4-Functionalized 1,3-diarylpyrazoles bearing benzenesulfonamide moiety as selective potent inhibitors of the tumor associated carbonic anhydrase isoforms IX and XII

• Library of 4-functionalized 1,3-diarylpyrazoles was synthesized.
• Compounds were screened against hCA isoforms I, II, IX and XII.
• Tested compounds showed excellent, low nanomolar affinity for CA isozymes.
• Some of the tested compounds showed high degree of selectivity for hCA IX and XII.

A library of 4-functionalized 1,3-diarylpyrazoles (3a–3h, 5a–5g and 6a–6g) was designed, synthesized and evaluated against four human carbonic anhydrase (CA, EC 4.2.1.1) isozymes representing two cytosolic isozymes hCA I and hCA II, and two transmembrane tumor associated ones, hCA IX and hCA XII. All the twenty two tested compounds exhibited excellent CA activity profile against the four CA isozymes when compared to the reference drug acetazolamide. Six of the tested compounds (3a–3b, 3f, 3h, 6a and 6b) displayed low nanomolar affinity (Ki < 5 nM) for hCA IX whereas seven compounds (3a–3b, 3d–3f, 3h and 6f) displayed Ki < 10 nM against hCA XII. In addition, they acted as selective CA inhibitors of isoforms IX and XII over the physiological isoforms I and II.

Newly synthesized 4-functionalized pyrazoles exhibited excellent activity profile against carbonic anhydrase isozymes hCA I, II, IX and XII.Figure optionsDownload as PowerPoint slide