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Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors
Author(s) -
Clima Lilia,
Craciun Bogdan Florin,
Angeli Andrea,
Petreni Andrea,
Bonardi Alessandro,
Nocentini Alessio,
Carta Fabrizio,
Gratteri Paola,
Pinteala Mariana,
Supuran Claudiu T.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000500
Subject(s) - carbonic anhydrase , gene isoform , chemistry , coumarin , in silico , squalene , enzyme , sulfonamide , biochemistry , in vitro , carbonic anhydrase ii , small molecule , active site , stereochemistry , farnesyl diphosphate farnesyltransferase , farnesyltransferase , gene , organic chemistry , prenylation
We report novel molecules incorporating the nontoxic squalene scaffold and different carbonic anhydrase inhibitors (CAIs). Potent inhibitory action, in the low‐nanomolar range, was detected against isoforms hCA II for sulfonamide derivatives, which proved to be selective against this isoform over the tumor‐associate hCA IX and XII isoforms. On the other hand, coumarin derivatives showed weak potency but high selectivity against the tumor‐associated isoform CA IX. These compounds are interesting candidates for preclinical evaluation in glaucoma or various tumors in which the two enzymes are involved. In addition, an in silico study of inhibitor‐bound hCA II revealed extensive interactions with the hydrophobic pocket of the active site and provided molecular insights into the binding properties of these new inhibitors.