2. Academic Validation
  3. Discovery of novel multi-target indole-based derivatives as potent and selective inhibitors of chikungunya virus replication

Discovery of novel multi-target indole-based derivatives as potent and selective inhibitors of chikungunya virus replication

  • Bioorg Med Chem. 2017 Jan 1;25(1):327-337. doi: 10.1016/j.bmc.2016.10.037.
Maria Scuotto 1,  Rana Abdelnabi 2,  Selene Collarile 1,  Chiara Schiraldi 1,  Leen Delang 2,  Antonio Massa 3,  Salvatore Ferla 4,  Andrea Brancale 4,  Pieter Leyssen 2,  Johan Neyts 2,  Rosanna Filosa 5
Affiliations

Affiliations

  • 1 Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
  • 2 Department of Chemistry, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, SA, Italy.
  • 3 KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
  • 4 School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
  • 5 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.
PMID: 27856239 DOI: 10.1016/j.bmc.2016.10.037
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.

Keywords

Arbidol; Chikungunya; Replication; Virus.

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