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Current Organic Chemistry


ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

Research Article

Design, Synthesis, In silico ADMET Prediction, Molecular Docking, Antimicrobial and Antioxidant Evaluation of Novel Diethyl Pyridinyl Phosphonate Derivatives

Author(s): Ahmed Hussain Jawhari, Yousef E. Mukhrish, Ahmed F. El-Sayed and Rizk E. Khidre*

Volume 27, Issue 10, 2023

Published on: 24 August, 2023

Page: [860 - 875] Pages: 16

DOI: 10.2174/1385272827666230809094204


A series of new diethyl 4,6-diarylpyridin-2-yl phosphonate derivatives 3a-f, and 5a,b were synthesized, in good yields, from the reaction of 2-bromo-4,6-diarylpyridines 1a,b with Wittig-Horner reagents 2a-c, and 4 in DMF containing sodium hydride at reflux temperature. The newly synthesized compounds were evaluated for antimicrobial and antioxidant activity. The results demonstrated that compounds 5a and 5b exhibited strong antimicrobial activity against S. aureus, E. faecalis, P. aeruginosa, and S. mutans. Compounds (3d, 3e, 3f) exhibited superior antioxidant scavenging activity with DPPH and ABTS activity with values (85.19 ± 0.33, 80.19 ± 0.98, 82.33 ± 0.90) and (70.11 ± 0.98, 63.55 ± 0.80, 69.54 ± 1.02) at concentrations (2.0, respectively. The results of the molecular docking simulation indicated that the synthesized compounds displayed lower binding energy with various types of interaction at the active sites of Dihydropteroate synthase, Sortase A, LasR, and Penicillin-binding proteins pockets, suggesting that they could have a potential inhibitory effect on the enzymes and exhibit promising antimicrobial properties. Additionally, the simulation of the active sites of the Peroxidase enzyme as an antioxidant receptor revealed that compounds (5a and 5b) exhibited minimal binding energy and a strong affinity for the active pocket of the peroxidase enzyme.

Keywords: Anti-inflammatory, pyridine, Wittig-Horner reagents, antimicrobial activity, docking, antioxidant activity.

