Tetrazole Derivatives as Multiclass Inhibitors of Bacterial Carbonic Anhydrases

This study investigates derivatives including a tetrazole zinc-binding group as inhibitors of the α-, β-, and γ-class carbonic anhydrase (CA) isoforms from pathogenic bacteria such as Vibrio cholerae, Escherichia coli, and Streptococcus mutans. A library of 22 previously synthesized compounds was evaluated for their inhibitory activity against bacterial CAs using a stopped-flow CO₂ hydrase assay. The tetrazole-based inhibitors displayed marked activity toward bacterial α- and β-class CAs, with inhibition constants (K_Is) ranging from 0.43 to 18.7 µM. Among them, 2i and 2p emerged as two of the most potent inhibitors. Selectivity studies showed that only a few compounds exhibited moderate (10- to 20-fold) selectivity for bacterial β-CAs over human CA I, with limited selectivity against human CA II. Molecular modelling studies of the most representative compounds elucidated the key interactions responsible for their potency and selectivity, in agreement with experimental findings. Overall, these results highlight tetrazole derivatives as promising scaffolds for the development of novel antibacterial CA inhibitors.