Structural Advances in Non-Sulfonamide Carbonic Anhydrase Inhibitors: Insights Into Design, Bioactivity, and Binding...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Enzymology

Background:

• Carbonic anhydrases (CAs) are metalloenzymes vital for physiological processes like pH regulation and respiration.
• Dysregulation of human CA (hCA) isoforms (I, II, IX, XII) is linked to diseases including glaucoma, epilepsy, obesity, and cancer.
• Existing sulfonamide inhibitors have limitations, driving the search for novel therapeutic agents.

Purpose of the Study:

• To review the latest advancements in non-sulfonamide carbonic anhydrase inhibitors.
• To explore the chemical diversity, binding modes, and structure-activity relationships of emerging CA inhibitor scaffolds.
• To guide the rational design of selective and effective non-sulfonamide CA inhibitors for clinical applications.

Main Methods:

• Comprehensive literature review of recent studies on non-sulfonamide CA inhibitors.
• Analysis of chemical structures and diversity of inhibitors including phenols, carboxylic acids, coumarins, dithiocarbamates, and polyamines.
• Examination of X-ray crystallography and computational modeling data to understand binding mechanisms.

Main Results:

• Identified diverse non-sulfonamide scaffolds with potential as CA inhibitors.
• Elucidated novel binding modes distinct from traditional sulfonamide interactions.
• Highlighted structure-activity relationships for various chemical classes.

Conclusions:

• Non-sulfonamide inhibitors represent a promising alternative to sulfonamides for targeting CA isoforms.
• Advances in structural biology and computational methods facilitate the design of selective inhibitors.
• Further research is warranted for the clinical development of these novel CA inhibitors.