title: Probing Mercaptobenzamides as HIV Inactivators via Nucleocapsid Protein 7.
abstract: Human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein 7 (NCp7), a zinc finger protein, plays critical roles in viral replication and maturation and is an attractive target for drug development. However, the development of drug-like molecules that inhibit NCp7 has been a significant challenge. In this study, a series of novel 2-mercaptobenzamide prodrugs were investigated for anti-HIV activity in the context of NCp7 inactivation. The molecules were synthesized from the corresponding thiosalicylic acids, and they are all crystalline solids and stable at room temperature. Derivatives with a range of amide side chains and aromatic substituents were synthesized and screened for anti-HIV activity. Wide ranges of antiviral activity were observed, with IC50values ranging from 1 to 100 μm depending on subtle changes to the substituents on the aromatic ring and side chain. Results from these structure-activity relationships were fit to a probable mode of intracellular activation and interaction with NCp7 to explain variations in antiviral activity. Our strategy to make a series of mercaptobenzamide prodrugs represents a general new direction to make libraries that can be screened for anti-HIV activity.
authors.affiliation: Synthetic Bioactive Molecules Section, LBC, NIDDK, NIH, 8 Center Drive, Room 404, Bethesda, MD, 20892, USA.
authors.forename: Mrinmoy
authors.initials: M
authors.lastname: Saha
authors.affiliation: Synthetic Bioactive Molecules Section, LBC, NIDDK, NIH, 8 Center Drive, Room 404, Bethesda, MD, 20892, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Scerba
authors.affiliation: Synthetic Bioactive Molecules Section, LBC, NIDDK, NIH, 8 Center Drive, Room 404, Bethesda, MD, 20892, USA.
authors.forename: Nathaniel I
authors.initials: NI
authors.lastname: Shank
authors.affiliation: ImQuest Biosciences, 7340 Executive Way, Suite R, Frederick, MD, 21704, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Hartman
authors.affiliation: ImQuest Biosciences, 7340 Executive Way, Suite R, Frederick, MD, 21704, USA.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Buchholz
authors.affiliation: ImQuest Biosciences, 7340 Executive Way, Suite R, Frederick, MD, 21704, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.affiliation: Laboratory of Cell Biology, NCI, NIH, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
authors.forename: Stewart R
authors.initials: SR
authors.lastname: Durell
authors.affiliation: Synthetic Bioactive Molecules Section, LBC, NIDDK, NIH, 8 Center Drive, Room 404, Bethesda, MD, 20892, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Appella
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006678:HIV / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*
chemical_list: D019380:Anti-HIV Agents; D001549:Benzamides; C071884:NCP7 protein, Human immunodeficiency virus 1; D011355:Prodrugs; D013438:Sulfhydryl Compounds; D054301:gag Gene Products, Human Immunodeficiency Virus
keywords: HIV; antiviral agents; mercaptobenzamides; nucleocapsid protein 7; prodrugs