Structure–activity relationships for the interaction of 5,10-dihydroindeno[1,2-b]indole derivatives with human and bovine carbonic anhydrase isoforms I, II, III, IV and VI

• DOI: 10.1016/j.ejmech.2011.12.022
• Publication Date: 2011-12-20T13:25:24Z
• Authors: Deniz Ekinci; Hüseyin Çavdar; Serdar Durdagi; Oktay Talaz; Murat Şentürk; Claudiu T. Supuran
• Keywords: Models, Molecular; 0301 basic medicine; Sulfonamide inhibitor; Carbonic anhydrase; Indoles; Animals, Carbonic Anhydrase Inhibitors; chemistry/pharmacology, Carbonic Anhydrases; metabolism, Cattle, Humans, Indoles; chemistry/pharmacology, Models; Molecular, Protein Isoforms; metabolism, Structure-Activity Relationship; 540; Docking; Structure-Activity Relationship; 03 medical and health sciences; Indole; Animals; Humans; Protein Isoforms; Cattle; Phenol inhibitor; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases

Several 5,10-dihydroindeno[1,2-b]indole derivatives incorporating methoxy, hydroxyl, and halogen (F, Cl, and Br) moieties on the indene fragment of the molecule were prepared and tested against five carbonic anhydrase (CA, EC 4.2.1.1) isoforms. The inhibitory potencies of these compounds against the human (h) isoforms hCA I, II, IV, VI and bovine (b) isoform bCA III were assessed. Most of them exhibited low micromolar inhibition of these enzymes. K(I) values of these compounds against hCA I and hCA II were in the range of 2.14-16.32 μM, and 0.34-2.52 μM, respectively. Isozyme hCA IV was inhibited with K(I)-s in the range of 0.435-5.726 μM, while hCA VI with K(I)-s of 1.92-12.84 μM bCA III was inhibited with K(I)-s in the range of 2.13-17.83 μM. The structurally related compounds, 1,2-dimethoxybenzene, catechol and indole were also tested in order to understand the structure activity relationship. In silico docking studies of some derivatives within the active site of hCA I and II were also carried out in order to rationalize the inhibitory properties of these compounds and understand their inhibition mechanism.