219309-96-3Relevant articles and documents
Optimization of unique, uncharged thioesters as inhibitors of HIV replication
Srivastava, Pratibha,Schito, Marco,Fattah, Rasem J.,Hara, Toshiaki,Hartman, Tracy,Buckheit Jr., Robert W.,Turpin, Jim A.,Inman, John K.,Appella, Ettore
, p. 6437 - 6450 (2007/10/03)
Synthesis and antiviral activity of uncharged thioesters is described. A combinatorial chemistry approach was employed to prepare a restricted library of N-substituted S-acyl-2-mercaptobenzamide thioesters. It was shown that many members of this chemotype display anti-HIV activity via their ability to interact with HIV-1, HIV-2, SIV-infected cells, cell-free virus, and chronically and latently infected cells in a manner consistent with targeting of the highly conserved HIV-1 NCp7 zinc fingers. Compounds were initially screened using two different in vitro antiviral assays and evaluated for stability in neutral buffer containing 10% pooled human serum using a spectrophotometric assay. These data revealed that there was no significant correlation between thioester stability and antiviral activity, however, a slight inverse correlation between serum stability and virucidal activity was noted. Based on the virucidal capability and the ability to select lead compounds to inhibit virus expression from latently infected TNFα-induced U1 cells, we next determined if these compounds could prevent HIV cell-to-cell transmission. Several thioesters demonstrated potent inhibition of HIV cell-to-cell transmission with EC 50 values in the 80-100 nM range. Thus, we have optimized a series of restricted thioesters and provided evidence that serum stability is not required for antiviral activity. Moreover, selected compounds show potential for development as topical microbicides.
2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids possessing anti-HIV activities: Synthesis and structure-activity relationship
Vara Prasad,Loo, Joseph A.,Boyer, Frederick E.,Stier, Michael A.,Gogliotti, Rocco D.,Turner, William J.,Harvey, Patricia J.,Kramer, Melissa R.,Mack, David P.,Scholten, Jefferey D.,Gracheck, Stephen J.,Domagala, John M.
, p. 1707 - 1730 (2007/10/03)
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. Copyright (C) 1998 Elsevier Science Ltd.
