title: A limited structural modification results in a significantly more efficacious diazachrysene-based filovirus inhibitor.
abstract: Ebola (EBOV) and Marburg (MARV) filoviruses are highly infectious pathogens causing deadly hemorrhagic fever in humans and non-human primates. Promising vaccine candidates providing immunity against filoviruses have been reported. However, the sporadic nature and swift progression of filovirus disease underlines the need for the development of small molecule therapeutics providing immediate antiviral effects. Herein we describe a brief structural exploration of two previously reported diazachrysene (DAAC)-based EBOV inhibitors. Specifically, three analogs were prepared to examine how slight substituent modifications would affect inhibitory efficacy and inhibitor-mediated toxicity during not only EBOV, but also MARV cellular infection. Of the three analogs, one was highly efficacious, providing IC(50) values of 0.696 µM ± 0.13 µM and 2.76 µM ± 0.21 µM against EBOV and MARV infection, respectively, with little or no associated cellular toxicity. Overall, the structure-activity and structure-toxicity results from this study provide a framework for the future development of DAAC-based filovirus inhibitors that will be both active and non-toxic in vivo.
authors.affiliation: University of Belgrade, Studentski trg 16, P.O. Box 51, Belgrade 11158, Serbia. zivota.selakovic@gmail.com
authors.forename: Zivota
authors.initials: Z
authors.lastname: Selaković
authors.forename: Dejan
authors.initials: D
authors.lastname: Opsenica
authors.forename: Brett
authors.initials: B
authors.lastname: Eaton
authors.forename: Cary
authors.initials: C
authors.lastname: Retterer
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.forename: James C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Solaja
authors.forename: Rekha G
authors.initials: RG
authors.lastname: Panchal
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D029043:Ebolavirus / Q000187:drug effects* / Q000502:physiology; D018702:Filoviridae Infections / Q000821:virology; D006801:Humans; D029024:Marburgvirus / Q000187:drug effects* / Q000502:physiology; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D011804:Quinolines