HIV-1 Integrase Inhibitors that Block HIV-1 Replication in Infected Cells. Planning Synthetic Derivatives from Natural Products

摘要

Combination therapy using reverse transcriptase (RT) and protease (PR) inhibitorsis currently the best clinical approach in combatting acquired immunodeficiency syndrome(AIDS), caused by infection from the human immunodeficiency virus type 1 (HIV-1).However, the emergence of resistant strains calls urgently for research on inhibitors of furtherviral targets such as integrase (IN), the enzyme that catalyzes the integration of the proviralDNA into the host chromosomes. Recently, we started studies on new IN inhibitors asanalogs of natural products, characterized by one or two 3,4-dihydroxycinnamoyl moieties,which were proven to be IN inhibitors in vitro. Then, we designed and synthesized a numberof derivatives sharing 3,4-dihydroxycinnamoyl groups, obtaining potent IN inhibitors activeat submicromolar concentrations. Unfortunately, these derivatives lacked antiretroviral activity,probably owing to their high cytotoxicity. So we designed a number of 3,4,5-trihydroxycinnamoylderivatives as less-cytotoxic IN inhibitors, which were proven to be antiretroviralsin cell-based assays. Finally, we designed and synthesized a number of aryldiketohexenoicacids, strictly related to the aryldiketo acid series recently reported by Merck Company,which were shown to be potent antiretroviral agents endowed with anti-IN activities either in3′ processing or in strand transfer steps.