Evaluation of Rhodanine Indolinones as AANAT Inhibitors

Circadian rhythm (CR) dysregulation negatively impacts health and contributes to mental disorders. The role of melatonin, a hormone intricately linked to CR, is still a subject of active study. The enzyme arylalkylamine N‐acetyltransferase (AANAT) is responsible for melatonin synthesis, and it is a...

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Published in:	ChemMedChem Vol. 19; no. 1; pp. e202300567 - n/a
Main Authors:	Hagemeister, Mackenzie, Hamilton, Luke, Wandrey, Nicole, Hill, Mackinzi, Mounce, Emery, Mosel, Noah, Lytle, Katie, Redinger, Makenna, Boley, Jake, Fancher, Nathan, Haynes, Alexis, Fill, Ianna, Cole, Philip A., Hill, Evan, Moxley, Michael A., Thomas, Allen A.
Format:	Journal Article
Language:	English
Published:	Germany Wiley Subscription Services, Inc 02-01-2024
Subjects:	acetyl transferase Acetyltransferases Animals Aralkylamine N-acetyltransferase Arylalkylamine N-Acetyltransferase - metabolism Carboxylic acids Cell permeability circadian rhythm Circadian rhythms enzyme models heterocycles Humans In vivo methods and tests Inhibitors Locomotion Melatonin Melatonin - metabolism Mental disorders Rhodanine - pharmacology Seasonal affective disorder Zebrafish acetyl transferase melatonin heterocycles enzyme models circadian rhythm
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Summary:	Circadian rhythm (CR) dysregulation negatively impacts health and contributes to mental disorders. The role of melatonin, a hormone intricately linked to CR, is still a subject of active study. The enzyme arylalkylamine N‐acetyltransferase (AANAT) is responsible for melatonin synthesis, and it is a potential target for disorders that involve abnormally high melatonin levels, such as seasonal affective disorder (SAD). Current AANAT inhibitors suffer from poor cell permeability, selectivity, and/or potency. To address the latter, we have employed an X‐ray crystal‐based model to guide the modification of a previously described AANAT inhibitor, containing a rhodanine‐indolinone core. We made various structural modifications to the core structure, including testing the importance of a carboxylic acid group thought to bind in the CoA site, and we evaluated these changes using MD simulations in conjunction with enzymatic assay data. Additionally, we tested three AANAT inhibitors in a zebrafish locomotion model to determine their effects in vivo. Key discoveries were that potency could be modestly improved by replacing a 5‐carbon alkyl chain with rings and that the central rhodanine ring could be replaced by other heterocycles and maintain potency. Starting from a known AANAT inhibitor containing a rhodanine‐indolinone scaffold, we made various structural modifications and evaluated compound potency using an enzymatic assay in conjunction with MD simulations to predict binding mode (depicted). We found that potency was enhanced by using rings to join a carboxylic acid to the central rhodanine ring and that the rhodanine ring could be replaced with alternative heterocycles.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1860-7179 1860-7187
DOI:	10.1002/cmdc.202300567