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

  • Medchemcomm. 2019 May 30;10(7):1173-1176. doi: 10.1039/c9md00225a.
Alex J Berkowitz  1  2 ,  Abaigeal D Franson  3 ,  Andreu Gazquez Cassals  3 ,  Katherine A Donald  3 ,  Alice J Yu  3 ,  Aswin K Garimallaprabhakaran  1 ,  Lynda A Morrison  3  4 ,  Ryan P Murelli  1  2
Affiliations
  • 1. Department of Chemistry , Brooklyn College , The City University of New York , Brooklyn , NY , USA . Email: [email protected].
  • 2. Ph.D. Program in Chemistry , The Graduate Center , The City University of New York , New York , NY , USA.
  • 3. Department of Molecular Microbiology and Immunology , Saint Louis University School of Medicine , St. Louis , MO , USA . Email: [email protected].
  • 4. Department of Internal Medicine , Saint Louis University School of Medicine , St. Louis , MO , USA.
PMID: 31391890 DOI: 10.1039/c9md00225a
Abstract

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.