Sulfonamide-Bearing Pyrazolone Derivatives as Multitarget Therapeutic Agents: Design, Synthesis, Characterization,...

Area of Science:

• Medicinal Chemistry
• Enzyme Inhibition
• Drug Discovery

Background:

• Alzheimer's disease and glaucoma are significant health concerns.
• Inhibition of cholinesterases (ChEs) and carbonic anhydrases (CAs) are key therapeutic strategies.
• Developing novel, selective inhibitors is crucial for effective treatment.

Purpose of the Study:

• To synthesize and characterize novel sulfonamide-bearing pyrazolone derivatives.
• To evaluate the in vitro and in silico inhibitory activities of these compounds against human carbonic anhydrase I and II (hCA I, hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE).
• To explore the potential of these compounds as therapeutic agents for Alzheimer's disease and glaucoma.

Main Methods:

• Synthesis of novel sulfonamide-bearing pyrazolone derivatives (compounds 1a-f and 2a-f).
• Characterization using spectroscopic and analytical techniques.
• In vitro enzyme inhibition assays for hCA I, hCA II, AChE, and BChE.
• In silico molecular docking studies using crystal structures of target enzymes.

Main Results:

• The synthesized compounds exhibited significant in vitro inhibitory activity against hCA I, hCA II, AChE, and BChE.
• Inhibition constants (K_I) ranged from 7.45 ± 0.98 nM for AChE to 135.70 ± 17.39 nM for BChE.
• Some compounds demonstrated higher potency than reference inhibitors.
• In silico studies identified potential binding sites and interactions with the target enzymes.

Conclusions:

• The novel sulfonamide-bearing pyrazolone derivatives possess promising inhibitory activities against ChEs and CAs.
• These compounds show potential as selective inhibitors for therapeutic applications in Alzheimer's disease and glaucoma.
• The findings support further development of these compounds as drug candidates.