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

The structure-activity relationships of monomeric and dimeric macrocyc lic 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 counterp arts, and the activity of a dimer is proportional to that of its const ituent monomers. For the monomeric compounds, the amount of positive c harge on the monomer rings, under physiological conditions was more im portant for anti-HIV activity than the ring size. On the basis of thes e findings, the 14-membered tetraamine cyclam was selected as the comp onent of dimeric compounds with potentially high activity. Of the seri es of newly synthesized bicyclams, in which the monomeric cyclams were linked at each C-6 position, a compound with an alkyl chain bridge th ree carbons in length was found to exhibit the maximum anti-HIV activi ty. For one particular strain (HIV-2(GH-1)), syncytium formation was i nhibited by the bicyclams at a similar concentration to that required to inhibit the viral cytopathic effect.