Graphical Abstract
Alizadeh, S.R.; Ebrahimzadeh, M.A. Antiviral activities of pyridine fused and pyridine containing heterocycles, a review (from 2000 to 2020). Mini Rev. Med. Chem., 2021, 21(17), 2584-2611.
[] [PMID: 33573543]
Attaby, F.A.; Eldin, S.M.; Razik, M.A. Reactions with cyanothioacetamide derivatives: synthesis and reactions of some pyridines and thieno[2,3- b]pyridine derivatives. Phosphorus Sulfur Silicon Relat. Elem., 1995, 106(1-4), 21-28.
Khidre, R.E.; Abdel-Wahab, B.F. Application of benzoylaceteonitrile in the synthesis of pyridines derivatives. Curr. Org. Chem., 2013, 17, 430-445.
Balasubramanian, M.; Keay, J.G. Comprehensive Heterocyclic Chemistry, 2nd ed; Katritzky, A.R.; Rees, C.W.; Scriven, E.F.V., Eds.; Pergamon: Oxford , 1996; 5, p. 245.
Altaf, A.A.; Shahzad, A.; Gul, Z.; Rasool, N.; Badshah, A.; Lal, B.; Khan, E. A review on the medicinal importance of pyridine derivatives. J. Drug Design Med. Chem, 2015, 1, 1-11.
Vitaku, E.; Smith, D.T.; Njardarson, J.T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem., 2014, 57(24), 10257-10274.
[] [PMID: 25255204]
Baumann, M.; Baxendale, I.R. An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles. Beilstein J. Org. Chem., 2013, 9, 2265-2319.
[] [PMID: 24204439]
Li, A.H.; Moro, S.; Forsyth, N.; Melman, N.; Ji, X.; Jacobson, K.A. Synthesis, CoMFA analysis, and receptor docking of 3,5-diacyl-2, 4-dialkylpyridine derivatives as selective A3 adenosine receptor antagonists. J. Med. Chem., 1999, 42(4), 706-721.
[] [PMID: 10052977]
Vacher, B.; Bonnaud, B.; Funes, P.; Jubault, N.; Koek, W.; Assié, M.B.; Cosi, C.; Kleven, M. Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J. Med. Chem., 1999, 42(9), 1648-1660.
[] [PMID: 10229633]
Song, Y.L.; Tian, C.P.; Wu, Y.; Jiang, L.; Shen, L.Q. Design, synthesis and antitumor activity of steroidal pyridine derivatives based on molecular docking. Steroids, 2019, 143, 53-61.
[] [PMID: 30590064]
Rao, H.; Senthilkumar, S. Review on the synthesis of 8-azasteroids. Curr. Org. Chem., 2004, 8(15), 1521-1528.
Misic-Vukovic, M.; Mijin, D.; Radojkovic-Velickovic, M.; Valentic, N.; Krstic, V. Condensation of 1, 3-diketones with cyanoacetamide: 4,6-disubstituted-3-cyano-2-pyridones. J. Serb. Chem. Soc., 1998, 63, 585.
Ušćumlić G.S.; Mijin, D.Z.; Valentić N.V.; Vajs, V.V.; Sušić B.M. Substituent and solvent effects on the UV/Vis absorption spectra of 5-(4-substituted arylazo)-6-hydroxy-4-methyl-3-cyano-2-pyridones. Chem. Phys. Lett., 2004, 397(1-3), 148-153.
Forlani, L.; Cristoni, G.; Boga, C.; Todesco, P.E.; Vecchio, E.D.; Selva, S.; Monari, M. Reinvestigation of the tautomerism of some substituted 2-hydroxypyridines. ARKIVOC, 2002, 2002(11), 198-215.
Krick-Othmer, Encyclopedia of Chemical Technology, 2nd ed ; Wiley Interscience Publication: New York,, 1968, 15, p. 638.
Wardle, N.; Bligh, S.; Hudson, H. Organophosphorus chemistry: therapeutic intervention in mechanisms of viral and cellular replication. Curr. Org. Chem., 2005, 9(18), 1803-1828.
Ntai, I.; Manier, M.L.; Hachey, D.L.; Bachmann, B.O. Biosynthetic origins of C-P bond containing tripeptide K-26. Org. Lett., 2005, 7(13), 2763-2765.
[] [PMID: 15957941]
Seto, H.; Kuzuyama, T.; Seto, H.; Kuzuyama, T. Bioactive natural products with carbon–phosphorus bonds and their biosynthesis. Nat. Prod. Rep., 1999, 16(5), 589-596.
[] [PMID: 10584333]
Fields, S.C. Synthesis of natural products containing a CP bond. Tetrahedron, 1999, 55(42), 12237-12273.
Falagas, M.E.; Vouloumanou, E.K.; Samonis, G.; Vardakas, K.Z. Fosfomycin. Clin. Microbiol. Rev., 2016, 29(2), 321-347.
[] [PMID: 26960938]
Takano, H.K.; Dayan, F.E. Glufosinate‐ammonium: A review of the current state of knowledge. Pest Manag. Sci., 2020, 76(12), 3911-3925.
Schwartz, D.; Berger, S.; Heinzelmann, E.; Muschko, K.; Welzel, K.; Wohlleben, W. Biosynthetic gene cluster of the herbicide phosphinothricin tripeptide from Streptomyces viridochromogenes Tü494. Appl. Environ. Microbiol., 2004, 70(12), 7093-7102.
