title: Mycobacterial carbonic anhydrase inhibition with phenolic acids and esters: kinetic and computational investigations.
abstract: 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 β-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic bacterium Mycobacterium tuberculosis, Rv1248, Rv3588 and Rv3273 β-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 nucleophilic attack of the zinc hydroxide on the substrate CO2. These compounds may be considered as interesting anti-mycobacterial lead compounds.
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via A. Moro 2, I-53100 Siena, Italy. botta.maurizio@gmail.com.
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Cau
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry*; D002109:Caffeic Acids / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D002256:Carbonic Anhydrases / Q000737:chemistry*; D020134:Catalytic Domain; D003373:Coumaric Acids / Q000737:chemistry; D004952:Esters / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D011422:Propionates / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D002109:Caffeic Acids; D002257:Carbonic Anhydrase Inhibitors; D003373:Coumaric Acids; D004952:Esters; D011422:Propionates; C004999:ferulic acid; D002256:Carbonic Anhydrases; C495469:p-coumaric acid; D015032:Zinc; C040048:caffeic acid