Design, Synthesis of New Pyridine and Pyrimidine Sugar Compounds as Antagonists Targeting the ERα via Structure-Based Virtual Screening

Author(s): Ibrahim F. Nassar*, Wael A. El-Sayed*, Tamer I.M. Ragab, Al Shimaa Gamal Shalaby, Ahmed B.M. Mehany.

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 5 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Abstract:

Background: New aryl substituted cyclohepta[b]pyridine and cyclohepta[d]pyrimidine derivatives were synthesized. The sugar hydrazones of the synthesized pyridine and pyrimidine compounds were also prepared.

Method: In addition, the 1,3,4-oxadiazolyl acyclic C-nucleoside analogs of the pyridine system were prepared. The hemolytic, prebiotic, anticancer and antimicrobial activities of some of the synthesized compounds were also studied. Compounds 10 and 12 showed high activity against MCF-7, HEPG-2 and HCT-116 cell lines with IC50 at range 3.56-8.55 µg/mL. In addition, the synthesized condensed thiopyrimidine derivative 10 exhibited more potent bactericidal activity while compound 7 demonstrated potent antifungal activity against Aspergillus niger. Furthermore, the synthetic compounds of the pyrimidine base promoted the growth of lactic acid bacteria.

Results: The predicted binding patterns of three of the prepared derivatives as possible antagonists against ERα were investigated which showed good binding patterns.

Keywords: Cyclohepta[d]pyrimidine, 1, 3, 4-Oxadiazolyl acyclic C-nucleoside, Haemolytic, Prebiotic, Anticancer, Antimicrobial.

