Exploration of 1,2,3-triazole linked benzenesulfonamide derivatives as isoform selective inhibitors of human carbonic anhydrase

Abstract

A novel series of 1,2,3-triazole benzenesulfonamide substituted 1,3-dioxoisoindolin-5-carboxylate (7a-l) inhibitors of human α-carbonic anhydrase (hCA) was designed using a tail approach. The design method relies on the hybridization of a benzenesulfonamide moiety with a tail of 1,3-dioxoisoindoline-5-carboxylate and a zinc-binding group on a 1,2,3-triazole scaffold. Among the synthesized analogues, 2‑iodophenyl (7f, K_I of 105.00 nM and S_I of 2.98) and 2‑naphthyl (7h, K_I of 32.11 nM and S_I of 3.48) analogues (over off-target hCA I) and phenyl (7a, K_I of 50.13 nM and S_I of 2.74) and 2,6‑dimethylphenyl (7d, K_I of 50.60 nM and S_I of 3.35) analogues (over off-target hCA II) exhibited a remarkable selectivity for tumor isoforms hCA IX and XII, respectively. Meanwhile, analogue 7a displayed a potent inhibitory effect against the tumor-associated isoform hCA IX (K_I of 18.29 nM) compared with the reference drug acetazolamide (AAZ, K_I of 437.20 nM), and analogue 7h showed higher potency (K_I of 9.22 nM) than AAZ (K_I of 338.90 nM) against another tumor-associated isoform hCA XII. However, adding the lipophilic large naphthyl tail to the 1,3-dioxoisoindolin-5-carboxylate analogues increased both the hCA inhibitory and selective activities against the target isoform, hCA XII. Additionally, these analogues (7a-l) showed IC₅₀ values against the human lung (A549) adenocarcinoma cancer cell line ranging from 129.71 to 352.26 μM. The results of the molecular docking study suggested that the sulfonamide moiety fits snugly into the hCAs active sites and interacts with the Zn²⁺ ion. At the same time, the tail extension engages in various hydrophilic and hydrophobic interactions with the nearby amino acids, which affects the potency and selectivity of the hybrids.