(Hetero-)(arylidene)arylhydrazides as Multitarget-Directed Monoamine Oxidase Inhibitors

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Enzyme Inhibition

Background:

• Monoamine oxidases (MAOs) and acetylcholinesterase (AChE) are key enzymes implicated in neurodegenerative diseases.
• Developing novel inhibitors targeting these enzymes is crucial for therapeutic intervention.
• Arylhydrazide derivatives represent a promising class of compounds for drug discovery.

Purpose of the Study:

• To synthesize novel (hetero-)(arylidene)arylhydrazide derivatives.
• To evaluate the inhibitory potential of these derivatives against MAO-A, MAO-B, and AChE.
• To identify lead compounds for potential multitarget inhibitors for neurodegenerative disorders.

Main Methods:

• Synthesis of fourteen (hetero-)(arylidene)arylhydrazide derivatives (ABH1-ABH14).
• In vitro enzymatic assays to determine IC50 values for MAO-A, MAO-B, and AChE inhibition.
• Determination of selectivity indices (SI) for MAO-B over MAO-A.
• Enzyme kinetics studies to elucidate the inhibition mechanism of lead compounds.

Main Results:

• Compound ABH5 demonstrated potent inhibition of MAO-B (IC50 = 0.025 μM) and AChE (IC50 = 16.5 μM).
• Compounds ABH2 and ABH3 also showed significant MAO-B inhibition.
• ABH2 exhibited the highest selectivity index (SI = 174) for MAO-B, followed by ABH5 (SI = 132).
• ABH5 acted as a reversible competitive inhibitor for both MAO-A and MAO-B.

Conclusions:

• The synthesized arylhydrazide derivatives show promising inhibitory activity against MAO-B and AChE.
• Compound ABH5 is identified as a potent and selective MAO-B inhibitor with dual activity against AChE.
• ABH5 represents a valuable candidate for further development as a multitarget therapeutic agent for neurodegenerative diseases.