Synthesis and antiviral activity of C2 analogs of enviroxime: an exploration of the role of critical functionality.
Enviroxime is a potent antiviral agent with broad spectrum activity in tissue culture against both rhinoviruses and enteroviruses. We have synthesized and studied a series of C2-substituted analogs in order to identify critical functionality and examine its role in antiviral activity. We have found that primary amino substitution is the most active. Ab initio calculations indicate that larger groups at C2 may provide a repulsive steric interaction at N3, and in those cases where this undesirable conformation has limited flexibility, the antiviral activity is severely reduced. Further the results show that an amino hydrogen at C2 is strongly hydrogen bonded to the N1 sulfonyl oxygen, which in the case of Enviroxime may act to enhance the activity by holding the second hydrogen in a desirable orientation for interaction at an antiviral site.
Victor
F
F
Lilly Research Laboratories, Indianapolis, Indiana 46285, USA.
Loncharich
R
R
Tang
J
J
Spitzer
W A
WA
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004770:Enterovirus / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010091:Oximes; D017955:Poliovirus / Q000187:drug effects; D012229:Rhinovirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides
D000998:Antiviral Agents; D001562:Benzimidazoles; D010091:Oximes; D013449:Sulfonamides; C021595:viroxime