ИСТИНА

Despite the undoubted success in the development of human immunodeficiency virus type 1 (HIV-1) therapy, this infection still remains a significant health threat. The key steps of the replication cycle of HIV-1 are the viral DNA synthesis and its integration into the cell genome. One of the current problems associated with HIV therapy is the emergence of drug-resistant virus variants. The resistance emergence is often associated with phosphorolytic excision of the 3’-drug-terminator. To date lots of inhibitors of different viral enzymatic activities are developed, however, a promising approach for development of novel and effective anti-HIV drugs is the design of multitarget compounds suppressing simultaneously several of these activities. Herein, we synthesized 40 methylenebisphosphonates (BPs), five of which simultaneously inhibited phosphorolytic activity of native and drug-resistant forms of HIV-1 reverse transcriptase (RT), RT catalyzed elongation and RNAse H activity and, moreover, two integrase activities. We assessed structural elements required for simultaneous inhibition of these reactions. BPs should be constructed of three pharmacophores: the methylenebisphosphonate backbone, the aromatic halogenated pharmacophore linked to the backbone through the inert aliphatic linker, and the Mg2+-coordinating group. The activity of BPs was also affected by the nature of the second substituent at the bridging carbon. The most active BPs inhibiting activities of the main HIV-1 enzymes are demonstrated below.