Indole-2-Carboxamide Derivatives: Synthesis and Estimation of Their Potential as Metallo-Beta-Lactamase Inhibitors

Bacterial resistance to β-lactam antibiotics is one of the key challenges in global healthcare. A major mechanism underlying this resistance is the production of β-lactamases by pathogens. These enzymes are classified into four groups (A–D), with class B metallo-β-lactamases, particularly the NDM family, posing the highest threat. These zinc-dependent enzymes are capable of inactivating nearly all β-lactam antibiotics, and to date, there are no clinically approved inhibitors for this class. Previous studies have shown that certain derivatives of indole-2-carboxylic acid, hydroxamic acids, and glycine-based compounds can inhibit NDM-1 by interacting with Zn²⁺ ions and amino acid residues within the enzyme’s active site. However, the antibacterial potential of indole-2-carboxamide derivatives of the aforementioned compounds has not yet been explored as inhibitors of metallo-β-lactamases. In the search for new candidates to develop specific metallo-β-lactamase inhibitors, a known indole-2-carboxylic acid-based NDM-1 inhibitor was modified to prepared previously undescribed analogues – indole-2-carboxamides bearing fragments derived from hydroxamic acid, glycine, and imino diacetic acid. To accomplish this, a method commonly used in peptide synthesis was adapted, employing the condensing agent PyBOP. The resulting compounds demonstrated the ability to inhibit NDM-1 in the micromolar concentration range (IC₅₀ = 20–60 µM), highlighting the significant role of the substituent at position 2 in binding to the enzyme’s active site. It was shown that modifying the carboxyl group at position 2 of the indole core with functional fragments possessing intrinsic inhibitory activity leads to a reduction in the activity of the parent indole-2-carboxylic acid derivative.

indole-2-carboxamides, indole-2-carboxylic acid, synthesis, NDM-1, metallo-β-lactamase inhibitors