DESIGN, SYNTHESIS AND STRUCTURE RELATIONSHIPS OF NEW N,N',N'',N'''-TETRAKIS (OMEGA-AMINO ALKYL) TETRAAZAMACROCYCLES

A number of N,N',N '',N'''-tetrakis (omega-aminoalkyl) tetraazamacrocy cles and related compounds were synthesized and evaluated for their in hibitory effects on human immunodeficiency virus type 1 (HIV-1) and du ck hepatitis 8 virus (DHBV) replication. The activity of these compoun ds was found to be highly dependent upon structural features: (i) the length of the alkyl linker connecting the nitrogen atoms of the macroc yclic ring to the exocyclic nitrogen atoms of the terminal amino group s (five methylenes favoured antiviral activity); (ii) substitution of the terminal amino groups of the linker reduced antiviral activity; an d (iii) the size of the tetraazamacrocyclic ring (14 or 15 atoms) did not markedly affect the antiviral activity. Some analogues were potent inhibitors of HIV-1 replication, with anti-HIV activity similar to th at of biscyclam (JM 2763). In contrast, other analogues were found to be highly toxic in duck hepatocyte primary culture, the 2.2.15 cell li ne and to a lesser extent in MT-4 cells. Structural parameters, macroc yclic ring size and metal-chelating ability have been used to develop a structure-activity relationship model in order to aid the design of antiviral molecules derived from N,N',N '',N'''-tetrakis (omega-aminoa lkyl) tetraazamacrocycles.