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Discovery and Structure-Activity-Relationship Study of N-Alkyl-5-hydroxypyrimidinone Carboxamides as Novel Antitubercular Agents Targeting Decaprenylphosphoryl-β-d-ribose 2'-Oxidase.

TitleDiscovery and Structure-Activity-Relationship Study of N-Alkyl-5-hydroxypyrimidinone Carboxamides as Novel Antitubercular Agents Targeting Decaprenylphosphoryl-β-d-ribose 2'-Oxidase.
Publication TypeJournal Article
Year of Publication2018
AuthorsOh S, Park Y, Engelhart CA, Wallach JB, Schnappinger D, Arora K, Manikkam M, Gac B, Wang H, Murgolo N, Olsen DB, Goodwin M, Sutphin M, Weiner DM, Via LE, Boshoff HIM, Barry CE
JournalJ Med Chem
Volume61
Issue22
Pagination9952-9965
Date Published2018 11 21
ISSN1520-4804
KeywordsAlkylation, Animals, Antitubercular Agents, Drug Design, Female, High-Throughput Screening Assays, Mice, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Targeted Therapy, Mycobacterium tuberculosis, Oxidoreductases, Protein Conformation, Pyrimidinones, Structure-Activity Relationship, Tissue Distribution
Abstract

Magnesium plays an important role in infection with Mycobacterium tuberculosis ( Mtb) as a signal of the extracellular environment, as a cofactor for many enzymes, and as a structural element in important macromolecules. Raltegravir, an antiretroviral drug that inhibits HIV-1 integrase is known to derive its potency from selective sequestration of active-site magnesium ions in addition to binding to a hydrophobic pocket. In order to determine if essential Mtb-related phosphoryl transfers could be disrupted in a similar manner, a directed screen of known molecules with integrase inhibitor-like pharmacophores ( N-alkyl-5-hydroxypyrimidinone carboxamides) was performed. Initial hits afforded compounds with low-micromolar potency against Mtb, acceptable cytotoxicity and PK characteristics, and robust SAR. Elucidation of the target of these compounds revealed that they lacked magnesium dependence and instead disappointingly inhibited a known promiscuous target in Mtb, decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1, Rv3790).

DOI10.1021/acs.jmedchem.8b00883
Alternate JournalJ Med Chem
PubMed ID30350998
PubMed Central IDPMC6257622

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