Synthesis and biological evaluation of coumarin-thiazole hybrids as selective carbonic anhydrase IX and XII...

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Cancer Biology

Background:

• Human carbonic anhydrases (hCAs) IX and XII are implicated in various cancers.
• Selective inhibition of these isoforms is a therapeutic strategy for cancer treatment.

Purpose of the Study:

• To synthesize and evaluate novel coumarin-linked thiazoles for their inhibitory activity against hCA IX and hCA XII.
• To identify potent and selective inhibitors for potential anticancer drug development.

Main Methods:

• Synthesis of a series of coumarin-linked thiazole compounds (6a-p).
• In vitro evaluation of inhibitory activity against purified human carbonic anhydrase IX and XII.
• Determination of inhibition constants (K_i) and docking studies for lead compounds.

Main Results:

• All synthesized compounds demonstrated selective inhibition against both hCA IX and hCA XII.
• Inhibition of hCA IX was observed in the moderate nanomolar to submicromolar range.
• hCA XII inhibition occurred in the low to moderate nanomolar range, with compound 6o showing the best activity (K_i = 91.1 nM).
• Docking studies of compound 6o's hydrolyzed form revealed favorable interactions with both hCA isoforms.

Conclusions:

• Coumarin-linked thiazoles are effective inhibitors of hCA IX and hCA XII.
• Compound 6o is a potent and selective inhibitor of hCA XII.
• Compound 6o serves as a promising template for developing novel anticancer therapeutics targeting hCA XII.