Rh^II‐Catalyzed De‐symmetrization of Ethane‐1,2‐dithiol and Propane‐1,3‐dithiol Yields Metallo‐β‐lactamase Inhibitors

Abstract

Diversity‐oriented synthesis (DOS) is a rich source for novel lead structures in Medicinal Chemistry. In this study, we present a DOS‐compatible method for synthesis of compounds bearing a free thiol moiety. The procedure relies on Rh(II)‐catalyzed coupling of dithiols to diazo building blocks. The synthetized library was probed against metallo‐β‐lactamases (MBLs) NDM‐1 and VIM‐1. Biochemical and biological evaluation led to identification of novel potent MBL inhibitors with antibiotic adjuvant activity.

Small-molecule inhibitors of bacterial-producing metallo-β-lactamases: insights into their resistance mechanisms and biochemical analyses of their activities

“…In a dose-dependent manner, the MIC value of imipenem significantly decreased against the engineered strain of E. coli carrying the VIM-1, dropping from 32 to 1 μg mL −1 (32-fold) at an S28 concentration of 128 μg mL −1 . 104 The sub-micromolar inhibitory range of S13 also extended to VIM-type enzymes where the inhibitor was reported with K i values of 0.15, 0.41 and 0.20 μM against VIM-1, VIM-2 and VIM-4, respectively. It demonstrated a potentiation on meropenem against multiple VIM-typecarrying clinical strains, with the MIC values for K. pneumonia expressing VIM-1 and VIM-4 being reduced by more than 500-fold (from 16 to 0.03 μg mL −1 ) and P. aeruginosa expressing VIM-2 reduced by 16-fold (from 128 to 8 μg mL −1 ).…”

“…S28 also could bind to and directly inhibit MBLs. 104 S13 was reported to have a strong inhibitory effect on NDM-type enzyme ( K i value against NDM-1 of 0.03 μM), despite having a modest impact on IMP-type enzyme. Furthermore, co-treatment with S13 at a concentration of 32 μg mL −1 could potentially revive the action of meropenem, given that the MIC of meropenem against an ultra-resistant E. coli clinical strain that produces NDM-1 was reduced from 64 to 0.06 μg mL −1 (>1000-fold).…”

“…In a dose-dependent manner, the MIC value of imipenem significantly decreased against the engineered strain of E. coli carrying the VIM-1, dropping from 32 to 1 μg mL −1 (32-fold) at an S28 concentration of 128 μg mL −1 . 104…”

Preparation and Synthetic Applications of Five-to-Seven-Membered Cyclic α-Diazo Monocarbonyl Compounds

“…The S-H insertion reaction of α-diazo-γ-butyrolactams as the means of desymmetrizing symmetrical dithiols (ethane-1,2-dithiol and propane-1,3-dithiol) was later reported as an efficient strategy in constructing novel metallo-β-lactamase inhibitors [ 134 ].…”