Design and synthesis of pyrrolidine derivatives with dual inhibitory activity of SBLs and MBLs and reversal of drug-resistant bacterial activity

In this study, 17 new unreported pyrrolidine derivatives 5a-5p, 6awere synthesized in a fully synthetic manner using the FDA-approved drug captopril as the basic structure, and the antimicrobial activity was tested in vitro against clinically isolated Klebsiella pneumoniae carrying the New Delhi metal beta lactamase (NDM-1) gene and Gram-negative E. coli carrying the Klebsiella pneumoniae carbacyticase-2 (KPC-2) gene. The results showed that 5jcould reduce the minimum inhibitory concentration (MIC) of meropenem (MEM) against clinically isolated Klebsiella pneumoniae containing NDM-1 to 32 μg·mL^-1, which was better than that of the positive drug captopril; 5l, 5m, and 5oreduce the MIC of MEM against KPC-2-containing Gram-negative E. coli to 2 μg·mL^-1, which was better than that of the positive drug captopril; the virtual molecular docking results of some pyrrolidine derivatives suggested the possible binding mode of pyrrolidine derivatives to NDM-1 and KPC-2.