[] [PMID: 15574905]
Ahmadi, F.; Alizadeh, A.A.; Shahabadi, N.; Rahimi-Nasrabadi, M. Study binding of Al–curcumin complex to ds-DNA, monitoring by multispectroscopic and voltammetric techniques. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2011, 79, 1466-1474.
Sugimoto, S.; Chi, G.; Kato, Y.; Nakamura, S.; Matsuda, H.; Yoshikawa, M. Medicinal Flowers. XXVI. structures of acylated oleanane-type triterpene oligoglycosides, yuchasaponins A, B, C, and D, from the flower buds of Camellia oleifera-gastroprotective, aldose reductase inhibitory, and radical scavenging effects. Chem. Pharm. Bull., 2009, 57(3), 269-275.
Abdou, W.M.; Khidre, R.E. Overview of the chemical reactivity of phosphonyl carbanions toward some carbon-nitrogen systems. Curr. Org. Chem., 2012, 16, 913-930.
Abdou, W.M.; Shaddy, A.A.; Khidre, R.E.; Awad, G.E.A. Synthesis and antimicrobial evaluation of newly synthesized N,S-bisphosphonate derivatives. J. Heterocycl. Chem., 2016, 53(2), 525-532.
Abdou, W.M.; Barghash, R.F.; Khidre, R.E. Antineoplastic activity of fused nitrogen-phosphorus heterocycles and derived phosphonates. Monatsh. Chem., 2013, 144(8), 1233-1242.
Abdou, W.M.; Khidre, R.E.; Shaddy, A.A. Synthesis of tetrazoloquinoline-based mono- and biphosphonate esters as potent anti-inflammatory agents. J. Heterocycl. Chem., 2013, 50(1), 33-41.
Abdou, W.M.; Kamel, A.A.; Khidre, R.E.; Geronikaki, A.; Ekonomopoulou, M.T. Synthesis of 5- and 6-N-heterocyclic methylenebisphosphonate derivatives of cytogenetic activity in normal human lymphocyte cultures. Chem. Biol. Drug Des., 2012, 79, 719-730.
[] [PMID: 22243546]
Abdou, W.M.; Khidre, R.E.; Kamel, A.A. Elaborating on efficient anti-proliferation agents of cancer cells and anti-inflammatory-based N-bisphosphonic acids. Arch. Pharm., 2012, 345(2), 123-136.
[] [PMID: 21989682]
Elgogary, S.R.; El-Telbani, E.M.; Khidre, R.E. Synthesis, molecular docking, and antitumor evaluation of some new pyrazole, pyridine, and thiazole derivatives incorporating sulfonamide residue. Polycycl. Aromat. Compd., 2022, 1-14.
Khidre, R.E.; Radini, I.A.M. Design, synthesis and docking studies of novel thiazole derivatives incorporating pyridine moiety and assessment as antimicrobial agents. Sci. Rep., 2021, 11(1), 7846.
[] [PMID: 33846389]
Moustafa, A.H.; El-Seadawy, N.A.; Hassan, A.A.; Pasha, S.H.; El-Sayed, H.A.; Shimess, N.A.; Hassan, N.A. Design, synthesis, biological and molecular docking studies of some o-hydroxycyanopyridine derivatives. Der. Chem., 2017, 2017(8), 313-332.
Forootanfar, H.; Adeli-Sardou, M.; Nikkhoo, M.; Mehrabani, M.; Amir-Heidari, B.; Shahverdi, A.R.; Shakibaie, M. Antioxidant and cytotoxic effect of biologically synthesized selenium nanoparticles in comparison to selenium dioxide. J. Trace Elem. Med. Biol., 2014, 28(1), 75-79.
[] [PMID: 24074651]
Mansoor, S.; Shahid, S.; Javed, M.; Saad, M.; Iqbal, S.; Alsaab, H.O.; Awwad, N.S.; Ibrahium, H.A.; Zaman, S.; Sarwar, M.N.; Fatima, A. Green synthesis of a MnO-GO-Ag nanocomposite using leaf extract of Fagonia arabica and its antioxidant and anti-inflammatory performance. Nano-Struct. Nano-Objects., 2022, 29, 100835.
Re, R.; Pellegrini, N.; Proteggente, A.; Pannala, A.; Yang, M.; Rice-Evans, C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic. Biol. Med., 1999, 26(9-10), 1231-1237.
[] [PMID: 10381194]
Magaldi, S.; Mata-Essayag, S.; Hartung de Capriles, C.; Pérez, C.; Colella, M.T.; Olaizola, C.; Ontiveros, Y. Well diffusion for antifungal susceptibility testing. Int. J. Infect. Dis., 2004, 8(1), 39-45.
[] [PMID: 14690779]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[] [PMID: 28256516]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform., 2011, 3(1), 33.
[] [PMID: 21982300]
Eberhardt, J.; Santos-Martins, D.; Tillack, A.F.; Forli, S. AutoDock Vina 1.2. 0: New docking methods, expanded force field, and python bindings. J. Chem. Inf. Model., 2021, 61(8), 3891-3898.
[] [PMID: 34278794]

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