Mycobacterial carbonic anhydrase inhibition with phenolic acids and esters: kinetic and computational investigations

A series of phenolic acids and some of their esters, derivatives of caffeic, ferulic, and p-coumaric acid, was investigated for the inhibition of three beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic bacterium Mycobacterium tuberculosis, Rv1248, Rv3588 and Rv3273 beta-CAs. Some of these compounds were low micromolar inhibitors of the pathogenic enzymes and they did not show inhibitory activity against the human widespread cytosolic isoforms CA I and II. The binding mode of these inhibitors to two of the bacterial enzymes was investigated by computational approaches. We propose that the inhibitors anchor to the zinc-coordinated water molecule from the CA active site interfering with the nucteophilic attack of the zinc hydroxide on the substrate CO2. These compounds may be considered as interesting anti-mycobacterial lead compounds.