A new class of HIV-1 integrase inhibitors: The 3,3,3 ',3 '-tetramethyl-1,1'-spirobi(indan)-5,5 ',6,6 '-tetrol family

Integration is a required step in HIV replication, but as yet no inhibitors of the integration step have been developed for clinical use. Many inhibit ors have been identified that are active against purified viral-encoded int egrase protein; of these many contain a catechol moiety. Though this substr ucture contributes potency in inhibitors, it is associated with toxicity an d so the utility of catechol-containing inhibitors has been questioned. We have synthesized and tested a systematic series of derivatives of a catecho l-containing inhibitor (1) with the goal of identifying catechol isosteres that support inhibition. We find that different patterns of substitution on the aromatic ring suffice for inhibition when Mn2+ is used as a cofactor. Importantly, the efficiency is different when Mg2+, the more likely in vivo cofactor, is used. These data emphasize the importance of assays with Mg2 and offer new catechol isosteres for use in integrase inhibitors.