centre for Life Sciences, #05-01, 28 Medical Drive, Singapore 117456.|Department of Pharmacy, Faculty of Science, National University of Singapore , Block S4A, Level 3, 18 Science Drive 4, Singapore 117543.
authors.forename: Kuan-Chieh
authors.initials: KC
authors.lastname: Ching
authors.affiliation: Singapore Immunology Network, A*STAR , 8A Biomedical Grove, Immunos Building, Level 4, Singapore 138648.
authors.forename: Yiu-Wing
authors.initials: YW
authors.lastname: Kam
authors.affiliation: Institute of Technology, University of Tartu , Nooruse 1, Tartu, Estonia 50411.
authors.forename: Andres
authors.initials: A
authors.lastname: Merits
authors.affiliation: Singapore Immunology Network, A*STAR , 8A Biomedical Grove, Immunos Building, Level 4, Singapore 138648.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore , Block MD6, Centre for Translational Medicine, 14 Medical Drive, #14-01T, Singapore 117599.
authors.forename: Lisa F P
authors.initials: LF
authors.lastname: Ng
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering , Centre for Life Sciences, #05-01, 28 Medical Drive, Singapore 117456.|Department of Pharmacy, Faculty of Science, National University of Singapore , Block S4A, Level 3, 18 Science Drive 4, Singapore 117543.|Institute of Chemical and Engineering Sciences, A*STAR , 8 Biomedical Grove, Neuros Building, #07-01/02/03, Singapore 138665.
authors.forename: Christina L L
authors.initials: CL
authors.lastname: Chai
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D065632:Chikungunya Fever / Q000188:drug therapy* / Q000821:virology; D002646:Chikungunya virus / Q000187:drug effects* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D011758:Pyrroles; D012367:RNA, Viral; D014764:Viral Proteins; C521801:thienopyrrole