Synthesis and biological properties of novel pyridinioalkanoyl thiolesters (PATE) as anti-HIV-1 agents that target the viral nucleocapsid protein zinc fingers.
Nucleocapsid p7 protein (NCp7) zinc finger domains of the human immunodeficiency virus type 1 (HIV-1) are being developed as antiviral targets due to their key roles in viral replication and their mutationally nonpermissive nature. On the basis of our experience with symmetrical disulfide benzamides (DIBAs; Rice et al. Science 1995, 270, 1194-1197), we synthesized and evaluated variants of these dimers, including sets of 4,4'- and 3,3'-disubstituted diphenyl sulfones and their monomeric benzisothiazolone derivatives (BITA). BITAs generally exhibited diminished antiviral potency when compared to their disulfide precursors. Novel, monomeric structures were created by linking haloalkanoyl groups to the benzamide ring through -NH-C(=O)- (amide) or -S-C(=O)- (thiolester) bridges. Amide-linked compounds generally lacked antiviral activity, while haloalkanoyl thiolesters and non-halogen-bearing analogues frequently exhibited acceptable antiviral potency, thus establishing thiolester benzamides per se as a new anti-HIV chemotype. Pyridinioalkanoyl thiolesters (PATEs) exhibited superior anti-HIV-1 activity with minimal cellular toxicity and appreciable water solubility. PATEs were shown to preferentially target the NCp7 Zn finger when tested against other molecular targets, thus identifying thiolester benzamides, and PATEs in particular, as novel NCp7 Zn finger inhibitors for in vivo studies.
Turpin
J A
JA
Laboratory of Antiviral Drug Mechanisms and Laboratory of Experimental and Computational Biology, National Cancer Institute-Frederick Cancer Research and Development Center, SAIC Frederick, Frederick, Maryland 21702-1201, USA.
Song
Y
Y
Inman
J K
JK
Huang
M
M
Wallqvist
A
A
Maynard
A
A
Covell
D G
DG
Rice
W G
WG
Appella
E
E
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002213:Capsid / Q000037:antagonists & inhibitors*; D036022:Capsid Proteins; D002460:Cell Line; D015683:Gene Products, gag / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014764:Viral Proteins; D014779:Virus Replication / Q000187:drug effects; D016335:Zinc Fingers; D054301:gag Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D036022:Capsid Proteins; D015683:Gene Products, gag; D008024:Ligands; C071884:NCP7 protein, Human immunodeficiency virus 1; D011726:Pyridinium Compounds; D013449:Sulfonamides; D013450:Sulfones; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus