Expansion of Pyrrole-2-carboxylic Acid-Based Metallo-Β-lactamase Inhibitors: C4 Functionalization Drives Dual NDM/VIM Inhibition.

The rapid spread of metallo-β-lactamase (MBL)-mediated resistance, particularly by NDM- and VIM-type enzymes, poses a major threat to the clinical efficacy of β-lactam antibiotics. Building on our previous work, we report the design, synthesis, and evaluation of 4-substituted 3,5-diarylpyrrole-2-carboxylic acids as MBL inhibitors. Structure-activity relationship studies revealed that both the nature and position of substituents in the A and B rings, as well as functionalization at the C4 position, critically influence inhibitory activity. Notably, C4 halogenation, especially bromination, significantly enhanced inhibition of VIM-2 while maintaining activity against NDM-1. Molecular modelling supported these findings, indicating distinct binding modes and coordination patterns within the enzyme active sites. The most active compounds displayed nanomolar potency and effectively restored the activity of β-lactam antibiotics, including meropenem, against NDM- and VIM-producing resistant strains. Importantly, the compounds exhibited no detectable cytotoxicity and lacked intrinsic antibacterial activity. These results identify C4-functionalized pyrrole-2-carboxylic acids as promising dual-target MBL inhibitors for combination antibacterial therapy.