Nucleocapsid protein (NCp7), which contains highly conserved retroviral zinc fingers, is essential in the early as well as the late phase of human immunodeficiency virus (HIV) life cycle and constitutes a novel target for
AIDS therapy. HIV-1 NCp7 is a basic 55
amino acid protein containing two C(X)2C(X)4H(X)4C motif zinc fingers flanked by
basic amino acids on each side. 2,2'-dithiobisbenzamides have previously been reported to release
zinc from these NCp7 zinc fingers and also to inhibit HIV replication. Specifically, 2,2'-dithiobisbenzamides derived from simple
amino acids showed good
antiviral activities. The
benzisothiazolone 3, the cyclic derivative of 2, was selected for clinical trials as an agent for
AIDS therapy. Herein we report the syntheses and
antiviral activities, including therapeutic indices, of 2,2'-dithiobisbenzamides derived from alpha-, beta- and gamma-
amino acids. Electrospray ionization mass spectrometry was used to study the
zinc-ejection activity of these compounds. Among the alpha-
amino acid derived 2,2'-dithiobisbenzamides, analogues containing alkyl side chains were found to be antivirally active with good therapeutic indices. 2,2'-Dithiobisbenzamides, derived from beta- and gamma-
amino acids, were found to possess better
antiviral and therapeutic efficacies than the alpha-
amino acid analogues. Thus compound 59 was found to possess an EC50 of 1.9 microM with a therapeutic index of > 50. Interestingly, 2,2'-dithiobisbenzamides derived from alpha-
amino acids containing a protected
acid function and polar side chains also exhibited very good
antiviral activity.