Discovery of Broad-Spectrum Herpes Antiviral Oxazolidinone Amide Derivatives and Their Structure-Activity Relationships

Abstract

Herpesvirus infections are ubiquitous, with over 95% of the adult population infected by at least one strain. While most of these infections resolve without treatment in healthy individuals, they can cause significant morbidity and mortality in immunocompromised, stem cell, or organ transplant patients. Current nucleoside standards of care provide meaningful benefit but are limited due to poor tolerability, resistance, and generally narrow spectrum of activity. Herpesviruses share a conserved DNA polymerase, the inhibition of which is validated as an effective strategy to disrupt viral replication. By utilizing a non-nucleoside inhibitor of the viral DNA polymerase, we sought to develop agents covering multiple herpesviruses (e.g., CMV, VZV, HSV1/2, EBV, and HHV6). Herein is described the invention of an oxazolidinone class of broad-spectrum non-nucleoside herpes antiviral inhibitors. A lead compound (42) with potent biochemical and broad-spectrum cellular activity was found to be efficacious in murine models against both HSV-1 and CMV infection.

Figure 1

Standard of care antiviral agents for herpesvirus infections

Scheme 1. Synthesis of Early Leads

Reagents and conditions: (a) Et₃N, DMF; (b) Hunigs base, DCM; (c) R¹-Br, or pinacol borate, Cs₂CO₃, PdCl₂DPPF, Ar-X, THF.

Scheme 2. Synthesis of Advanced Leads

Reagents and conditions: (a) Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, NiCl₂Glyme, dtbbpy, (TMS)₃SiH, Lutidine, DME, blue LED; (b)Hunigs base, DCM, acid chloride-R₃.

Figure 2

Crystal structure of HSV-1 polymerase in complex with primer-template duplex and (44).

Figure 3

Survival of therapeutically treated mice post HSV-1 challenge.

Figure 4

Mean HSV-1 DNA load in the lung at day 4.

Figure 5

Mean HSV-1 DNA load in the brain at day 4.

Figure 6

Survival of prophylactically treated mice post HSV-1 challenge

Figure 7

Mean mCMV DNA load in the spleen at day 4.

Figure 8

Mean mCMV DNA load in salivary glands on day 10.

Figure 9

Modeled binding mode of (42) in HSV1 polymerase crystal structure.