title: Structural Optimizations of Thieno[3,2-b]pyrrole Derivatives for the Development of Metabolically Stable Inhibitors of Chikungunya Virus.
abstract: Chikungunya virus (CHIKV) is a re-emerging vector-borne alphavirus, and there is no approved effective antiviral treatment currently available for CHIKV. We previously reported the discovery of thieno[3,2-b]pyrrole 1b that displayed good antiviral activity against CHIKV infection in vitro. However, it has a short half-life in the presence of human liver microsomes (HLMs) (T1/2= 2.91 min). Herein, we report further optimization studies in which potential metabolically labile sites on compound 1b were removed or modified, resulting in the identification of thieno[3,2-b]pyrrole 20 and pyrrolo[2,3-d]thiazole 23c possessing up to 17-fold increase in metabolic half-lives in HLMs and good in vivo pharmacokinetic properties. Compound 20 not only attenuated viral RNA production and displayed broad-spectrum antiviral activity against other alphaviruses and CHIKV isolates but also exhibited limited cytotoxic liability (CC50> 100 μM). These studies have identified two compounds that have the potential for further development as antiviral drugs against CHIKV infection.
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering , Centre for Life Sciences, No. 05-01, 28 Medical Drive, 117456, Singapore.|Department of Pharmacy, Faculty of Science, National University of Singapore , Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore.
authors.forename: Kuan-Chieh
authors.initials: KC
authors.lastname: Ching
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore , Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore.
authors.forename: Thi Ngoc Quy
authors.initials: TN
authors.lastname: Tran
authors.affiliation: Singapore Immunology Network, A*STAR , 8A Biomedical Grove, Immunos Building, No. 04-06, 138648, Singapore.
authors.forename: Siti Naqiah
authors.initials: SN
authors.lastname: Amrun
authors.affiliation: Singapore Immunology Network, A*STAR , 8A Biomedical Grove, Immunos Building, No. 04-06, 138648, Singapore.
authors.forename: Yiu-Wing
authors.initials: YW
authors.lastname: Kam
authors.affiliation: Singapore Immunology Network, A*STAR , 8A Biomedical Grove, Immunos Building, No. 04-06, 138648, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore , Block MD6, Centre for Translational Medicine, 14 Medical Drive, No. 14-01T, 117599, Singapore.
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, No. 05-01, 28 Medical Drive, 117456, Singapore.|Department of Pharmacy, Faculty of Science, National University of Singapore , Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore.|Institute of Chemical and Engineering Sciences, A*STAR , 8 Biomedical Grove, Neuros Building, No. 07-01/02/03, 138665, Singapore.
authors.forename: Christina L L
authors.identifier: 0000-0002-9199-851X
authors.initials: CL
authors.lastname: Chai
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D065632:Chikungunya Fever / Q000188:drug therapy*; D002646:Chikungunya virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D011758:Pyrroles; D012367:RNA, Viral; C521801:thienopyrrole