2,2′-dithiobisbenzamides derived from α-, β- and γ-amino acids possessing anti-HIV activities: synthesis and structure–activity relationship

Abstract

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 α-, β- and γ-amino acids. Electrospray ionization mass spectrometry was used to study the zinc-ejection activity of these compounds. Among the α-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 β- and γ-amino acids, were found to possess better antiviral and therapeutic efficacies than the α-amino acid analogues. Thus compound 59 was found to possess an EC50 of 1.9μM with a therapeutic index of >50. Interestingly, 2,2′-dithiobisbenzamides derived from α-amino acids containing a protected acid function and polar side chains also exhibited very good antiviral activity.