Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit human immunodeficiency virus replication. 2. Effect of heteroaromatic linkers on the activity of bicyclams.
A series of bicyclam analogs connected through a heteroaromatic linker have been synthesized and evaluated for their inhibitory effects on HIV-1 (IIIB) and HIV-2 (ROD) replication in MT-4 cells. The activity of pyridine- and pyrazine-linked bicyclams was found to be highly dependent upon the substitution of the heteroaromatic linker connecting the cyclam rings. For example, 2,6- and 3,5-pyridine-linked bicyclams were potent inhibitors of HIV-1 and HIV-2 replication, whereas the 2,5- and 2,4-substituted pyridine-linked compounds exhibited substantially reduced activity and, in addition, were found to be highly toxic to MT-4 cells. We have subsequently discovered that these effects are not unique; amino-substituted linkers also have the potential to deactivate phenylenebis(methylene)-linked bicyclams. A model is proposed to explain the deactivating effects of the pyridine group in certain substitution patterns based on the ability of the pyridine nitrogen to participate in pendant conformations (complexation) with the adjacent azamacrocyclic ring, which may involve hydrogen bonding or coordination to a transition metal. The introduction of a sterically hindering group such as phenyl at the 6-position of the 2,4-substituted pyridine-linked bicyclam appears to prevent pendant conformations, providing an analog with comparable anti-HIV-1 and anti-HIV-2 activities to the parent m-phenylenebis(methylene)-linked bicyclam. The results of this study have been used to develop a quantitative structure-activity relationship model with improved predictive capability in order to aid the design of antiviral bis-azamacrocyclic analogs.
Bridger
G J
GJ
Johnson Matthey Pharmaceutical Research, West Chester, Pennsylvania 19380, USA.
Skerlj
R T
RT
Padmanabhan
S
S
Martellucci
S A
SA
Henson
G W
GW
Abrams
M J
MJ
Joao
H C
HC
Witvrouw
M
M
De Vreese
K
K
Pauwels
R
R
De Clercq
E
E
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008968:Molecular Conformation; D015394:Molecular Structure; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D001372:Aza Compounds; D006571:Heterocyclic Compounds