[1]
Joule, J.A.; Smith, G.; Mills, K. Heterocyclic Chemistry, 3rd ed; Chapman and Hall: London, 1995, pp. 72-119.
[2]
Roth, H.J.; Kleeman, A. Eds.; Pharmaceutical Chemistry, Drug Synthesis; Prentice Hall Europe: London,., 1988, 1, p. 407.
[3]
Henry, G.D. De novo synthesis of substituted pyridines. Tetrahedron, 2004, 60, 6043.
[4]
Vacher, B.; Bonnaud, B.; Funes, P.; Jubault, N.; Koek, W.; Assie, M.B.; Cos, C.; Kleven, M. Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J. Med. Chem., 1999, 42, 1648-1660.
[5]
El-Essawy, F.A.; El-Sayed Wael, A.; Morshedy, A.S.; Rahman, A.A.; Anti-Hepatitis, B. Virus Activity of New 1,2,4-Triazol-2-yl- and 1,3,4-Oxadiazol-2-yl-2-pyridinone Derivatives. Zeitschrift für Naturforschung, 2008, 63c, 667-674.
[6]
Abbas, H-A.S.; El Sayed, W.A.; Fathy, N.M. Synthesis and antitumor activity of new dihydropyridine thioglycosides and their corresponding dehydrogenated forms. Europ. J. Med. Chem., 2010, 45, 973-982.
[7]
Rashad, A.E.; El-Sayed, W.A.; Ewas, A.M.; Ali, M.M. Synthesis of new quinoline derivatives as inhibitors of human tumor cells growth. Arch.der Pharmazie, 2010, 8, 440-448.
[8]
Fadda, A.A.; Abdel-Rahman, A.A-H.; El-Sayed, W.A.; Zidan, T.A.; Farid, A.B. Synthesis of novel 1,3,4-oxadiazole derivatives and their nucleoside analogues with antioxidant, and antitumor activities. Khimiya Geterotsiklicheskhikh Soedinenii, 2011, 7, 1045-1054.
[9]
El-Sayed, W.A.; Metwally, M.A.; Nada, D.S.; Abdel-Rahman, A.A-H. Synthesis and antimicrobial activity of new substituted 5-(Pyridine-3-yl)-1,3,4-thiadiazoles and their sugar derivatives. J. Heterocyc. Chem., 2013, 50, 194-201.
[10]
El-Essawy, F.A.; El-Sayed, W.A.; El-Etrawy, A.Sh.; El-Bayaha, M.N. Synthesis of new isolated and fused tri- and tetracyclic pyridine derivatives with antimicrobial evaluation. Chem. Het. Comp., 2013, 48, 1977-1986.
[11]
El-Sayed, W.A.; Khalaf, H.S.; Mohamed, S.F.; Hssien, H.A.; Kutkat, O.M.; Amr, A-E.E. Synthesis and antiviral activity of 1,2,3-triazole glycosides based substituted pyridine via click cycloaddition. Russian . J. Gen. Chem., 2017, 87(10), 2444-2453.
[12]
Cieplik, J. Pyrimidines as the cytostatic drugs. Acta Pol. Pharm., 1992, 49, 51-57.
[13]
Pogorelcnik, B.; Brvar, M.; Zegura, B.; Filipic, M.; Solmajer, T.; Perdih, A. Discovery of mono- and disubstituted 1H-pyrazolo[3,4]-pyrimidines and 9H-purines as catalytic inhibitors of human DNA topoisomerase IIalpha. ChemMedChem, 2015, 10, 345-359.
[14]
Ogilvie, K.K.; Hamilton, R.G.; Gillen, M.F.; Radatus, B.K.; Smith, K.O.; Galloway, K.S. Uracil analogues of the acyclonucleoside 9-[[2-hydroxy-1-(hydroxylmethyl) ethoxy]-methyl]guanine (BIOLF-62). Can. J. Chem., 1984, 62, 16-21.
[15]
Zenker, N. Thyroid function and thyroid drugs. In: W.O. Foye (Ed.), Principles of Medicinal Chemistry, third ed; Lea & Febiger: Philadelphia, London, 1990; pp. 603-621.
[16]
Deshmukh, M.B.; Salunkhe, S.M.; Patil, D.R.; Anbhule, P.V. A novel and efficient one step synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl pyrimidines and their anti-bacterial activity. Eur. J. Med. Chem., 2009, 44, 2651-2654.
[17]
Masoud, M.S.; Ibrahim, A.A.; Khalil, E.A.; El-Marghany, A. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2007, 67, 662-668.
[18]
Odani, A.; Kozlowski, H.; Swiatek-Kozlowska, J.; Brasun, J.; Operschall, B.P.; Sigel, H. Extent of metal ion-sulfur binding in complexes of thiouracil nucleosides and nucleotides in aqueous solution. J. Inorg. Biochem., 2007, 101, 727-735.
[19]
Prachayasittikul, S.; Sornsongkhram, N.; Pingaew, R.; Techatanachai, S.; Ruchirawat, S.; Prachayasittikul, V. Synthesis and novel bioactivities of substituted 6-Propylthiouracils. Eur. J. Sci. Res., 2009, 36, 236-245.
[20]
Elion, G.B. The purine path to chemotherapy. Science, 1989, 244, 41.
[21]
Legraverend, M.; Aubertin, A.M.; Oberg, G.; Huel, C.; Bisagni, E. Synthesis and Anti-HIV Evaluation of 7-Deaza Analogues of Carbovir. Nucleosides Nucleotides Nucleic Acids, 1994, 13, 915-923.
[22]
Gudmundsson, K.S.; Freeman, G.A.; Drach, J.C.; Townsend, L.B.J. synthesis of fluorosugar analogues of 2,5,6-Trichloro-1-(β-d-ribofuranosyl) benzimidazole as antivirals with potentially increased glycosidic bond stability. J. Med. Chem., 2000, 43, 2473-2478.
[23]
Zackny, V.L.; Gershburg, E.; Davis, M.G.; Biron, K.K.; Pagano, J.S. Inhibition of Epstein-Barr virus replication by a benzimidazole L-riboside: Novel antiviral mechanism of 5,6-dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole. J. Virol., 1999, 73, 7271.
