title: 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.
mesh_terms: D000667:Ampicillin / Q000494:pharmacology; D002437:Cefazolin / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004357:Drug Synergism; D006090:Gram-Negative Bacteria / Q000201:enzymology; D006094:Gram-Positive Bacteria / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
chemical_list: D013450:Sulfones; D065093:beta-Lactamase Inhibitors; D000667:Ampicillin; D002437:Cefazolin