Sulfonamide bearing pyrazolylpyrazolines as potent inhibitors of carbonic anhydrase isoforms I, II, IX and XII.
Bioorg Med Chem Lett, 2015/8/15;25(16):3208-12.
Khloya P[1], Ceruso M[2], Ram S[1], Supuran CT[3], Sharma PK[4]
Affiliations
PMID: 26105196
Impact factor: 2.94
Abstract
A series of pyrazolylpyrazolines was designed, synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against cytosolic human (h) isozymes hCA I and hCA II as well as transmembrane tumor associated isozymes, hCA IX and hCA XII. All the tested compounds exhibited an excellent CA activity profile against hCA I, hCA II and hCA XII when compared to the reference drug acetazolamide (AZA). Compounds 6d, 6f and 7a-7f have exhibited better inhibition profile against hCA XII (Ki = 0.47-5.1 nM) as compared with AZA (Ki = 5.7 nM) especially, compounds 6a, 7a, 7c and 7d which were nearly 10-fold better than reference drug. Against hCA II, all of the tested compounds were better than the standard drug especially compounds 6c, 6d, 7c and 7d (Ki = 1.1-1.7 nM) were many fold better inhibitors than AZA (Ki = 12.1 nM). In addition, they acted as selective CA inhibitors of isoform hCA XII over the physiological isoform hCA I.
Keywords: Acetazolamide; Carbonic anhydrase isoforms I, II, IX, XII; Pyrazoles
MeSH terms
Acetazolamide; Antigens, Neoplasm; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase IX; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Cytosol; Humans; Isoenzymes; Magnetic Resonance Spectroscopy; Neoplasms; Structure-Activity Relationship; Sulfonamides
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