DIMERIC MACROCYCLIC POLYAMINES WITH POTENT INHIBITORY ACTIVITY AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS

The structure-activity relationships of monomeric and dimeric macrocyclic polyamines were studied in an attempt to find potent inhibitors of human immunodeficiency virus (HIV) types 1 and 2. In general, dimeric polyamines are superior as HIV inhibitors to their monomeric counterparts, and the activity of a dimer is proportional to that of its constituent monomers. For the monomeric compounds, the amount of positive charge on the monomer rings, under physiological conditions was more important for anti-HIV activity than the ring size. On the basis of these findings, the 14-membered tetraamine cyclam was selected as the component of dimeric compounds with potentially high activity. Of the series of newly synthesized bicyclams, in which the monomeric cyclams were linked at each C-6 position, a compound with an alkyl chain bridge three carbons in length was found to exhibit the maximum anti-HIV activity. For one particular strain (HIV-2(GH-1)), syncytium formation was inhibited by the bicyclams at a similar concentration to that required to inhibit the viral cytopathic effect.