Novel N-Substituted 3-Aryl-4-(diethoxyphosphoryl)azetidin-2-ones as Antibiotic Enhancers and Antiviral Agents in Search for a Successful Treatment of Complex Infections.

A novel series of N-substituted - and -3-aryl-4-(diethoxyphosphoryl)azetidin-2-ones were synthesized by the Kinugasa reaction of N-methyl- or N-benzyl-(diethyoxyphosphoryl)nitrone and selected aryl alkynes. Stereochemistry of diastereoisomeric adducts was established based on vicinal H3-H4 coupling constants in azetidin-2-one ring. All the obtained azetidin-2-ones were evaluated for the antiviral activity against a broad range of DNA and RNA viruses. Azetidin-2-one - showed moderate inhibitory activity against human coronavirus (229E) with EC = 45 µM. The other isomer - was active against influenza A virus H1N1 subtype (EC = 12 µM by visual CPE score; EC = 8.3 µM by TMS score; MCC > 100 µM, CC = 39.9 µM). Several azetidin-2-ones and were tested for their cytostatic activity toward nine cancerous cell lines and several of them appeared slightly active for Capan-1, Hap1 and HCT-116 cells values of IC in the range 14.5-97.9 µM. Compound - was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3,4)- can be responsible for the promising activity due to the potency in displacing oxacillin at β-lactamase, thus protecting the antibiotic from undesirable biotransformation.