Coumarin-Containing Aromatic Sulfonamides With Carbonic Anhydrase Inhibitory Properties Against Human and Fungal...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Enzymology

Background:

• Carbonic anhydrases (CAs) are crucial enzymes catalyzing CO2 hydration, involved in various physiological and pathological processes.
• CA inhibitors are vital for treating conditions like glaucoma, epilepsy, and certain cancers.
• Fungal CAs represent underexplored targets for therapeutic intervention.

Purpose of the Study:

• To synthesize and evaluate coumarin-based sulfonamides as inhibitors of human and fungal carbonic anhydrases.
• To investigate the inhibitory mechanisms of these compounds against specific CA isoforms, particularly hCA IX.
• To identify potent CA inhibitors with potential applications in medicine and antifungal therapy.

Main Methods:

• Synthesis of eighteen coumarin-based sulfonamide derivatives.
• Enzymatic assays to determine inhibitory activity against human isoforms (hCA I, hCA II, hCA IX) and fungal CAs (MgCA, MpaCA, MreCA).
• Computational docking studies to elucidate binding interactions within the hCA IX active site.

Main Results:

• Several compounds exhibited significant inhibitory activity against fungal CAs, with some exceeding the potency of acetazolamide against Malassezia globosa and Malassezia pachydermatis.
• 16 out of 18 compounds showed lower Ki values than acetazolamide against MpaCA.
• Four compounds were more potent inhibitors of hCA I than acetazolamide, and two were more potent against hCA II.
• Docking studies provided insights into the binding modes of active compounds within the hCA IX active site.

Conclusions:

• Coumarin-based sulfonamides are promising candidates for developing novel carbonic anhydrase inhibitors.
• These compounds demonstrate significant potential for targeting fungal CAs, offering new avenues for antifungal drug discovery.
• Further investigation into their therapeutic efficacy and safety profiles is warranted.