Synthesis and biological evaluation of histamine Schiff bases as carbonic anhydrase I, II, IV, VII, and IX activators

Abstract

A series of 20 histamine Schiff base was synthesised by reaction of histamine, a well known carbonic anhydrase (CA, E.C 4.2.2.1.) activator pharmacophore, with substituted aldehydes. The obtained histamine Schiff bases were assayed as activators of five selected human (h) CA isozymes, the cytosolic hCA I, hCA II, and hCA VII, the membrane-anchored hCA IV and transmembrane hCA IX. Some of these compounds showed efficient activity (in the nanomolar range) against the cytosolic isoform hCA VII, which is a key CA enzyme involved in brain metabolism. Moderate activity was observed against hCA I and hCA IV (in the nanomolar to low micromolar range). The structure-activity relationship for activation of these isoforms with the new histamine Schiff bases is discussed in detail based on the nature of the aliphatic, aromatic, or heterocyclic moiety present in the aldehyde fragment of the molecule, which may participate in diverse interactions with amino acid residues at the entrance of the active site, where activators bind, and which is the most variable part among the different CA isoforms.

Keywords: Alzheimer’s disease; Carbonic anhydrase activators; Schiff bases; histamine; isozymes.

Figure 1.

Superimposed ribbon diagram (a) and active site detail (b) of the CA II isozyme (PDB codes 1AVN and 3HS4³⁷) with the activator histamine and the well known CAI 5-acetamido-1,3,4-thiadiazole-2-sulphonamide (acetazolamide, AZM). Acetazolamide is coordinated to the zinc ion being bound deep within the active site, whereas histamine does not interact with the metal ion and is bound at the entrance of the cavity. The zinc ion (magenta) is coordinated by three histidine residues (His 94, His 96, and His 119, in orange) and some key amino acids on active site were shown (in red). The proton shuttle residue His 64 is also shown (in cyan). Figure made using PyMol (DeLano Scientific).

Scheme 1.

General synthetic route for the synthesis of histamine Schiff bases H(1–20).