title: Design, synthesis, and biological evaluation of 4-alkyliden-beta lactams: new products with promising antibiotic activity against resistant bacteria.
abstract: The design, synthesis, and antibacterial activity of 4-alkyliden-azetidin-2-ones as new antimicrobial agents against multidrug-resistant pathogens is reported. 4-Alkyliden-azetidin-2-ones were easily obtained using an original protocol starting from 4-acetoxy-azetidinones and diazoesters. Parent compounds were further elaborated to obtain a small library of 4-alkylidene derivatives. A molecular modeling approach using GRID descriptors based on the concept of VRS identified attractive drug candidates and contributed to the rationalization of functional group effects in QSARs. The in vitro antibacterial activity of the new agents was evaluated against 43 recent clinical isolates of antibiotic-susceptible and -resistant Gram-positive and Gram-negative pathogens by determining their minimum inhibitory concentrations (MICs). The most active compound showed MIC values ranging from 0.25 to 32 mg/L against some of the bacterial species tested. Interestingly, some compounds demonstrated similar activity against methicillin-susceptible and -resistant strains of Staphylococcus aureus suggesting possible alternative mechanisms of action of these agents, supported by citotoxicity and preliminary scanning electron microscopy studies.
authors.affiliation: Department of Clinical Medicine, Prevention and Biotechnology, University of Milano-Bicocca, Via Cadore 48, I-20052 Monza, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Broccolo
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Cainelli
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Caltabiano
authors.forename: Clementina E A
authors.initials: CE
authors.lastname: Cocuzza
authors.forename: Cosimo G
authors.initials: CG
authors.lastname: Fortuna
authors.forename: Paola
authors.initials: P
authors.lastname: Galletti
authors.forename: Daria
authors.initials: D
authors.lastname: Giacomini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Musumarra
authors.forename: Rosario
authors.initials: R
authors.lastname: Musumeci
authors.forename: Arianna
authors.initials: A
authors.lastname: Quintavalla
mesh_terms: D000478:Alkylation; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D016983:Enterococcus / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015394:Molecular Structure; D013210:Staphylococcus / Q000187:drug effects; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams