Unveiling the CTX‐M‐14 Type β‐Lactamase Inhibitory Potential of Coumarin‐Linked Schiff Bases

Abstract Treatment of bacterial infections caused by Gram‐negative bacteria has been a global health challenge, with significant economic consequences. The rise of multidrug‐resistance has severely limited the treatment options. β‐Lactamases play a central role in this resistance, with CTX‐M‐14 being one of the most important variants. Keeping in view the limitations of existing antimicrobial treatments, the aim of present study was to identify new, safe and effective inhibitors targeting CTX‐M‐14 type of β‐lactamase enzyme (from K. pneumonia ). For this purpose, enzyme was produced using recombinant technology and purified via affinity chromatography. A series of 18 previously reported coumarin‐linked Schiff bases ( 1–18 ) has been evaluated against CTX‐M‐14 type β‐lactamase enzyme. Results showed promising inhibitory activity by compounds 7 , 13 , and 16 with IC 50 values ranging between 57 to 98 µM. Based on mechanistic studies, these compounds exhibited a mixed‐type of inhibition. In silico studies were also performed for these selected analogs to gain structural insights into CTX‐M‐14 enzyme‐inhibitor complex. Compounds 7 , 13 , and 16 showed binding interactions with catalytically important active site residues of CTX‐M‐14 β‐lactamase enzyme. Compounds 7 , 13 , and 16 were also analyzed for antibacterial activity against K. pneumoniae , where they exhibited weak inhibitory effects. Additionally, compounds 7 , 13 , and 16 were found to be noncytotoxic against 3T3 cells. This systematic study provides a solid base for further research on such compounds in antibacterial drug design and development.