Design, synthesis, and biological evaluation of 4-alkyliden-beta lactams: new products with promising antibiotic activity against resistant bacteria

Journal of Medicinal Chemistry
Francesco BroccoloArianna Quintavalla

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.

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Citations

Aug 30, 2008·Expert Opinion on Drug Delivery·Sampath C Abeylath, Edward Turos
Mar 1, 2012·European Journal of Medicinal Chemistry·Antonio Palumbo PiccionelloAndrea Pace
Jun 29, 2015·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Ilaria ColziSandra Ristori
Oct 12, 2016·Journal of Medicinal Chemistry·Monica BaiulaDaria Giacomini
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May 22, 2008·Chemistry & Biodiversity·Gianfranco CainelliRiccardo Sinisi
Oct 13, 2009·ChemMedChem·Paola GallettiDaria Giacomini
Aug 18, 2017·Medicinal Research Reviews·Lena DecuyperStanislav Gobec
May 21, 2010·Bioorganic & Medicinal Chemistry Letters·Natarajan ArumugamNarayanasamy Mathivanan

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Antimicrobial Resistance (ASM)

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Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.