Alkynyl-coumarinyl ethers as MAO-B inhibitors

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Organic Synthesis

Background:

• Monoamine oxidase B (MAO-B) is a key enzyme in neurotransmitter metabolism, implicated in neurological disorders.
• Developing selective MAO-B inhibitors is crucial for therapeutic interventions.
• Coumarin derivatives offer a versatile scaffold for drug design.

Purpose of the Study:

• To synthesize and evaluate novel alkynyl-coumarinyl ethers as potential MAO-B inhibitors.
• To explore the structure-activity relationships of these compounds.
• To identify potent and selective inhibitors for MAO-B.

Main Methods:

• Synthesis of 31 new coumarin derivatives using the Mitsunobu reaction.
• Optimization of alkynyloxy chain length, position, and substituents at position 3.
• Inhibition assays to determine potency (IC₅₀) and selectivity against MAO-A and MAO-B.

Main Results:

• A hex-5-ynyloxy chain at position 7 proved advantageous for inhibitory activity.
• Compound 36 exhibited dual inhibition of MAO-A and MAO-B (IC₅₀ < 10 nM).
• Compound 44 demonstrated high potency against MAO-B (IC₅₀ = 3.0 nM) and excellent selectivity (>3400-fold).

Conclusions:

• Alkynyl-coumarinyl ethers represent a promising class of MAO-B inhibitors.
• Specific structural modifications, such as the 7-hex-5-ynyloxy chain and position 3 substituents, enhance potency and selectivity.
• Compound 44 is a highly potent and selective MAO-B inhibitor with therapeutic potential.