Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators

Area of Science:

• Biochemistry
• Enzymology
• Medicinal Chemistry

Background:

• Specific human carbonic anhydrase (hCA) isoforms regulate signal processing pathways.
• Reduced hCA expression is linked to cognitive impairments, including Alzheimer's disease and aging-related dysfunction.

Purpose of the Study:

• To identify activators for human carbonic anhydrase isoforms (hCA I, II, IV, VII).
• To investigate the potential of natural and synthetic nitrogen-containing cyclic compounds as hCA modulators.
• To explore the therapeutic implications for cognitive health.

Main Methods:

• Assay of a small library of nitrogen-containing cyclic derivatives against hCA I, II, IV, and VII.
• In vitro CO₂ hydration method to determine activation constants (KAs).
• In silico molecular modeling to elucidate binding interactions.

Main Results:

• Most compounds activated hCA I, IV, and VII in the micromolar range (KAs 3.46–80.5 μM).
• Compounds showed minimal activity against hCA II (KAs > 100 μM).
• L-(+)-ergothioneine and melatonin exhibited nanomolar KAs for hCA VII, demonstrating selective activation.

Conclusions:

• Nitrogen-containing cyclic compounds can selectively activate specific hCA isoforms.
• L-(+)-ergothioneine and melatonin are potent hCA VII activators, with potential therapeutic applications for cognitive disorders.
• Molecular modeling supports the in vitro findings and provides insights into enzyme-activator interactions.