Abstract
A novel series of N-substituted cis- and trans-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 trans-11f showed moderate inhibitory activity against human coronavirus (229E) with EC50 = 45 µM. The other isomer cis-11f was active against influenza A virus H1N1 subtype (EC50 = 12 µM by visual CPE score; EC50 = 8.3 µM by TMS score; MCC > 100 µM, CC50 = 39.9 µM). Several azetidin-2-ones 10 and 11 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 IC50 in the range 14.5–97.9 µM. Compound trans-11f was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant S. aureus strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3R,4S)-11f can be responsible for the promising activity due to the potency in displacing oxacillin at β-lactamase, thus protecting the antibiotic from undesirable biotransformation.
Highlights
The compounds containing azetidinone are of special importance both in chemistry and medicine
Since the lack of direct antibacterial activity of the obtained azetidinones was observed, all isomers trans and cis were investigated on their “adjuvant” properties, i.e., an ability to enhance the effectiveness of antibiotics against S. aureus strains
The compounds were evaluated against different herpesviruses, including herpes simplex virus type 1 (HSV-1) strain KOS, thymidine kinase-deficient (TK−) HSV-1 KOS strain resistant to ACV (ACVr), herpes simplex virus type 2 (HSV-2) strain G, varicella-zoster virus (VZV) strain Oka, TK− VZV strain 07-1, human cytomegalovirus (HCMV) strains AD169 and Davis as well as vaccinia virus, adenovirus-2, human coronavirus, parainfluenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, respiratory syncytial virus (RSV) and influenza A virus subtypes H1N1 (A/PR/8), H3N2 (A/HK/7/87) and influenza B virus (B/HK/5/72), were based on inhibition of virus-induced cytopathicity or plaque formation in human embryonic lung (HEL) fibroblasts, African green monkey kidney cells (Vero), human epithelial cervix carcinoma cells (HeLa) or Madin Darby canine kidney cells (MDCK)
Summary
The compounds containing azetidinone are of special importance both in chemistry and medicine. The azetidinone ring is a common structural motif of a vast number of compounds possessing a wide range of other biological properties, including antimalarial [7], antitubercular [8], anti-inflammatory [9], antifungal [10], antidepressant [11] and nootropic activity [11]. The isomer cis-11f appeared to be active against influenza A virus H1N1 subtype (EC50 = 12 μM by visual CPE score; EC50 = 8.3 μM by TMS score; MCC > 100 μM, CC50 = 39.9 μM) in Madin Darby canine kidney cells (MDCK) and its potency was comparable to ribavirin used as a reference compound (EC50 = 8.9 μM by visual CPE score; EC50 = 6.6 μM by TMS score; MCC > 100 μM, CC50 ≥ 100 μM), but much lower than that of zanamivir, amantadine and rimantadine. FFiigguurree33..AAnnttiivviirraallaaccttiivviittyy ffoouunndd ffoorr tthhee sstteerreeooiissoommeerrss ooff 33--mmeetthhyyll--44--fflluuoorroopphheennyyllddeerrivivaatitviveessooff aazzeettididiinnoonneettrraannss--1111ff aanndd cciiss--1111ff iinn ccoommppaarriissoonnwwiitthhrreefeferreenncceeaanntitviviriaral lagaegnetnst:sr:ibriabvaivriinri(nR(eRf-e1f)-,1), gvgaaannlcuciecicl(olμovvMirir)(.R(*ReEfe-fC2-)25,0)c,bicdyidovfoiosfvouivaril(rCR(eRPfEe-3f-s)3c. TThheetetestseteddcocmompopuonudnsdds iddidnontoint hinibhiitbtihtethgerogwrothwothf eoitfheeirthSe. rauSr.eauusrseturasisntsraaitncsoantcecnotnrcaetinotnrasutpiotnos 2ump tMo .2TmhuMs,. tThheuirs,atnhteibiraactnetriibaalcatcetriivailtyacctaivnitbyeccaonnbsiedceorendsindeegrelidginbeleg.ligible
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