6-[1-(4-Fluorophenyl)methyl-1H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester a novel diketo acid derivative which selectively inhibits the HIV-1 viral replication in cell culture and the ribonuclease H activity in vitro

Identification of Highly Conserved Residues Involved in Inhibition of HIV-1 RNase H Function by Diketo Acid Derivatives

“…Starting from these results, in the present study we synthesized 6 new couples of diketo ester and DKA derivatives with various structural features, to be used as chemical tools in the characterization of RNase H binding modes. In agreement with previous studies (30,31), among the designed molecules all of the acids were more potent against IN, while three esters (RDS1759, RDS2291, and RDS2400) proved to selectively inhibit RNase H activity, compared to IN. Interestingly, a few DKA derivatives were also able to inhibit RDDP activity.…”

“…DKAs have been reported to be the first active site agents that can effectively inhibit both HIV-1 RNase H and IN functions, or only one of them, in the low micromolar range and that can also inhibit HIV-1 replication in cell-based assays (30,44 (24). Starting from these results, in the present study we synthesized 6 new couples of diketo ester and DKA derivatives with various structural features, to be used as chemical tools in the characterization of RNase H binding modes.…”

“…Among them, 6-[1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester (RDS1643) was the first ligand proven to be able to inhibit both HIV-1 RNase H in biochemical assays and viral replication in cell culture (30). Recently, a new series of pyrrolyl DKAs that are active against both HIV-1 IN and RNase H has been reported (31), with acidic compounds being more effective with IN and ester counterparts being active with both enzymes, with no particular difference.…”

“…Diketo acid (DKA) derivatives are among the first compounds reported to bind the Mg 2ϩ cofactors in the active site of influenza virus endonuclease (27), HIV-1 IN (28), and HIV-1 RNase H (29,30). Among them, 6-[1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester (RDS1643) was the first ligand proven to be able to inhibit both HIV-1 RNase H in biochemical assays and viral replication in cell culture (30).…”

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“…It is able to block the replication of wild type HIV-1 at the concentration of 13μM and is cytotoxic at a concentration of 63 μM 26 . 4-amino-5-hexenoic acid commonly known as 'Vigabatrin' is an important GABA-T inhibitor, which is another important application of 5-hexenoic acid.…”