Investigation of carbonic anhydrase inhibitory effects and cytotoxicities of pyrazole-based hybrids carrying hydrazone and zinc-binding benzenesulfonamide pharmacophores

Pyrazole-based carbohydrazone hybrids have been considered to be a remarkable class of compounds in pharmaceutical chemistry. Here, we reported bioactivities of 4-(3-(2-(arylidene)hydrazin-1-carbonyl)-5-phenyl-1 H - pyrazol-1-yl)benzenesulfonamides ( 1 - 27 ) towards CA isoenzymes (hCA I, hCA II, hCA IX) and human oral squamous cell carcinoma cell line. Compounds 19 (Ki = 10.1 nM, hCA I/hCA IX = 749.6), 22 (Ki = 18.5 nM, hCA I/hCA IX = 429.2), 26 (Ki = 14.5 nM, hCA I/hCA IX = 596.9), 27 (Ki = 21.5 nM, hCA I/hCA IX = 413.1) were more potent and selective inhibitors of cancer -associated hCA IX isoenzyme. Compounds 22 and 26 were also found to be approximately three times more selective hCA IX inhibitors over off -target hCA II at low nanomolar. Compounds 19 , 22 , 23 , 24, and 26 with IC 50 of 1.6 -1.7 mu M showed potent cytotoxicity against human oral squamous cell carcinoma cell line as compared with human gingival fibroblast, producing the tumor -specificity value over 100. This was due to its cytostatic growth inhibition accompanied by a slight but significant dosedependent increase in cell shrinkage and subG1 cell accumulation and marginal activation of caspase 3 substrates. Bioassay results showed that carbohydrazone-based hybrids could be useful candidates to design novel anticancer compounds and selective carbonic anhydrase inhibitors.

Journal

BIOORGANIC CHEMISTRY

Year

2022

Volume

127

ISSN

0045-2068

eISSN

1090-2120

DOI

10.1016/j.bioorg.2022.105969

WoS UID

WOS:001234545800001