A series of ureas was prepared by reacting mono- or di- isocyanates with 3-amino-1H-1,2,4-triazole derivatives. The new carboxamides were investigated as activators of two human (h) carbonic anhydrases (CAs, EC 4.2.1.1), the physiologically relevant isoforms hCA I and II, considering the fact that they have structural resemblance to histamine, a well-known CA activator. Highly effective activators were detected in the series, with potency in the low nanomolar and subnanomolar range, depending on the substitution pattern at the 1,2,4-triazole ring and the nature of the linker between the two heterocyclic rings, in the case of the diureas. The most effective hCA II activator (KA of 0.05nM) ever reported has been evidenced in this study. Although CA activators do not have pharmacological applications for the moment, in animal models it has been shown that they enhance cognition, making them interesting for conditions in which CA activity is diminished, such as aging or Alzheimer's disease.
Keywords: 1,2,4-triazole; Activator; Carbonic anhydrase; Histamine; Ureas.
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