Exploration of 1,3,5-trisubstituted pyrazoline derivatives as human carbonic anhydrase inhibitors: Synthesis, biological evaluation and in silico studies

The human carbonic anhydrase (hCA) IX and XII isoforms are overexpressed in hypoxic conditions, contributing to cancer. Lack of isoform selectivity has been one of the main challenges associated with the existing drugs targeting hCAs. Hence, the development of alternative approaches, such as tail approach to develop more selective hCA IX and XII inhibitors is need of the hour. In the present work, we designed and synthesized 24 new 1,3.5-trisubstituted-pyrazoline derivatives with diverse substitutions. The synthesized analogs were evaluated for their hCA inhibitory activities against hCA I, II, IX, and XII isoforms. Among the tested compounds, derivative 8 displayed good inhibitory activity against hCA IX (Ki = 331 nM) and XII (Ki = 96.7 nM). In addition, 9a-g also exhibited some inhibitory activities against hCA IX and XII, with Kis ranging from 574–799 nM and 137–369 nM, respectively. Molecular modelling studies of compound 8 displayed metal coordination with zinc ion and hydrophobic, hydrophilic interactions with adjacent amino acid residues, and maintained stable interactions throughout 100 ns. In addition, ADMET studies demonstrated that compound 8 obeyed the Lipinski's rule of five and was found to be druggable and non-toxic. Hence, compound 8 was identified as potential lead for further development. [Display omitted] •Designed and synthesized 24 new 1,3,5-trisubstituted pyrazoline derivatives based on tail approach strategy•Compounds 8 and 9a-g exhibited good hCA inhibition towards the hCA IX and XII isoforms.•Compounds 8 and 9a-g showed selectivity towards hCA IX and XII compared to hCA I and II isoforms.•Compound 8 maintained stable interactions in the catalytic site of hCA IX and XII isoforms throughout 100 ns.•During ADMET predictions, the lead 8 obeyed the Lipinski rule of five and was found to be druggable and non-toxic.