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Pure Appl. Chem., 2003, Vol. 75, No. 2-3, pp. 195-206

HIV-1 integrase inhibitors that block HIV-1 replication in infected cells. Planning synthetic derivatives from natural products

Roberto Di Santo1, Roberta Costi1, Marino Artico1, E. Tramontano2, P. La Colla2 and A. Pani2

1 Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici (Dip. 63), Università di Roma “La Sapienza”, Piazzale A. Moro 5, I-00185 Roma, Italy
2 Dipartimento di Biologia Sperimentale, Sezione di Microbiologia, Università di Cagliari, Cittadella Universitaria, SS 554, I-09042 Monserrato, Cagliari, Italy

Abstract: Combination therapy using reverse transcriptase (RT) and protease (PR) inhibitors is 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 further viral targets such as integrase (IN), the enzyme that catalyzes the integration of the proviral DNA into the host chromosomes. Recently, we started studies on new IN inhibitors as analogs 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 number of derivatives sharing 3,4 dihydroxycinnamoyl groups, obtaining potent IN inhibitors active at submicromolar concentrations. Unfortunately, these derivatives lacked antiretroviral activity, probably owing to their high cytotoxicity. So we designed a number of 3,4,5-trihydroxycinnamoyl derivatives as less-cytotoxic IN inhibitors, which were proven to be antiretrovirals in cell-based assays. Finally, we designed and synthesized a number of aryldiketohexenoic acids, 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 in 3' processing or in strand transfer steps.