β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

Abstract

The diazabicyclooctane (DBO) scaffold is the backbone of non-β-lactam-based second generation β-lactamase inhibitors. As part of our efforts, we have synthesized a series of DBO derivatives A1–23 containing amidine substituents at the C2 position of the bicyclic ring. These compounds, alone and in combination with meropenem, were tested against ten bacterial strains for their antibacterial activity in vitro. All compounds did not show antibacterial activity when tested alone (MIC >64 mg/L), however, they exhibited a moderate inhibition activity in the presence of meropenem by lowering its MIC values. The compound A12 proved most potent among the other counterparts against all bacterial species with MIC from <0.125 mg/L to 2 mg/L, and is comparable to avibactam against both E. coli strains with a MIC value of <0.125 mg/L.

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

“…Amidine substituted DBOs: Our group synthesized the amidine derivative of avibactam by replacing its amide group at the C2 of the DBO ring. The amidine-substituted derivative was further modified by reacting the NH 2 group of the amidine moiety with numerous functionalities [82][83][84][85][86][87]. Amidine derivatives 79 and 82 were the key intermediates for the synthesis of the target compounds.…”

“…The synthesis of intermediate 82 started from 78 via the palladium-catalyzed hydrogenation of the benzyl ether using EtOAc/CH 2 Cl 2 as a solvent mixture leading to hydroxy compound 80 [88]. The hydroxyl group in 80 was then protected by TBS using tert-butyldimethylsilyl chloride in the presence of imidazole, and the resulting compound 81 was subjected to the aforementioned Garigipati conditions to form the target compound 82 (Scheme 15) [82,83].…”