Structure-activity relationships of 6-(heterocyclyl)-methylene penam sulfones. A new class of .BETA.-lactamase inhibitors.

Abstract

6-(Heterocyclyl)methylene penam sulfones (1) are effective beta-lactamase inhibitors and potent ampicillin and cefazolin potentiators against both Gram-positive and Gram-negative beta-lactamase producing bacteria. Several of these analogs having a pi-deficient 2-heteroaryl substituent attached to the C6-methylene position showed better inhibitory activity than clavulanic acid, Ro 15-1903, 6 beta-bromopenicillanic acid, and sulbactam against a variety of beta-lactamases. The compounds were devoid of any antibacterial activity, but in combination with ampicillin or cefazolin, exhibited synergistic activity at least equal to clavulanic acid, Ro 15-1903, 6 beta-bromopenicillanic acid or sulbactam against beta-lactamase producing strains. Structure-activity relationships for a number of compounds are described. The structure-activity relationships can be rationalized by an enzyme inhibition mechanism which we have previously proposed on the basis of methanolysis of 6-(2-pyridyl)methylene penam sulfone (1a). Two synthetic routes to prepare compounds of structural type 1 via either a Wittig reaction or an aldol condensation are reported. beta-Lactamase inhibition and MIC data are presented.