Type 1 Transcription by Piperazinyloxoquinoline Derivatives

We have found novel piperazinyloxoquinoline derivatives to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in both acutely and chronically infected cells. 8-Difluoromethoxy-1-ethyl-6-fluoro-1,4-didehydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid (K-12), the most potent congener of the series, completely inhibited HIV-1 replication in acutely infected MOLT-4 cells at a concentration of 0.16 to 0.8 mM without showing any cytotoxicity. The compound completely suppressed tumor necrosis factor alpha (TNF-a)-induced HIV-1 expression in latently infected cells (OM-10.1) and constitutive viral production in chronically infected cells (MOLT-4/IIIB) at a concentration of 0.8 mM. K-12 could also inhibit HIV-1 antigen expression in OM-10.1 and MOLT-4/IIIB cells at this concentration. Northern blot analysis revealed that K-12 selectively prevented the accumulation of HIV-1 mRNA in MOLT-4/IIIB and TNF-a-treated OM-10.1 cells in a dose-dependent fashion. It was not inhibitory to HIV-1 Tat or the cellular transcription factors NF-kB and Sp1, suggesting that the piperazinyloxoquinoline derivatives are a group of HIV-1 transcription inhibitors with a unique mechanism of action. A number of compounds have been reported to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) in vitro (7). At present, six reverse transcriptase inhibitor