Synthesis of novel bisindolylmethanes: New carbonic anhydrase II inhibitors, docking, and 3D pharmacophore studies

• Synthesis of 45 sulfonamide derivatives of bisindolylmethane.
• In-vitro carbonic anhydrase II inhibitory activity.
• Docking studies were carried out to confirm binding of active compounds with enzyme.
• Pharmacophore studies done to identify contribution of bisindolylmethane moiety.

In this study, 45 bisindolylmethanes having sulfonamide moiety had been synthesized through 3 steps. In vitro assay for inhibition of carbonic anhydrase showed that some of the compounds having sulfonamide moiety are capable of inhibiting carbonic anhydrase II. Bisindoles having halogens at fifth position showed better inhibitory activity as compared to unsubstituted bisindoles. The results obtained from in vitro inhibitory activity were subjected through 3D QSAR and docking studies to identify important features contributing to the activity and further improve the structure. Pharmacophore studies suggest that bisindolylmethane moiety is contributing significantly towards the inhibition activity. Docking studies showed that compounds having nitro substituent (5g and 5i) were found to be able interact with Zn2+ ion, Thr199, His94, His96, and His119, which interferes with the ZnOHThr199Glu106 hydrogen bond network. Bulky nitro substituent at ortho position for compound 5g prevents the compound from interacting with other residues like Thr199 and Thr200. Methyl substituent at ortho position for Compound 5i induces less steric hindrance effect, thus allowing second oxygen atom of sulfonamide to interact with Thr199 (2.51 Å). Hydrogen bonding between NH on indole ring with Glu69 might have increased stability of ligand-receptor complex.

Synthesis and carbonic anhydrase inhibition activity of novel bisindolylmethane derivatives (3a–5o).Figure optionsDownload as PowerPoint slide