Probing Mercaptobenzamides as HIV Inactivators via Nucleocapsid Protein7

Human immunodeficiency virus type1 (HIV-1) nucleocapsid protein7 (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 challeng...

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Bibliographic Details
Published in:ChemMedChem 2017-05, Vol.12 (10), p.714
Main Authors: Saha, Mrinmoy, Scerba, Michael T, Shank, Nathaniel I, Hartman, Tracy L, Buchholz, Caitlin A, Buckheit, Robert W, Durell, Stewart R, Appella, Daniel H
Format: Article
Language:English
Subjects:
Antiviral activity
Aromatic compounds
Chemical synthesis
Drug development
Drugs
HIV
Human immunodeficiency virus
Inactivation
Inactivators
Nucleocapsids
Prodrugs
Room temperature
Structure-activity relationships
Temperature effects
Zinc finger proteins
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Summary:Human immunodeficiency virus type1 (HIV-1) nucleocapsid protein7 (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 IC50 values ranging from 1 to 100µm 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.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700141