Synthesis of a 3-Amino-2,3-dihydropyrid-4-one and Related Heterocyclic Analogues as Mechanism-Based Inhibitors of BioA, a Pyridoxal Phosphate-Dependent Enzyme

Carter G. Eiden, Courtney C. Aldrich

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12 Scopus citations

Abstract

Amiclenomycin (ACM) is a chemically unstable antibiotic with selective activity against Mycobacterium tuberculosis (Mtb) due to mechanism-based inhibition of BioA, a pyridoxal 5′-phosphate (PLP)-dependent aminotransferase. The first-generation ACM analogue dihydro-2-pyridone 1 maintains a similar bioactivation mechanism concluding with covalent labeling of the PLP cofactor. To improve on 1, we report the synthesis of dihydro-4-pyranone 2, dihydro-4-pyridone 3, and dihydro-4-thiopyranone 13, which were rationally designed to boost the rate of enzyme inactivation by lowering the pKa of their α-protons. We employed a unified synthetic strategy for construction of the desired heterocycles featuring α-amino ynone generation followed by 6-endo-dig cyclization. However, competitive 5-exo-dig cyclization, β-elimination of the ynone, and dimerization of the resultant α-amino carbonyls all complicated the syntheses of the dihydro-4-pyranone and dihydro-4-pyridone scaffolds. These obstacles were overcome by Teoc protection of the β-amino group in the assembly of 3 and Boc-MOM protection of the α-amino group in the synthesis of 2, enabling the efficient construction of 2 and 3 in seven steps from commercially available starting materials. Dihydro-4-pyridone 3 possessed improved enzyme inhibition as measured by its kinact value against BioA.

Original languageEnglish (US)
Pages (from-to)7806-7819
Number of pages14
JournalJournal of Organic Chemistry
Volume82
Issue number15
DOIs
StatePublished - Aug 4 2017

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© 2017 American Chemical Society.

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