Screening Campaign and Docking Investigations in Identifying New Hit Compounds as Inhibitors of Human Carbonic Anhydrases Expressed In Tumour Cells

Abstract

AbstractThe tumor‐expressed human carbonic anhydrase (hCA) isoforms hCA IX and hCA XII have been extensively studied to develop anticancer agents targeting solid tumors in combined therapy. These CA  isoforms are considered key factors in controlling tumor microenvironment (TME) of cancer lines that develop high metastatic activity. Herein, we report the discovery of potent hCA IX/hCA XII inhibitors that were disclosed through a screening campaign on an in‐house collection of arylsulfonamides preliminary tested toward other hCAs. Among them, the N‐(4‐sulfamoylphenyl)naphthalene‐2‐carboxamide (12) and N‐(4‐sulfamoylphenyl)‐3,4‐dihydroisoquinoline‐2(1H)‐carbothioamide (15) proved to be the most intriguing hCA IX/hCA XII inhibitors displaying favourable selectivity ratios over widespread hCA I and hCA II isoforms. To explore their binding mode, we conducted docking studies that described the poses of the best inhibitors in the catalytic site of hCA IX and hCA XII, thus suggesting the privileged pattern of interactions. These structural findings might further improve the knowledge for a successful identification of new sulfonamides as adjuvant agents in cancer management.