Derivatives of Aristoquinoline Accessed through a Ritter-like Reaction.

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Organic Synthesis

Background:

• Aristoquinoline (1a) and isoaristoquinoline (1b) are alkaloids known to inhibit the α3β4 nicotinic acetylcholine receptor (nAChR).
• Understanding the structure-activity relationships of these compounds is crucial for developing novel nAChR modulators.

Purpose of the Study:

• To synthesize novel aristoquinoline and isoaristoquinoline derivatives.
• To investigate the impact of structural modifications on α3β4 nAChR inhibitory activity.
• To explore the utility of a Ritter-like reaction in constructing azabicyclic scaffolds.

Main Methods:

• A Ritter-like reaction was employed to synthesize the [3.3.1]- and [3.2.1]-azabicyclic core structures of aristoquinoline and isoaristoquinoline.
• Systematic modifications were made to the aliphatic core of the azabicyclic scaffolds.
• Imine intermediates were reduced to yield final derivative compounds.
• Inhibitory activity against α3β4 nAChRs was assessed for the synthesized compounds.

Main Results:

• The Ritter-like reaction successfully formed the target azabicyclic scaffolds.
• Modifications to the aliphatic core significantly influenced product formation, leading to exclusive [3.2.1]-azabicyclic products in some cases.
• Electronic properties of aryl nitriles did not affect product ratios or enantioselectivity.
• Several synthesized derivatives demonstrated improved inhibitory potency against α3β4 nAChRs compared to the parent compounds.

Conclusions:

• The study successfully synthesized novel aristoquinoline and isoaristoquinoline derivatives with potent α3β4 nAChR inhibitory activity.
• Structural modifications, particularly within the aliphatic core, are key to optimizing inhibitory potency.
• The Ritter-like reaction is a viable synthetic strategy for accessing these important neuroactive scaffolds.