Discovery of Symmetrical o-Methylpyridine Substituted Tertiary Amines and Dy(III) Complexes as Metallo-β-Lactamase Inhibitor and Antimicrobial.

Due to the lack of metallo-β-lactamase (MβL) inhibitors for clinical purposes, the antibiotic resistance mediated by MβL poses a clear threat to public health. In this work, twelve symmetrical o-methylpyridine substituted tertiary amines P1-P6 and their Dy(III) complexes D1-D6 were synthesized, characterized, and confirmed. Nine compounds displayed inhibitory activity against MβLs from subclasses B1, B2, and B3. Encouragingly, D2 and D6 exhibited dual inhibitory activity targeting both imipenem-hydrolyzing MβL S (ImiS) and MβL L1 (L1). Mechanistic studies uncovered P2 exerted a competitive inhibition mode on New Delhi MβL-1 (NDM-1), while D6 showed a noncompetitive inhibition mode against ImiS and L1. Microbiological assays indicated the obtained inhibitors could restore the antibacterial activity of cefazolin and meropenem against six bacterial strains, including resistant ones, while P4, D1, and D6 alone exhibited bactericidal effect. Cytotoxicity assays showed the tested inhibitors performed a reasonable biological toxicity against L929 cells. Docking simulation reveals a molecular-level rationale for the dual-target inhibitory activity of D2, indicating the introduction of Dy(III) can regulate the inhibitory activity against both ImiS and L1. In short, the study demonstrate o-methylpyridine substituted tertiary amines and their Dy(III) complexes are promising scaffolds for the development of MβLs inhibitors and antibacterial agents.