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
  • 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.
Products