Synthesis and biological properties of amino acid amide ligand-based pyridinioalkanoyl thioesters as anti-HIV agents.
Hyper-mutable retroviruses such as HIV can become rapidly resistant to drugs used to treat infection. Strategies for coping with drug-resistant strains of virus include combination therapies, using viral protease and reverse transcriptase inhibitors. Another approach is the development of antiviral agents that attack mutationally nonpermissive targets that have functions essential for viral replication. Thus, the highly conserved nucleocapsid protein, NCp7, was chosen as a prime target in our search for novel anti-HIV agents that can overcome the problem of viral drug resistance. Recently, we reported (J. Med. Chem. 1999, 42, 67) a novel chemotype, the pyridinioalkanoyl thioesters (PATEs), based on 2-mercaptobenzamides as the thiol component and having its amide nitrogen substituted with various phenylsulfonyl moieties. These compounds were identified as relatively nontoxic anti-HIV agents in the XTT cytoprotection assay. In this study, we wish to report a separate genre of active PATEs wherein the thiol component consists of an N-2-mercaptobenzoyl-amino acid derivative. Active derivatives (EC(50) < 10 microM) reported herein were confined to amino acid primary amides or methyl amides having side chains no larger than isobutyl. Amino acids terminating in free carboxyl or carboxylic acid ester groups were mostly inactive. Selected compounds were shown to be active on chronically infected CEM/SK-1, TNFalpha-induced U1, ACH-2 cells and virucidal on cell-free virus, latently infected U1 cells and acutely infected primary peripheral blood mononuclear cells (PBMCs).
Song
Yongsheng
Y
Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, USA.
Goel
Atul
A
Basrur
Venkatesha
V
Roberts
Paula E A
PE
Mikovits
Judy A
JA
Inman
John K
JK
Turpin
Jim A
JA
Rice
William G
WG
Appella
Ettore
E
D000596:Amino Acids; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides; D002213:Capsid; D036022:Capsid Proteins; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D015683:Gene Products, gag / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008826:Microbial Sensitivity Tests; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus
D000596:Amino Acids; D019380:Anti-HIV Agents; D001549:Benzamides; D036022:Capsid Proteins; D004952:Esters; D015683:Gene Products, gag; D008024:Ligands; C071884:NCP7 protein, Human immunodeficiency virus 1; D011726:Pyridinium Compounds; D013438:Sulfhydryl Compounds; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus