Inhibition of the β-class carbonic anhydrases from Mycobacterium tuberculosis with carboxylic acids.
The growth of Mycobacterium tuberculosis is strongly inhibited by weak acids although the mechanism by which these compounds act is not completely understood. A series of substituted benzoic acids, nipecotic acid, ortho- and para-coumaric acid, caffeic acid and ferulic acid were investigated as inhibitors of three β-class carbonic anhydrases (CAs, EC 4.2.1.1) from this pathogen, 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 scaffold present in the carboxylic acid. mtCA 3 was the isoform mostly inhibited by these compounds (K(I)s in the range of 0.11-0.97 µM); followed by mtCA 2 (K(I)s in the range of 0.59-8.10 µM), whereas against mtCA 1, these carboxylic acids showed inhibition constants in the range of 2.25-7.13 µM. This class of relatively underexplored β-CA inhibitors warrant further in vivo studies, as they 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 or extensive multi-drug resistance.
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino (Florence), Italy.
Alfonso
A
Maresca
Daniela
D
Vullo
Andrea
A
Scozzafava
Gheorghe
G
Manole
Claudiu T
CT
Supuran
D055162:Biocatalysis; D002245:Carbon Dioxide / Q000737:chemistry / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000254:growth & development; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D002257:Carbonic Anhydrase Inhibitors; D002264:Carboxylic Acids; D020033:Protein Isoforms; D002245:Carbon Dioxide; D002256:Carbonic Anhydrases