Abstract
Arboviral encephalitis is a potentially devastating human disease with no approved therapies that target virus replication. We previously discovered a novel class of thieno[3,2-b]pyrrole-based inhibitors active against neurotropic alphaviruses such as western equine encephalitis virus (WEEV) in cultured cells. In this report, we describe initial development of these novel antiviral compounds, including bioisosteric replacement of the 4H-thieno[3,2-b]pyrrole core with indole to improve metabolic stability and the introduction of chirality to assess target enantioselectivity. Selected modifications enhanced antiviral activity while maintaining low cytotoxicity, increased stability to microsomal metabolism, and also revealed striking enantiospecific activity in cultured cells. Furthermore, we demonstrate improved outcomes (both symptoms and survival) following treatment with indole analogue 9h (CCG-203926) in an in vivo mouse model of alphaviral encephalitis that closely correlate with the enantiospecific in vitro antiviral activity. These results represent a substantial advancement in the early preclinical development of a promising class of novel antiviral drugs against virulent neurotropic alphaviruses.
© 2012 American Chemical Society
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Alphavirus / drug effects*
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Alphavirus / genetics
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Alphavirus / physiology
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Alphavirus Infections / drug therapy*
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Alphavirus Infections / mortality
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Alphavirus Infections / pathology
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Brain / drug effects
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Brain / pathology
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Cell Survival / drug effects
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Encephalitis, Viral / drug therapy*
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Encephalitis, Viral / mortality
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Encephalitis, Viral / pathology
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Membranes, Artificial
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Mice
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Microsomes, Liver / metabolism
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Neurons / drug effects
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Neurons / pathology
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Permeability
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Replicon / drug effects
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Spinal Cord / drug effects
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Spinal Cord / pathology
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Stereoisomerism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
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Viral Tropism
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Virus Replication / drug effects
Substances
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1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)-N-(1-phenylethyl)piperidine-4-carboxamide
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Antiviral Agents
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Indoles
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Membranes, Artificial
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Piperidines
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Pyrroles
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Thiophenes