Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

Area of Science:

• Neuropharmacology
• Cellular Biology
• Drug Discovery

Background:

• Neurodegenerative diseases share common pathways like proteostasis dysfunction and neuronal apoptosis, presenting therapeutic targets.
• Flupirtine, a known analgesic, serves as a scaffold for developing novel neuroprotective agents.
• Identifying structure-activity relationships is crucial for optimizing drug candidates for central nervous system (CNS) therapeutics.

Purpose of the Study:

• To synthesize and evaluate a library of aromatic carbamate derivatives for neuroprotective activity.
• To investigate the mechanism of action underlying the neuroprotective effects of these novel compounds.
• To identify derivatives with improved efficacy and favorable physicochemical properties for CNS delivery.

Main Methods:

• Synthesis of a library of aromatic carbamate derivatives based on flupirtine.
• Assessment of neuroprotective effects using human induced pluripotent stem cell-derived neurons exposed to etoposide-induced apoptosis.
• Analysis of cellular mechanisms including Bcl-2/Bax ratio modulation and autophagy induction via beclin 1.

Main Results:

• Several aromatic carbamate derivatives demonstrated potent neuroprotection, preserving up to 80% of neurons at 100 nM concentrations.
• The identified compounds possess desirable physicochemical properties for CNS therapeutics.
• The neuroprotective mechanism involves increasing the anti-apoptotic Bcl-2/Bax ratio and activating autophagy through beclin 1 induction, distinct from the parent scaffold's known actions.

Conclusions:

• Novel aromatic carbamates exhibit significant neuroprotective potential against apoptosis in neuronal cells.
• These compounds represent a promising new class of therapeutics for neurodegenerative diseases by targeting key cell survival pathways.
• The findings elucidate a novel mechanism of action involving Bcl-2/Bax ratio and autophagy activation.