Importance of lipophilicity for potent anti-herpes simplex virus-1 activity of α-hydroxytropolones

We previously reported that troponoid compounds profoundly inhibit replication of herpes simplex virus (HSV)-1 and HSV-2 in cell culture, including acyclovir-resistant mutants. Synthesis of 26 alpha-hydroxylated tropolones (αHTs) led to a preliminary structure-activity relationship highlighting the...

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Bibliographic Details
Published in:MedChemComm 2019-07, Vol.1 (7), p.1173-1176
Main Authors: Berkowitz, Alex J, Franson, Abaigeal D, Gazquez Cassals, Andreu, Donald, Katherine A, Yu, Alice J, Garimallaprabhakaran, Aswin K, Morrison, Lynda A, Murelli, Ryan P
Format: Article
Language:English
Subjects:
Acyclovir
Antiviral agents
Cell culture
Chains
Function analysis
Herpes simplex
Herpes viruses
Lipophilic
Lipophilicity
Molecular structure
Mutants
NMR
Nuclear magnetic resonance
Optimization
Resistant mutant
Structure-function relationships
Viruses
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Summary:We previously reported that troponoid compounds profoundly inhibit replication of herpes simplex virus (HSV)-1 and HSV-2 in cell culture, including acyclovir-resistant mutants. Synthesis of 26 alpha-hydroxylated tropolones (αHTs) led to a preliminary structure-activity relationship highlighting the potency of bi-phenyl side chains. Here, we explore the structure-activity relationship in more detail, with a focus on various biaryl and other lipophilic molecules. Along with our prior structure-function analysis, we present a refined structure-activity relationship that reveals the importance of the lipophilicity and nature of the side chain for potent anti-HSV-1 activity in cells. We expect this new information will help guide future optimization of αHTs as HSV antivirals. Lipophilic side-chains enhance αHT antiviral potency.
ISSN:2040-2503
2040-2511
DOI:10.1039/c9md00225a