Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

Antimicrobial Agents and Chemotherapy
Peter J IrelandLynda A Morrison

Abstract

Herpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as β-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic α-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the α-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 μM, and 10 compounds inhibited HSV-1 and HSV-2 at 5 μM, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC50) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC50] of 50 to >100 μM). Therapeutic indexes ranged from >170 to >1,200. These data indicate...Continue Reading

References

Dec 1, 1977·Proceedings of the National Academy of Sciences of the United States of America·G B ElionH J Schaeffer
Nov 1, 1982·Antimicrobial Agents and Chemotherapy·N E AllenH A Kirst
Jul 20, 1982·The American Journal of Medicine·P V McGuirt, P A Furman
Feb 15, 1995·Structure·W Yang, T A Steitz
Jan 1, 1997·Annual Review of Biochemistry·P E Boehmer, I R Lehman
Jan 14, 2003·Archives of Internal Medicine·Michele ReyesUNKNOWN Task Force on Herpes Simplex Virus Resistance
Jan 15, 2003·Clinical Microbiology Reviews·Teresa H BaconDavid Sutton
Feb 19, 2003·Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology·Florence Morfin, Danielle Thouvenot
Apr 2, 2003·Molecular Cell·Susana M CerritelliRobert J Crouch
May 22, 2003·Dermatologic Clinics·Suneel Chilukuri, Ted Rosen
Dec 2, 2004·Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology·Růzena StránskáAnton M van Loon
Jul 17, 2008·The Journal of Infectious Diseases·Rui DuanGeorges M G M Verjans
Sep 12, 2008·The Journal of Infectious Diseases·Karen E MarkLawrence Corey
Oct 25, 2008·Bulletin of the World Health Organization·Katharine J LookerGeorge P Schmid
Dec 31, 2008·Journal of American College Health : J of ACH·P Davis Smith, Craig M Roberts
Jan 24, 2009·EMBO Reports·Marcin Nowotny
Sep 25, 2010·Journal of American College Health : J of ACH·Robert HorowitzBernette Melby
Jan 26, 2011·Pediatric Dermatology·Stephanie Frisch, Elaine C Siegfried
Jul 23, 2011·Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology·Yi WangTao Peng
Sep 1, 2011·Biochimica Et Biophysica Acta·Heini RuhanenTakehiro Yasukawa
Jan 6, 2012·The New England Journal of Medicine·Robert B BelsheUNKNOWN Herpevac Trial for Women
Aug 23, 2012·PLoS Pathogens·April J SchumacherSandra K Weller
Oct 23, 2012·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·David I BernsteinRobert B Belshe

❮ Previous
Next ❯

Citations

Mar 29, 2016·The Journal of Organic Chemistry·Michael P D'ErasmoRyan Patrick Murelli
Jan 17, 2017·MedChemComm·Michael P D'ErasmoRyan P Murelli
Nov 4, 2017·Organic & Biomolecular Chemistry·D R HirschR P Murelli
Feb 9, 2017·Antimicrobial Agents and Chemotherapy·Maureen J DonlinRyan P Murelli
Aug 1, 2018·Antimicrobial Agents and Chemotherapy·Jennifer T MillerStuart F J Le Grice
Oct 6, 2020·Frontiers in Microbiology·Estefanía CastilloPablo A González
May 6, 2019·Journal of Medicinal Chemistry·Gaochan WuPeng Zhan
Jan 18, 2018·The Journal of Organic Chemistry·Michael P D'Erasmo, Ryan P Murelli

❮ Previous
Next ❯

Related Concepts

Related Feeds

Aminoglycosides (ASM)

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside. Discover the latest research on aminoglycoside here.

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Aminoglycosides

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside. Discover the latest research on aminoglycoside here.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

CRISPR Screens in Drug Resistance

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of CRISPR-Cas system in high-throughput genome-wide screens to identify genes that may confer drug resistance.