Carbonic Anhydrase Activity Modulators: Synthesis of Inhibitors and Activators Incorporating 2-substituted-thiazol-4-yl-methyl Scaffolds

Abstract

A small series of 2-[4-(4-substituted-phenylsulfonyl)-phenyl]-4-chloromethylthiazoles has been used as a scaffold for the preparation of carbonic anhydrase (CA) inhibitors and activators. For obtaining CA inhibitors, zinc-binding functions of the sulfamide and sulfamate type have been introduced into the molecules of these compounds, by reaction of the chloromethyl derivatives with sodium sulfamide/sodium sulfamate. For obtaining CA activators, the primary amino function has been introduced in these molecules by means of the Gabriel syntheses. The new sulfamide/sulfamates were effective CA II and CA IV inhibitors, but showed no inhibitory activity against isozyme I. The new amines on the other hand were much more effective CA I, II and IV activators compared to histamine, the lead compound used for their synthesis.

Key Words:

• Carbonic anhydrase
• Thiazole
• Sulfamide
• Sulfamate
• Amine
• Histamine