2,2'-Dithiobisbenzamides derived from alpha-, beta- and gamma-amino acids possessing anti-HIV activities: synthesis and structure-activity relationship.
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.
Prasad
J V
JV
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Loo
J A
JA
Boyer
F E
FE
Stier
M A
MA
Gogliotti
R D
RD
Turner
W J
WJ
Harvey
P J
PJ
Kramer
M R
MR
Mack
D P
DP
Scholten
J D
JD
Gracheck
S J
SJ
Domagala
J M
JM
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry*; D002213:Capsid / Q000737:chemistry / Q000187:drug effects; D036022:Capsid Proteins; D015683:Gene Products, gag / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D008969:Molecular Sequence Data; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013329:Structure-Activity Relationship; D014764:Viral Proteins; D015032:Zinc / Q000737:chemistry; D054301:gag Gene Products, Human Immunodeficiency Virus
D000596:Amino Acids; D019380:Anti-HIV Agents; D001549:Benzamides; D036022:Capsid Proteins; D015683:Gene Products, gag; C071884:NCP7 protein, Human immunodeficiency virus 1; D016329:Sp1 Transcription Factor; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; D015032:Zinc