Dihalogenated sulfanilamides and benzolamides are effective inhibitors of the three β-class carbonic anhydrases from Mycobacterium tuberculosis

Abstract

A series of halogenated sulfanilamides and halogenated benzolamide derivatives have been investigated as inhibitors of three β-carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Mycobacterium tuberculosis, mtCA 1 (Rv1284), mtCA 2 (Rv3588c) and mtCA 3 (Rv3273). All three enzymes were inhibited with efficacies between the submicromolar to the micromolar one, depending on the substitution pattern at the sulfanilamide moiety/fragment of the molecule. Best inhibitors were the halogenated benzolamides (K_Is in the range of 0.12–0.45 μM) whereas the halogenated sulfanilamides were slightly less inhibitory (K_Is in the range of 0.41–4.74 μM). This class of β-CA inhibitors may have the potential for developing antimycobacterial agents with a diverse mechanism of action compared to the clinically used drugs for which many strains exhibit multi-drug/extensive multi-drug resistance.

Keywords::

• Carbonic anhydrase
• β-carbonic anhydrase
• sulfonamide
• dihalogenated sulfanilamide/benzolamide
• enzyme inhibitor
• Mycobacterium tuberculosis