Design, synthesis, and evaluation of novel pyrrole-based hybrid organic molecules as inhibitors of antibiotic-resistant Metallo-β-lactamase enzymes

The global emergence of antimicrobial resistance (AMR), notably AMR mediated by metallo-β-lactamases (MBLs) has generated an urgent demand for novel enzyme inhibitors to restore the activity of β-lactam antibiotics. This work was focused on the search for novel pyrrole-based hybrid organic compounds with different zinc-binding groups (ZBGs), which were synthesized and characterized structurally and physiologically assessed for their capacity to inhibit the NDM-1 enzyme. The synthetic technique involves the assembly of a pyrrole backbone and its functionalization with several ZBGs such as hydroxamic acid, carboxylic acid and thiol groups. The whole characterization was performed using Fourier-transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance ( 1 H NMR), carbon-13 nuclear magnetic resonance ( 13 C NMR), and high-resolution mass spectrometry (HRMS). All compounds that were synthesized were obtained in good yields (65–81%). Biological evaluation in vitro Inhibition studies against NDM-1 revealed the inhibitory action to be strongly dependent on the type of zinc-binding group. Among the synthesized derivatives, compound 3 which contains thiol showed the highest inhibitory effect with an IC50 value of 2.8 ± 0.4 μM. For example, hydroxamic acid derivative (compound 4) had an IC50 value of 9.3 ± 0.9 μM, but the carboxylic acid derivative (compound 2) had an IC50 value of 18.5 ± 1.2 μM. The importance of zinc chelation in the mechanism of inhibition was established as the control medication without a zinc binding group showed no significant inhibition. The results of this study suggest that pyrrole-thiol hybrid compounds could be a useful starting point for the development of novel MBL inhibitors to tackle infections caused by antibiotic-resistant bacteria.