Indazolylketones as new multitarget cannabinoid drugs

Area of Science:

• Medicinal Chemistry
• Neuropharmacology
• Drug Discovery

Background:

• Alzheimer's disease (AD) poses a significant therapeutic challenge.
• Multitarget strategies, including cannabinoid receptor modulation, are being explored for AD.
• Existing treatments have limitations, necessitating novel therapeutic approaches.

Purpose of the Study:

• To synthesize and evaluate a novel series of indazolylketones with a multitarget profile.
• To assess the compounds' activity at cannabinoid receptors, cholinesterase (AChE/BuChE), and BACE-1.
• To investigate the neuroprotective effects and mechanisms of action in cellular models relevant to Alzheimer's disease.

Main Methods:

• Computational design and medicinal chemistry for compound development.
• In vitro synthesis and pharmacological evaluation of indazolylketones.
• Functional assays for cannabinoid receptor activity, enzyme inhibition (AChE/BuChE, BACE-1), and cellular neuroprotection studies.

Main Results:

• Successful synthesis of a new class of indazolylketones.
• Identification of compounds (5, 6) acting as CB2 cannabinoid agonists.
• Demonstrated simultaneous inhibition of butyrylcholinesterase (BuChE) and/or BACE-1 by these derivatives.

Conclusions:

• Indazolylketones represent a promising scaffold for multitarget drug development against Alzheimer's disease.
• Compounds 5 and 6 exhibit a dual mechanism of action, targeting cannabinoid receptors and key AD-related enzymes.
• This multitarget approach offers a potential therapeutic strategy for Alzheimer's disease.