[24]
Underwood, M.R.; Harvey, R.J.; Stanat, S.C.; Hemphill, M.L.; Miller, T.; Drach, J.C.; Townsend, L.B.; Biron, K.K. Inhibition of human cytomegalovirus DNA maturation by a benzimidazole ribonucleoside is mediated through the UL89 gene product. J. Virol., 1998, 72, 717-725.
[25]
Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.; Inouye, N.; Baba, M.; Shigeta, S.; Walker, R.T.; Clercq, E.D.; Miyasaka, T. Synthesis and antiviral activity of 6-Benzyl analogs of 1-[(2-Hydroxyethoxy)methyl]-5-(phenylthio)thymine (HEPT) as potent and selective Anti-HIV-1 Agents. J. Med. Chem., 1995, 38, 2860-2865.
[26]
Genini, D.; Adachi, S.; Chao, Q.; Rose, D.W.; Carrera, C.J.; Cottam, H.B.; Carson, D.A.; Leoni, L.M. Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood, 2000, 96, 3537.
[27]
Ramez, M.M.M.; El-Sayed, W.A.; Hagag, E.; Abdel-Rahman, A.A-H. Synthesis and antiviral activity of new substituted pyrimidine glycosides. J. Heterocycl. Chem., 2011, 48, 1028-1038.
[28]
Nassar, I.F.; El Farargy, A.F.; Abdelrazek, F.M.; Ismail, N.S.M. Design, synthesis and anticancer evaluation of novel pyrazole, pyrazolo [3, 4-d] pyrimidine and their glycoside derivatives. Nucleosides Nucleotides Nucleic Acids, 2017, 36(4), 275.
[29]
Nassar, I.F.; El Farargy, A.F.; Abdelrazek, F.M. Synthesis of some novel pyrazoles and their glycoside derivatives. J. Heterocycl. Chem., 2018, 55, 1709-1719.
[30]
Vetter, C.; Wagner, C.; Kaluderovic, G.N.; Paschke, R.; Steinborn, D. Synthesis, characterization, and cytotoxicity of trimethylplatinum (IV) complexes with 2-thiocytosine and 1-methyl-2-thiocytosine ligands. Inorg. Chim. Acta, 2009, 362, 189-195.
[31]
Hasaninejad, A.; Zare, A.; Balooty, L.; Mehregan, H.; Shekouhy, M. Solvent-Free, cross-aldol condensation reaction using silica-supported, phosphorus-containing reagents leading to α,α′-Bis (arylidene)cycloalkanones. Synth. Communicat., 2010, 40(23), 3488-3495.
[32]
Zeid, I.F.; Kassem, E.M.; Mohamed, N.A.; Salman, A.A.; Shalaby, Al. G. Enhancement of different biomedical activities of newly synthesized quinazoline derivatives. J. Heterocyc. Chem., 2018.
[http://dx.doi.org/ 10.1002/jhet.3147..]
[33]
Pepeljnjak, S.; Lalodera, Z.; Zovko, M. Investigation of antimicrobial activity of Pelargonium radula (Cav.) L’ Hérit. Acta Pharm., 2005, 55, 409-415.
[34]
Shalaby, A.l.G.; Ragab, I.M.T.; Belal, A.; Mehany, M.; Helal, M.M.I.; Helmy, W.A. Antitumor and prebiotic activities of novel sulfated acidic polysaccharide from ginseng; Biocatal. Agricult. Biotechnol, 2018, pp. 402-409.
[35]
Abdel-Aal, M.T.; El-Sayed, W.A.; El-Ashry, E.S.H. Synthesis and antiviral evaluation of some sugararylglycinoylhydrazones and their oxadiazoline derivatives. Arch. Pharm. Chem. Life Sci., 2006, 339, 656-663.
[36]
Rival, Y.; Grassy, G.; Michel, G. Synthesis and antimicrobial activity of some Imidazo [1,2-a] pyrimidine derivatives. Chem. Pharm. Bull., 1992, 40, 1170-1176.
[37]
Snell, Mitchell. Purine and pyrimidine bases as growth substances for lactic acid bacteria. Proceed. Natl. Acad. Sci., 1941, 27, 1-7.
[38]
Nassar, E. Synthesis, (in vitro) antitumor and antimicrobial activity of some pyrazoline, pyridine, pyrimidine derivatives linked to indol moiety. J. Am. Sci., 2010, 6(8), 338-347.
[39]
Shoda, T.; Kato, M.; Fujisato, T.; Misawa, T.; Demizu, Y.; Inoue, H.; Naito, M.; Kurihara, M. Synthesis and evaluation of raloxifene derivatives as a selective estrogen receptor down-regulator. Bioorg. Med. Chem., 2016, 24, 2914-2919.
[40]
De Savi, C.; Bradbury, R.H.; Rabow, A.A.; Norman, R.A.; de Almeida, C.; Andrews, D.M.; Ballard, P.; Buttar, D.; Callis, R.J.; Currie, G.S.; Curwen, J.O.; Davies, C.D.; Donald, C.S.; Feron, L.J.; Gingell, H.; Glossop, S.C.; Hayter, B.R.; Hussain, S.; Karoutchi, G.; Lamont, S.G.; MacFaul, P.; Moss, T.A.; Pearson, S.E.; Tonge, M.; Walker, G.E.; Weir, H.M.; Wilson, Z. Optimization of a novel binding motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a potent and orally bioavailable selective estrogen receptor down regulator and antagonist. J. Med. Chem., 2015, 58(81), 28-40.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 19
ISSUE: 5
Year: 2019
Page: [395 - 409]
Pages: 15
DOI: 10.2174/1389557518666180820125210
Price: $58

Article Metrics

PDF: 19
HTML: 3
EPUB: 1