SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF PHENYLENEBIS(METHYLENE)-LINKED BIS-TETRAAZAMACROCYCLES THAT INHIBIT HIV REPLICATION - EFFECTS OF MACROCYCLIC RING SIZE AND SUBSTITUENTS ON THE AROMATIC LINKER

We have previously described the potent and selective inhibition of se veral strains of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by JM2763, an n-propyl-linked dimer of the 1,4,8,11-tetraaza macrocyclic (cyclam) ring system. Upon further investigation, we have also found that incorporating an aromatic rather than aliphatic linker leads to analogs with higher antiviral potency. The prototype, JM3100 (19a, isolated as the octahydrochloride salt), which contains a p-phe nylenebis(methylene) moiety linking the cyclam rings, inhibited the re plication of HIV-1 (IIIB) and HIV-2 (ROD) at EC(50)'s of 4.2 and 5.9 n M, respectively, while remaining nontoxic to MT-4 cells at concentrati ons exceeding 421 mu M. In order to identify the structural features o f bis-tetraazamacrocycle s required for potent activity, we have prepa red a novel series of phenylenebis(methylene)-linked analogs, in which the macrocyclic ring size was varied from 12 to 16 ring members. Depe nding upon the substitution of the phenylenebis(methylene) linker (par a or meta), sub-micromolar anti-HTV activity was exhibited by analogs bearing macrocycles of 12-14 ring members but with varying cytotoxicit y to MT-4 cells. Furthermore, while we found that identical macrocycli c rings are not required for activity, substituting an acyclic polyami ne equivalent for one of the cyclam rings in 19a resulted in a substan tial reduction in anti-HN potency, clearly establishing the importance of the constrained macrocyclic structure. A short series of transitio n metal complexes of 19a were also prepared and evaluated. Complexes o f low kinetic stability such as the bis-zinc complex retained activity comparable to that of the parent compound. Finally, the activity of b icyclam analogs appears to be insensitive to the electron-withdrawing or -donating properties of substituents introduced onto the linker, bu t sterically hindering groups such as phenyl markedly reduced activity . As a result, several analogs with anti-HTV potency comparable to tha t of 19a have been identified.