Synthesis and Biological Activity Characterization of Novel 5-Oxopyrrolidine Derivatives with Promising Anticancer and Antimicrobial Activity

The 1-(4-acetamidophenyl)-5-oxopyrrolidine carboxylic acid was applied for synthesizing derivatives bearing azole, diazole, and hydrazone moieties in the molecule. Modification of an acetamide fragment to the free amino group afforded compounds with two functional groups, which enabled to provide a series of 4-substituted-1-(4-substituted phenyl)pyrrolidine-2-ones. The resulted compounds 2 and 4–22 were subjected to the in vitro anticancer and antimicrobial activity determination. The compounds 18–22 exerted the most potent anticancer activity against A549 cells. Furthermore, compound 21 bearing 5-nitrothiophene substituents demonstrated promising and selective antimicrobial activity against multidrug-resistant Staphylococcus aureus strains, including linezolid and tedizolid-resistant S. aureus. These results demonstrate that 5-oxopyrolidine derivatives are attractive scaffolds for the further development of anticancer and antimicrobial compounds targeting multidrug-resistant Gram-positive pathogens.

[1]  R. Ahmad,et al.  Phytoconstituents from Moringa oleifera fruits target ACE2 and open spike glycoprotein to combat SARS-CoV-2: An integrative phytochemical and computational approach. , 2022, Journal of food biochemistry.

[2]  R. Vaickelionienė,et al.  Synthesis and Antibacterial Activity of New Azole, Diazole and Triazole Derivatives Based on p-Aminobenzoic Acid , 2021, Molecules.

[3]  Ahmad J. Obaidullah,et al.  Synthesis, potential antitumor activity, cell cycle analysis, and multitarget mechanisms of novel hydrazones incorporating a 4-methylsulfonylbenzene scaffold: a molecular docking study , 2021, Journal of enzyme inhibition and medicinal chemistry.

[4]  G. Jeong,et al.  Salinosporamide A, a Marine-Derived Proteasome Inhibitor, Inhibits T Cell Activation through Regulating Proliferation and the Cell Cycle , 2020, Molecules.

[5]  Peiyuan Yin,et al.  N-Ethyl-2-Pyrrolidinone-Substituted Flavan-3-Ols with Anti-inflammatory Activity in Lipopolysaccharide-Stimulated Macrophages Are Storage-Related Marker Compounds for Green Tea. , 2020, Journal of agricultural and food chemistry.

[6]  A. Fayeulle,et al.  Design, synthesis and evaluation of hydrazine and acyl hydrazone derivatives of 5-pyrrolidin-2-one as antifungal agents. , 2020, Bioorganic & medicinal chemistry letters.

[7]  F. Badria,et al.  Synthesis, Anticancer Activity, and Molecular Modeling of New Halogenated Spiro[pyrrolidine-thiazolo-oxindoles] Derivatives , 2020, Applied Sciences.

[8]  N. Betti,et al.  Synthesis and Biological Evaluation of Some Pyrrolidine-2-one Derivatives , 2020 .

[9]  D. Matulis,et al.  Synthesis and structure-affinity relationship of chlorinated pyrrolidinone-bearing benzenesulfonamides as human carbonic anhydrase inhibitors. , 2020, Bioorganic chemistry.

[10]  L. Désaubry,et al.  Discovery of 3,3'-pyrrolidinyl-spirooxindoles as cardioprotectant prohibitin ligands. , 2019, European journal of medicinal chemistry.

[11]  C. Pessoa,et al.  Synthesis, structural characterization, and cytotoxic evaluation of chalcone derivatives , 2019, Medicinal Chemistry Research.

[12]  H. Ben Mansour,et al.  Cardioprotective effects of (E)-4-hydroxy-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide: a newly synthesized coumarin hydrazone against isoproterenol-induced myocardial infarction in a rat model. , 2019, Canadian journal of physiology and pharmacology.

[13]  V. Tzankova,et al.  Design, synthesis, antioxidant properties and mechanism of action of new N,N′-disubstituted benzimidazole-2-thione hydrazone derivatives , 2018, Journal of Molecular Structure.

[14]  I. Lampronti,et al.  Benzofuran hydrazones as potential scaffold in the development of multifunctional drugs: Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity. , 2018, European journal of medicinal chemistry.

