| Abstract | The human immunodeficiency virus type 1 (HIV-1) causes the acquired immune deficiency syndrome (AIDS). Three essential enzymes are necessary for HIV-1 replication: reverse transcriptase (RT), integrase (IN), and protease (PR). Current drugs target RT and PR, but there is substantial interest in inhibitors targeted at IN, which catalyzes the integration of the proviral DNA into the host cell's DNA. The only two reported classes of compounds considered lead molecules for clinically useful HIV IN inhibitors are the dicaffeoyltartaric acids, of which L-chicoric acid (L-CA) is the lead compound, and the second are the aryl diketo acids (DKAs). These compounds prevent proviral DNA integration and inhibit HIV-1 replication at non-toxic concentrations in cell culture.^Our research focused on: 1) scaffold modification of L-CA; 2) catechol modification of L-CA; and 3) synthesis of hybrid DKA/catechol molecules.In the first part, three conformationally restricted cyclopentane analogues of L-CA were synthesized and tested against HIV IN, and HIV replication. Several showed good anti-HIV IN activity, with the isomer having caffeoyl groups on the opposite side of the ring from the carboxyl group being the most active, thus suggesting this preferred conformation in the IN active site. Neither the rigid analogues nor a synthesized open-chain analogue had significant anti-HIV replication activity.^In the second part, six 2-pyridone analogues of L-CA were synthesized, but only one had moderate anti-HIV IN and anti-HIV activity supporting the conclusion that catechols are required for anti-HIV and anti-HIV IN activity and that simple 2-pyridones are not bioisosteres of catechols.In the third part, six synthesized DKA/catechol hybrids were potent IN inhibitors with the compound with the diketo acid and catechol moiety in a meta-orientation being the most active, even more so than L-CA and some DKA drug candidates. Against HIV replication, only two compounds showed moderate activity, but less so than either L-CA or simple DKAs. The results suggest that caffeoyl are preferred to simple catechol groups and one caffeoyl group is sufficient for inhibition of either HIV IN or HIV replication. Methyl esters in all the above series were less active than their corresponding acids in both assays. |
