Synthesis and biological activity of AM-112 and related oxapenem analogues

Thirty five oxapenem analogues substituted with a range of tertiary groups at C-2 have been synthesised and evaluated as broad-spectrum beta-lactamase inhibitors. All analogues enhanced the activity of ceftazidime against bacterial isolates producing Class A and Class C beta-lactamases. Compounds with cyclic substituents at C-1' (attached to C-6) were associated with enhanced antibacterial activity against Staphylococcus aureus. (R) Stereochemistry at C-1' led to synergistic activity against beta-lactamase negative enterococci. (S) Stereochemistry at C-1' was associated with enhanced inhibition of Class A beta-lactamases and lack of synergistic activity against enterococci. AM-113 was unstable in serum and not detectable following subcutaneous or oral dosing in mice. AM-112 and AM-115 achieved good serum levels following subcutaneous dosing. AM-114 exhibited 30% bioavailability following oral dosing. AM-112 [(1'R,5R,6R)-2-(4-ammonio-1,1-dimethylbutyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate] achieved the greatest protection of ceftazidime against Gram-negatives producing Class A or C beta-lactamases.