Tricyclic Isatin Derivatives as Anti-Inflammatory Compounds with High Kinase Binding Affinity.

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Neuroscience

Background:

• Oximes possess diverse pharmaceutical properties, including anticancer, anti-inflammatory, and neuroprotective activities.
• Many oximes function as kinase inhibitors, targeting various signaling pathways implicated in disease.

Purpose of the Study:

• To synthesize and evaluate novel oxime derivatives of tricyclic isatins for their anti-inflammatory effects.
• To assess the kinase binding affinity of these compounds.
• To explore their potential as therapeutic agents for neurodegenerative diseases.

Main Methods:

• Synthesis of a panel of tricyclic isatin oxime derivatives.
• Evaluation of inhibition of lipopolysaccharide (LPS)-induced inflammatory responses in monocytic cell lines (THP-1Blue and MonoMac-6).
• Determination of binding affinity to various kinases and molecular modeling studies.

Main Results:

• Compounds 5a and 5d significantly inhibited LPS-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity and interleukin-6 (IL-6) production.
• These compounds also reduced the production of other pro-inflammatory cytokines (IL-1α, IL-1β, MCP-1, TNF).
• Compounds 5a and 5d exhibited nanomolar/submicromolar binding affinity to multiple kinases, including DYRK1A, DYRK1B, PIM1, and others.

Conclusions:

• Tricyclic isatin oximes, particularly compounds 5a and 5d, demonstrate potent anti-inflammatory activity.
• These compounds show promise as kinase inhibitors with potential therapeutic applications.
• The findings suggest that these oximes could be developed into anti-inflammatory drugs with neuroprotective effects for neurodegenerative diseases.