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Potent Neuronal Nicotinamide Adenine Dinucleotide-Boosting Tetrahydroquinoxalines: Structure-Activity Relationships

Petra Cuřínová1, Melissa Jöe2, Filip Cesar1

  • 1Department of Organic Chemistry, University of Chemistry and Technology in Prague, 166 28 Prague, Czech Republic.

ACS Medicinal Chemistry Letters
|April 15, 2026
PubMed
Summary
This summary is machine-generated.

Researchers developed novel tetrahydroquinoxaline compounds that boost nicotinamide adenine dinucleotide (NAD) levels in neurons. These compounds show promise as neuroprotective agents, with favorable drug-like properties identified.

Keywords:
Neurodegeneration; NAD metabolism; NMNAT2; tetrahydroquinoxaline derivatives

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Area of Science:

  • Medicinal Chemistry
  • Neuroscience
  • Pharmacology

Background:

  • Nicotinamide adenine dinucleotide (NAD) is crucial for neuronal function and energy metabolism.
  • Declining NAD+ levels are implicated in neurodegenerative diseases.
  • Developing agents to boost neuronal NAD+ is a key therapeutic strategy.

Purpose of the Study:

  • To design, synthesize, and evaluate novel 1,2,3,4-tetrahydroquinoxaline derivatives as neuronal NAD+-boosting agents.
  • To establish structure-activity relationships (SAR) for identifying key molecular features driving NAD+ enhancement.
  • To assess the drug metabolism and pharmacokinetic (DMPK) properties of lead compounds.

Main Methods:

  • Synthesis of a novel series of 1,2,3,4-tetrahydroquinoxaline derivatives.
  • Evaluation of compounds for their ability to increase NAD+ levels in primary cortical neurons.
  • Structure-activity relationship (SAR) and 3D-SAR analyses to guide optimization.
  • In vitro assessment of drug metabolism and pharmacokinetic (DMPK) properties, including cell permeability and metabolic stability in liver microsomes.

Main Results:

  • Several tetrahydroquinoxaline derivatives demonstrated nanomolar potency in increasing neuronal NAD+ levels.
  • Clear SAR and favorable 3D-SAR features were identified for potent NAD+ enhancement.
  • Lead compounds exhibited good cell permeability and species-dependent metabolic stability.
  • Human liver microsomes showed improved metabolic stability compared to rodent systems.

Conclusions:

  • Tetrahydroquinoxalines represent a promising class of compounds for boosting neuronal NAD+ levels.
  • The identified SAR provides a foundation for optimizing neuroprotective drug candidates.
  • These findings support the further development of tetrahydroquinoxalines for potential therapeutic applications in neurological disorders.