Dithiocarbamates strongly inhibit the β-class carbonic anhydrases from Mycobacterium tuberculosis

A series of N-mono- and N,N-disubstituted dithiocarbamates have been investigated as inhibitors of two beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Mycobacterium tuberculosis, mtCA 1 (Rv1284) and mtCA 3 (Rv3273). Both enzymes were inhibited with efficacies between the subnanomolar to the micromolar one, depending on the substitution pattern at the nitrogen atom from the dithiocarbamate zinc-binding group. Aryl, arylalkyl-, heterocyclic as well as aliphatic and amino acyl such moieties led to potent mtCA 1 and 3 inhibitors in both the N-mono- and N,N-disubstituted dithiocarbamate series. This new class of beta-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.