title: Synthesis of new C-6 alkyliden penicillin derivatives as beta-lactamase inhibitors.
abstract: New penicillin, penicillin sulfone and sulfoxide derivatives bearing a C-6-alkyliden substituent were prepared. Their chemical synthesis, in vitro antibacterial activity and inhibition properties against two selected enzymes representing Class A and C beta-lactamases are reported. Compounds 3a-c, 7a-c were able to inhibit either TEM-1 (a Class A enzyme, from Escherichia coli) or P-99 (a Class C enzyme, from E. cloacae), or both enzymes, when tested in competition experiments using nitrocefin as the reporter substrate. However, when tested in combination with amoxicillin, the same compounds did not show synergistic effects against E. coli and E. cloacae strains producing TEM-1 and P99 enzymes, respectively. This finding is most likely related to poor penetration through the bacterial cell wall, as shown by using a more permeable isogenic E. coli strain. Interestingly, a synergistic effect against a strain of S. aureus which produces PC1-enzyme (a Class A beta-lactamase) was observed for compound 3a when used in combination with amoxicillin.
authors: Istituto di Chimica Farmaceutica, Università di Urbino, Italy. barbara@uniurb.it
authors: B
authors: B
authors: Di Giacomo
authors: G
authors: G
authors: Tarzia
authors: A
authors: A
authors: Bedini
authors: G
authors: G
authors: Gatti
authors: F
authors: F
authors: Bartoccini
authors: C
authors: C
authors: Balsamini
authors: A
authors: A
authors: Tontini
authors: W
authors: W
authors: Baffone
authors: E
authors: E
authors: Di Modugno
authors: A
authors: A
authors: Felici
mesh_terms: D000658:Amoxicillin / Q000494:pharmacology; D004347:Drug Interactions; D016972:Enterobacter cloacae / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D010397:Penicillanic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010406:Penicillins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
chemical_list: D004791:Enzyme Inhibitors; D010406:Penicillins; D065093:beta-Lactamase Inhibitors; D000658:Amoxicillin; D010397:Penicillanic Acid; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1