[15]  A. Iwasaki,et al.  Ypaoamides B and C, Linear Lipopeptides from an Okeania sp. Marine Cyanobacterium. , 2018, Journal of natural products.

[16]  R. Vaickelionienė,et al.  Synthesis of novel 1,2- and 2-substituted benzimidazoles with high antibacterial and antioxidant activity , 2018, Monatshefte für Chemie - Chemical Monthly.

[17]  S. Memon,et al.  Synthesis and investigation of antimicrobial properties of pyrrolidine appended calix[4]arene , 2017, Journal of Analytical Science and Technology.

[18]  B. Song,et al.  Antiviral and Antibacterial Activities of N‐(4‐Substituted phenyl) Acetamide Derivatives Bearing 1,3,4‐Oxadiazole Moiety , 2016 .

[19]  P. Andreeva-Gateva,et al.  Recent Developments of Hydrazide/Hydrazone Derivatives and Their Analogs as Anticonvulsant Agents in Animal Models , 2016, Drug development research.

[20]  Jian Li,et al.  Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs , 2016, Molecules.

[21]  S. Dan,et al.  Pyrrocidine A, a metabolite of endophytic fungi, has a potent apoptosis-inducing activity against HL60 cells through caspase activation via the Michael addition , 2015, The Journal of Antibiotics.

[22]  A. Ariffin,et al.  Correlation of antioxidant activities with theoretical studies for new hydrazone compounds bearing a 3,4,5-trimethoxy benzyl moiety. , 2015, European journal of medicinal chemistry.

[23]  A. Fuentefria,et al.  Synthesis and Biological Evaluation of Hydrazone Derivatives as Antifungal Agents , 2015, Molecules.

[24]  M. Correa,et al.  Synthesis, antioxidant and photoprotection activities of hybrid derivatives useful to prevent skin cancer. , 2014, Bioorganic & medicinal chemistry.

[25]  M. Ghareeb,et al.  Antioxidant Activity of Heterocyclic Compounds Derived from 4-( 4-Acetamidophenyl )-4-oxobut-2-enoic Acid , 2014 .

[26]  F. Kobarfard,et al.  Synthesis of novel indole hydrazone derivatives and evaluation of their antiplatelet aggregation activity. , 2013, Chemical & pharmaceutical bulletin.

[27]  M. Stasevych,et al.  Synthesis and antimicrobial activity of 1,3-disubstituted pyrrolidinones with hydrazone and naphthoquinone moieties , 2013 .

[28]  Y. Tunalı,et al.  Antimicrobial activity and a SAR study of some novel benzimidazole derivatives bearing hydrazone moiety. , 2010, European journal of medicinal chemistry.

[29]  N. Meanwell,et al.  Solid phase synthesis of novel pyrrolidinedione analogs as potent HIV-1 integrase inhibitors. , 2010, Journal of combinatorial chemistry.

[30]  A. V. Adhikari,et al.  A new class of anticonvulsants possessing 6 Hz activity: 3,4-dialkyloxy thiophene bishydrazones. , 2009, European journal of medicinal chemistry.

[31]  I. Hewlett,et al.  Synthesis and antiviral activities of novel acylhydrazone derivatives targeting HIV-1 capsid protein. , 2009, Bioorganic & medicinal chemistry letters.

[32]  G. Aktay,et al.  1-Acylthiosemicarbazides, 1,2,4-triazole-5(4H)-thiones, 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones: synthesis, analgesic-anti-inflammatory and antimicrobial activities. , 2007, Bioorganic & medicinal chemistry.

[33]  V. Mickevičius,et al.  Synthesis and structural investigation of some 1,4-disubstituted-2-pyrrolidinones , 2005 .

[34]  Yukihiro Asami,et al.  Azaspirene: a novel angiogenesis inhibitor containing a 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton produced by the fungus Neosartorya sp. , 2002, Organic letters.

[35]  A. Lambeir,et al.  Structure-activity relationship of diaryl phosphonate esters as potent irreversible dipeptidyl peptidase IV inhibitors. , 1999, Journal of medicinal chemistry.

[36]  C. Cavé,et al.  Antihypertensive hydrazidones: α-aminoacylated 2-chlorobenzylidene hydrazines , 1994 .

[37]  J. Waitz.  Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically , 1990 .