Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII

Abstract

a b s t r a c tNew series of benzenesulfonamide derivatives incorporating pyrazole and isatin moieties were prepared using celecoxib as lead molecule. Biological evaluation of the target compounds was performed against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely against the human isoforms hCA I, II (cytosolic), IX and XII (transmembrane, tumor-associated enzymes). Most of the tested compounds efficiently inhibited hCA I, II and IX, with K I s of 2.5e102 nM, being more effective than the reference drug acetazolamide. Compounds 11e, 11f, 16e and 16f were found to inhibit hCA XII with Ki of 3.7, 6.5, 5.4 and 7.2 nM, respectively. Compounds 11e and 16e, with 5-NO 2 substitution on the isatin ring, were found to be selective inhibitors of hCA IX and hCA XII. Docking studies revealed that the NO 2 group of both compounds participate in interactions with Asp132 within the hCA IX active site, and with residues Lys67 and Asp130 in hCA XII, respectively.

Pharmaceutical and medicinal significance of sulfur (SVI)-Containing motifs for drug discovery: A critical review

“…36) showed good carbonic anhydrases inhibition to the cell lines hCA IX (K i ¼ 15.7 and 7.4 nM, respectively) and hCA XII (K i ¼ 3.7 and 5.4 nM, respectively). The SAR studies suggested that the presence of EWGs (NO 2 ) on the phenyl ring to increased the activity and sulphonamide played a major role in the enhancing the CA activity [231]. In 2014, Tiangong and co-workers developed compound (307 and 308) (Fig.…”

3-Hydrazinoindolin-2-one derivatives: Chemical classification and investigation of their targets as anticancer agents

“…Ibrahim et al [59] was responsible for the synthesis of different isatin-pyrazole benzenesulfonamide hybrids 39 as inhibitors of tumor-associated carbonic anhydrases M A N U S C R I P T…”

Synthesis and Antimicrobial Study of Novel 1‐Benzylated Water‐Soluble Isatin‐3‐hydrazones

“…They are shown to act as caspases‐3 and ‐7 inhibitors, antitubercular, [ ][ ] antileukemia and antimicrobial agents [ ][ ] ( Figure ). The analysis of works on design and target synthesis of biologically active isatin‐3‐acylhydrazones showed a strong dependence of the type and level of activity on the structure of the functional substituent in the hydrazone fragment . However, despite the large number of such studies, the problem of solubility of the target compounds in biorelevant solvents remains urgent.…”