Inhibition of HSV-1 replication and HSV DNA polymerase by the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(β- d-ribofuranosyl) quinoline-3-carboxylic acid and its aglycone

Abstract

We describe in this paper that the synthetic chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(β- d-ribofuranosyl) quinoline-3-carboxylic acid (compound A) and its free aglycogene base (compound B) inhibit, with low cytotoxicity, the replication of herpes simplex virus type 1 and 2 (HSV-1 and HSV-2). Compound A inhibited HSV-1 replication in Vero cells with an EC 50 of 1.3 and 1.4 μM for an acyclovir (ACV)-sensitive strain and an ACV-resistant strain of this virus, respectively. Additionally, it inhibited HSV-2 replication with an EC 50 of 1.1 μM. Compound B also inhibited the ACV-sensitive and -resistant HSV-1 strains, and HSV-2 at EC 50 values of 1.7, 1.9 and 1.6 μM, respectively. Time-of-addition assays, performed with compound A, suggested that this molecule at an early time point of the HSV replication cycle. Kinetic assays demonstrated that compounds A and B inhibit the HSV DNA polymerase activity in a noncompetitive fashion, with a K i equal to 0.1 and 0.2 μM, respectively. Taken together, our results suggest that compounds A and B represent promising lead molecules for further anti-HSV drug design.