Anti-herpes simplex virus activity of substituted 1-hydroxyacridones.
5-Chloro-1,3-dihydroxyacridone, 1, is a potent and selective inhibitor of Herpes Simplex Virus Type-1 (HSV-1).(1) Substituted 1,3-dihydroxyacridones represent a new class of nonnucleoside HSV-1 inhibitors, and biochemical studies indicate a novel mechanism of action for 1, although the target is not yet defined.(2) With the goal of lead optimization, analogues of 1 were synthesized in an effort to describe the structure-activity relationships between 1 and its hypothetical binding site. Modifications of key functional groups led to the identity of several features of 1 that were important for activity. In the process, a more expedient and reliable synthesis of 1 and its analogues was developed. Analogues were evaluated against HSV-1 and HSV-2 using a viral plaque-elimination assay for viral inhibition of HSV-1 and HSV-2, and effects on replication of the host cell were also measured in order to assess a therapeutic index (TI) of selectivity. Several new analogues with significant antiviral activity were identified, including 5-methoxy-1,3-dihydroxyacridone (11), which inhibits replication of several HSV-2 strains with a mean ED(50) of 0.7 muM and a TI range of 25-60-fold.
Lowden
Christopher T
CT
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. Christopher.Lowden@rtp.ppdi.com
Bastow
Kenneth F
KF
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054831:Acridones; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000254:growth & development; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D014709:Vero Cells; D010948:Viral Plaque Assay
C479687:1,3-dihydroxy-5-methoxyacridone; D000166:Acridines; D054831:Acridones; D000998:Antiviral Agents