3 years ago

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

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
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.

Publisher URL: http://dx.doi.org/10.1021/acs.joc.7b00847

DOI: 10.1021/acs.joc.7b00847

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.