Development of benzene and benzothiazole-sulfonamide analogues as selective inhibitors of the tumor-associated carbonic anhydrase IX

• Published in: European journal of medicinal chemistry 2022-12, Vol.243, p.114793-114793, Article 114793
• Main Authors: Manzoor, Shoaib, Angeli, Andrea, Zara, Susi, Carradori, Simone, Rahman, Md Ataur, Raza, Md Kausar, Supuran, Claudiu T., Hoda, Nasimul
• Format: Article
• Language: English
• Subjects: Anti-proliferative; Benzene and benzothiazole-sulfonamide; Carbonic anhydrase inhibitors; Molecular docking; Selective hCA IX inhibition
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114793

With an aim to develop novel potential antitumor agents, two series of benzene- and benzothiazole-sulfonamide derivatives, acting as effective human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors, have been developed using the tail approach. The synthesized compounds (XS-1 to XS-22) were assayed for the inhibition of physiologically relevant isoforms of hCA, the cytosolic CA I and II, the membrane-bound CA IV and tumor-associated CA IX. It was found the compounds of both series displayed low to medium nanomolar range inhibition against CA I, II and IX, and weak inhibition against CA IV. Some of the derivatives displayed selective inhibition towards tumor-associated CA IX isoform, within the nanomolar range. These potent compounds were also screened for their selective toxicity to evaluate their in vitro anti-proliferative effects on Human Gingival Fibroblasts (HGFs) and breast adenocarcinoma cell line (MCF7). Lastly, molecular docking studies were carried out to explain those structural requirements that were liable for the discrimination among selected human carbonic anhydrase isoforms. [Display omitted] •Two series of benzene- and benzothiazole-sulfonamide derivatives were designed and synthesized.•Compounds XS-1 to XS-22 were tested for carbonic anhydrase inhibitory activity against hCA I, II, IV and XII.•Compounds XS-3, XS-14, XS-15, XS-16 and XS-22 were selective against the tumor associated isoforms hCA IX.•Compounds XS-3, XS-14, XS-15, XS-16 and XS-22 displayed good biocompatibility against non-tumor cells at 50 μM.•Compounds XS-3, XS-14, XS-15, XS-16 and XS-22 were also screened for antiproliferative effect against cancer cells in association to doxorubicin.