title: Discovery of novel multi-target indole-based derivatives as potent and selective inhibitors of chikungunya virus replication.
abstract: We recently identified indole derivatives (IIIe and IIIf) with anti-chikungunya virus (CHIKV) activities at lower micro molar concentrations and a selective index of inhibition higher than the lead compound Arbidol. Here we highlight new structural information for the optimization of the previously identified lead compounds that contain the indole chemical core. Based on the structural data, a series of indole derivatives was synthesized and tested for their antiviral activity against chikungunya virus in Vero cell culture by a CPE reduction assay. Systematic optimization of the lead compounds resulted in tert-butyl-5-hydroxy-1-methyl-2-(2-trifluoromethysulfynyl)methyl)-indole-3-carboxylate derivative IIc with a 10-fold improved anti-CHIKV inhibitory activity (EC50=6.5±1μM) as compared to Arbidol demonstrating a potent, selective and specific inhibition of CHIKV replication with only a moderate cell protective effect against other related alphaviruses. The reported computational insights, together with the accessible synthetic procedure, pave the road towards the design of novel synthetic derivatives with enhanced anti-viral activities.
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Scuotto
authors.affiliation: Department of Chemistry, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, SA, Italy.
authors.forename: Rana
authors.initials: R
authors.lastname: Abdelnabi
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
authors.forename: Selene
authors.initials: S
authors.lastname: Collarile
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Schiraldi
authors.affiliation: Department of Chemistry, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, SA, Italy.
authors.forename: Leen
authors.initials: L
authors.lastname: Delang
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
authors.forename: Antonio
authors.initials: A
authors.lastname: Massa
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ferla
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: Department of Chemistry, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, SA, Italy.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: Department of Chemistry, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, SA, Italy.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy; Consorzio Sannio Tech, Via Appia, SNC, 82030 Apollosa (BN), Italy. Electronic address: rosanna.filosa@unina2.it.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Filosa
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002646:Chikungunya virus / Q000187:drug effects* / Q000502:physiology; D002522:Chlorocebus aethiops; D006023:Glycoproteins / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D013454:Sulfoxides / Q000494:pharmacology*; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects*; D013440:Sulfides
chemical_list: D000998:Antiviral Agents; D006023:Glycoproteins; D007211:Indoles; D013454:Sulfoxides; D014759:Viral Envelope Proteins; C000625535:tert-butyl 5-hydroxy-1-methyl-2-(2-trifluoromethysulfynyl)methyl)indole-3-carboxylate; C086979:umifenovir; D013440:Sulfides
keywords: Arbidol; Chikungunya; Replication; Virus