2. Academic Validation
  3. Hydantion indolinones as AANAT inhibitors

Hydantion indolinones as AANAT inhibitors

  • Bioorg Med Chem Lett. 2026 Feb 1:131:130459. doi: 10.1016/j.bmcl.2025.130459.
Nicole Wandrey 1,  Jake Boley 1,  Dirce Gómez-Galicia 1,  Mackinzi Hill 1,  Mason Bach 1,  Sidney Gawrych 1,  Mackenzie Hagemeister 1,  Philip A Cole 2,  Michael A Moxley 1,  Allen A Thomas 3
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Nebraska at Kearney, Kearney, NE 69949, USA.
  • 2 Division of Genetics, Department of Medicine, Brigham and Women's Hospital; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Department of Chemistry, University of Nebraska at Kearney, Kearney, NE 69949, USA. Electronic address: [email protected].
PMID: 41176235 DOI: 10.1016/j.bmcl.2025.130459
Abstract

Arylalkylamine N-acetyltransferase (AANAT) is a key enzyme in melatonin biosynthesis and a regulator of circadian rhythm, with potential relevance to mood disorders such as seasonal affective disorder (SAD). We report a series of hydantoin indolinone-based AANAT inhibitors, developed as more stable alternatives to a previously reported rhodanine scaffold. Guided by docking studies and prior structure-activity data, we modified four regions of the molecule to improve potency. Substitution at the 5-position of the indolinone ring led to marked increases in activity, with compound 5g (bearing a CH3CO2CH2- substituent) resulting in an IC₅₀ of 1.1 μM-representing a 19-fold improvement over the parent compound. Kinetic mechanism studies were also conducted with respect to acetyl-CoA and serotonin to explore inhibitor binding. These findings establish a promising starting point for the development of more potent AANAT inhibitors as chemical probes for studying melatonin's function.

Keywords

Acetyl transferase; Circadian rhythm; Melatonin; Mood disorders.

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