Synthesis and Human Carbonic Anhydrase I, II, IX, and XII Inhibition Studies of Sulphonamides Incorporating Mono-, Bi- and Tricyclic Imide Moieties

Abstract

New derivatives were synthesised by reaction of amino-containing aromatic sulphonamides with mono-, bi-, and tricyclic anhydrides. These sulphonamides were investigated as human carbonic anhydrases (hCAs, EC 4.2.1.1) I, II, IX, and XII inhibitors. hCA I was inhibited with inhibition constants (Kis) ranging from 49 to >10,000 nM. The physiologically dominant hCA II was significantly inhibited by most of the sulphonamide with the Kis ranging between 2.4 and 4515 nM. hCA IX and hCA XII were inhibited by these sulphonamides in the range of 9.7 to 7766 nM and 14 to 316 nM, respectively. The structure-activity relationships (SAR) are rationalised with the help of molecular docking studies.

Keywords: SAR; anhydride; benzenesulphonamide; docking; human carbonic anhydrase inhibitors.

Figure 1

3D multiple superpositions of four α-hCAs crystal structures (high sequence alignment homology) [23]. The multiple superpositions involved the following crystal structures: 1AZM (hCA I); 1ZFQ (CA II); 3IAI (CA IX); and 1JD0 (CA XII) with the Zn ion shown as red sphere, and its coordinating residues His 94, His 96, and His 119 shown in pink. The protein backbone is shown in green [1,20].

Figure 2

Resulting designed structural element (HIT) as hCA inhibitor from the outcome of ligand and structure-based drug design (CoMFA, CoMSIA, and pharmacophore modelling) [21].

Scheme 1

Synthesis of sulphonamide derivatives 1–13 incorporating phthalic anhydride moiety to different benzene sulphonamides [22,23,24,29]. n = 0 (1, 6, 9, 10, 11, 12, and 13); n = 1 (7); n = 2 (2, 8). -(CH₂)n = para for 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, and 13; -(CH₂)n = meta for 9; -(CH₂)n = ortho for 10 in the benzene ring. X = F (5, 11); X = Cl (3, 12); X = Br (4, 13); Z = F (5) in the benzene ring of anhydride. i = glacial acetic acid; ii = stirring with heating.

Figure 3

The proposed steps of the reaction mechanism.

Figure 4

Protein ligand interactions in the 3IAI active site. (a) AAZ coordinates to the zinc ion and formed H-bond with THR 199, THR 200, and two water molecules; (b) Compound 1, the deprotonate sulphonamide binds to the zinc ion and forms H-bonds with HIS 64 (1.87 Å), and THR 199 (2.156 Å).