Novel synthesized SLC-0111 thiazole and thiadiazole analogues: Determination of their carbonic anhydrase inhibitory activity and molecular modeling studies

Abstract In the presented work, we report the design and synthesis of novel SLC-0111 thiazole and thiadiazole analogues ( 11a–d , 12a–d , 16a–c and 17a–d ). A bioisosteric replacement approach was adopted to replace the 4-fluorophenyl tail of SLC-0111 with thiazole and thiadiazole ones, which were thereafter extended with lipophilic un/substituted phenyl moieties. All the newly synthesized SLC-0111 analogues were evaluated in vitro for their inhibitory activity towards a panel of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, II, IX and XII), using a stopped-flow CO 2 hydrase assay. All the examined isoforms were inhibited by the primary sulfonamide derivatives ( 11a–d and 12a–d ) in variable degrees with the following K I ranges: 162.6–7136 nM for hCA I, 9.0–833.6 nM for hCA II, 7.9–153.0 nM for hCA IX, and 9.4–94.0 nM for hCA XII. In particular, compounds 12b and 12d displayed 5.5-fold more potent inhibitory activity ( K I s = 8.3 and 7.9 nM, respectively) than SLC-0111 ( K I  = 45 nM) towards hCA IX. Molecular docking study was carried out for 12d within the hCA IX (PDB 3IAI ) active site, to justify its inhibitory activity.