Isosteviol – A new scaffold for the synthesis of carbonic anhydrase II inhibitors

• Published in: Results in Chemistry 2024-01, Vol.7, p.101426, Article 101426
• Main Authors: Denner, Toni C., Heise, Niels V., Csuk, René
• Format: Article
• Language: English
• Subjects: Carbonic anhydrase II; Inhibitors; Isosteviol; Sulfamates
• ISSN: 2211-7156; 2211-7156
• DOI: 10.1016/j.rechem.2024.101426

[Display omitted] •Isosteviol was synthesized from renewable resource stevioside.•Isosteviol was transformed into sulfamates.•These sulfamates were screened for inhibitory activity for carbonic anhydrase CA II.•Several of them were excellent inhibitors of this enzyme.•Compound 11 showed 99.9 % inhibition and a Ki = 2.59 μM (competitive inhibitor) The diterpene isosteviol can easily be synthesized via hydrolysis from stevioside, a renewable resource adding particular utility to its potential for drug synthesis. Of late, there has been an increase in scientific studies focusing on inhibitors of the enzyme carbonic anhydrase II, CA II, since this enzyme is not used just in glaucoma treatment but also in mitigating the side effects of Alzheimer’s disease antibody therapy. The presence of a sulfamate or a sulfonamide group is a key structural feature in many CA II inhibitors. Thus, isosteviol was transformed into sulfamates, either spacered or unspacered, to scrutinize their ability to perform as CA II inhibitors. Three particular derivatives were discovered to be effective inhibitors. As a competitive inhibitor with a Ki = 2.59 μM, a 16-O-acetyl-isosteviol compound holding a 5-amino-1,3,4-thiadiazol-2-yl-amino substituent attached to a succinoyl ester nearly entirely inhibited CA II.