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

08:00 EDT 3rd April 2019 | BioPortfolio

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

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 isoforms (hCA I, II, IX and XII), using a stopped-flow CO 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 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 (Ks = 8.3 and 7.9 nM, respectively) than SLC-0111 (K = 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.


Journal Details

This article was published in the following journal.

Name: Bioorganic chemistry
ISSN: 1090-2120
Pages: 794-802


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