Novel benzofuran-based sulphonamides as selective carbonic anhydrases IX and XII inhibitors: synthesis and in vitro biological evaluation

Mohamed A Abdelrahman,Wagdy M Eldehna,Alessio Nocentini,Hany S Ibrahim,Hadia Almahli,Hatem A Abdel-Aziz,Sahar M Abou-Seri,Claudiu T Supuran

doi:10.1080/14756366.2019.1697250

Abstract

Pursuing on our efforts toward searching for efficient hCA IX and hCA XII inhibitors, herein we report the design and synthesis of new sets of benzofuran-based sulphonamides (4a,b, 5a,b, 9a–c, and 10a–d), featuring the zinc anchoring benzenesulfonamide moiety linked to a benzofuran tail via a hydrazine or hydrazide linker. All the target benzofurans were examined for their inhibitory activities toward isoforms hCA I, II, IX, and XII. The target tumour-associated hCA IX and XII isoforms were efficiently inhibited with K Is spanning in ranges 10.0–97.5 and 10.1–71.8 nM, respectively. Interestingly, arylsulfonehydrazones 9 displayed the best selectivity toward hCA IX and XII over hCA I (SIs: 39.4–250.3 and 26.0–149.9, respectively), and over hCA II (SIs: 19.6–57.1 and 13.0–34.2, respectively). Furthermore, the target benzofurans were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Only benzofurans 5b and 10b possessed selective and moderate growth inhibitory activity toward certain cancer cell lines.

Highlights

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes, present in all kingdoms life, catalyse the reversible reaction of the hydration of carbon dioxide to bicarbonate and protons1
In continuation to our previous effort in the search for efficient hCA IX and hCA XII inhibitors25–27, we report the design and synthesis of new sets of benzofuran-based sulphonamides (4a,b, 5a,b, 9a–c, and 10a–d, Figure 1), featuring the zinc
Reaction courses and product mixtures were routinely monitored by thin layer chromatography (TLC) that carried out using glass sheets pre-coated with silica gel 60 F254 purchased by Merk

Summary

Introduction

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes, present in all kingdoms life, catalyse the reversible reaction of the hydration of carbon dioxide to bicarbonate and protons. Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes, present in all kingdoms life, catalyse the reversible reaction of the hydration of carbon dioxide to bicarbonate and protons1 This simple reaction play a vital role in many physiological and pathological processes associated with pH control, ion transport, and fluid secretion. It is well established that these metalloenzymes possess a significant role in several pathological processes. It is well established that these metalloenzymes possess a significant role in several pathological processes1,8–10 Modulators of these enzymes could be used as diuretics, anti-glaucoma agents, anti-epileptics, and more recently as antitumor agents. The human (h) isoform CA IX is ectopically expressed in hypoxic tumours, acting as a key player in cancer cells survival, proliferation, and metastasis, and its inhibition has been suggested as a promising strategy for treatment of human malignancies

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Conclusion