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Synthesis and in vitro antiplatelet aggregation screening of novel fluorinated diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate derivatives

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Abstract

Seven fluorinated derivatives of diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate (a–g) as well as a nitro and chloro derivative (h–i) were prepared in five steps from glycine, ethyl formate, diethyl oxalate, potassium thiocyanate and substituted benzyl bromides. The structures of the synthesised compounds were elucidated and verified using 1H, 13C and 2D NMR spectroscopy where appropriate. The synthesised compounds exhibited concentration dependent antiplatelet aggregation activity on both the thrombin and ADP-induced platelet aggregation. The 4-nitro and 4-fluoro compounds exhibited the highest activity from the compounds tested, with IC50 values of 1.06 and 1.20 mM for the thrombin-induced assay and 18.57 and 12.91 mM in the ADP-induced platelet aggregation assay respectively. Three of the compounds, the 3′′,4′′-difluoro (6c), 4′′-nitro (6h) and 3′′-chloro (6i) derivatives, have reasonable activity in both of the assays and could have potential as broad spectrum antiplatelet inhibitors. With the exception of 6c, the fluoro derivatives were not as active as the nitro and chloro compounds.

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References

  • Anderson WK, Bhattacharjee D, Houston DM (1989) Design, synthesis, antineoplastic activity and chemical properties of bis(carbamate) derivatives of 4,5-bis(hydroxymethy1)imidazole. J Med Chem 32:119–127

    Article  CAS  PubMed  Google Scholar 

  • Bagrii AK, Vasilenko TE (1978) Study of the cyanethylation of aryl derivatives of 2-thioimidazole. Farm Zh (Kiev) 4:33–36

    Google Scholar 

  • Ballabeni M, Ballini R, Bigi F, Maggi R, Parrini M, Predieri G, Sartori G (1999) Synthesis of symmetrical N,N′-disubstituted thioureas and heterocyclic thiones from amines and CS2 over a ZnO/Al2O3 composite as heterogeneous and reusable catalyst. J Org Chem 64:1029–1032

    Article  CAS  PubMed  Google Scholar 

  • Bhatnagar A, Sharma PK, Kumar N (2011) A review on “Imidazoles”: their chemistry and pharmacological potentials. Int J PharmTech Res 3:268–282

    CAS  Google Scholar 

  • Billheimer JT, Gillies PJ, Wilkerson WW (1990) Anti hypercholesterolemic 4,5-diaryl-2-substituted thioimidazoles. US Patent 4900744

  • Boldron C, Besse A, Bordes M-F et al (2014) N-[6-(4-Butanoyl-5-methyl-1H-pyrazol-1-yl)pyridazin-3-yl]-5-chloro-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-indole-3-carboxamide (SAR216471), a novel intravenous and oral, reversible, and directly acting P2Y12 antagonist. J Med Chem 57:7293–7316

    Article  CAS  PubMed  Google Scholar 

  • Buhler S, Goettert M, Schollmeyer D, Albrecht W, Laufer SA (2011) Chiral sulfoxides as metabolites of 2-thioimidazole-based p38α mitogen-activated protein kinase inhibitors: enantioselective synthesis and biological evaluation. J Med Chem 54:3283–3297

    Article  PubMed  Google Scholar 

  • Caroff E, Meyer E, Treiber A, Hilpert K, Riederer MA (2014) Optimization of 2-phenyl-pyrimidine-4-carboxamides towards potent, orally bioavailable and selective P2Y12 antagonists for inhibition of platelet aggregation. Bioorg Med Chem Lett 24:4323–4331

    Article  CAS  PubMed  Google Scholar 

  • Davi G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494

    Article  CAS  PubMed  Google Scholar 

  • Dawood KM, Wahab-Abdel BF (2010) Synthesis, reactions, and biological activity of 4,5-diarylimidazole-2-thiones (Review). Chem Heterocycl Compd 46:255–278

    Article  CAS  Google Scholar 

  • Doerge DR, Decker CJ, Takazawall RS (1993) Chemical and enzymatic oxidation of benzimidazoline-2-thiones: a dichotomy in the mechanism of peroxidase inhibition. Biochemistry 32:58–65

    Article  CAS  PubMed  Google Scholar 

  • Fabre J, Gurney ME (2010) Limitations of current therapies to prevent thrombosis: a need for novel strategies. Mol BioSyst 6:305–315

    Article  CAS  PubMed  Google Scholar 

  • Giordanetto F, Barlaam B, Berglund S, Edman K, Karlsson O, Lindberg J, Nylander S, Inghardt T (2014) Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as oral PI3Kβ inhibitors, useful as antiplatelet agents. Bioorg Med Chem Lett 24:3936–3943

    Article  CAS  PubMed  Google Scholar 

  • Harris LF, Killard AJ (2014) Moving away from heparin: the new antithrombotic and antiplatelet drugs. In: Wlkinson NB (ed) Heparin. Nova Science Publishers, New York, pp 21–39

    Google Scholar 

  • Hayashi M, Yokomori S, Hatayama K, Kaoru S (1989) Preparation of pyridylmethylthio- and methylsulfinyl imidazole derivatives as platelet aggregation inhibitors. Jpn Kokai Tokkyo Koho JP 62187469

  • Hozien ZA, El-Wareth AOSA, El-Sherief HAH, Mahmoud AM (2000) An efficient route for synthesis of 5,6-diphenylimidazo-[2,1-b]thiazoles as antibacterial agents. J Heterocycl Chem 37:943–949

    Article  CAS  Google Scholar 

  • Imbalzano E, Creazzo M, Trapani G, Stellitano A, Zucco M, Quartuccio S, Lizio G, Dattilo G, Saitta A (2014) Heparin: which molecule? What Clinical applications? In: Wilkinson NB (ed) Heparin. Nova Science Publishers, New York, pp 1–20

    Google Scholar 

  • Iradyan MA, Ayvazyan AKh, Mirzoyan VS, Paronikyan GM, Sarkisyan TP, Stepanyan GM, Arsenyan FG, Garibdzhanyan BT (1987) Imidazole derivatives. XIX. Synthesis and biological activity of 4-nitro-5-thioimidazole derivatives. Pharm Chem J 21:403–408

    Article  Google Scholar 

  • Jones RG (1952) Studies on imidazoles. VI. Synthesis of 4,5-imidazoledicarboxylates. J Am Chem Soc 74:1085–1086

    Article  CAS  Google Scholar 

  • Lagoja IM, Pannecouque C, van Aerschot A, Witvrouw M, Debyser Z, Balzarini J, Herdewijn P, de Clercq E (2003) N-Aminoimidazole derivatives inhibiting retroviral replication via a yet unidentified mode of action. J Med Chem 46:1546–1553

    Article  CAS  PubMed  Google Scholar 

  • Maduskuie TP, Wilde RG, Billheimer JT, Cromley DA, Germain S, Gillies PJ, Higley A, Johnson AL, Pennev P, Shimshick EJ, Wexler RR (1995) Design, synthesis, and structure-activity relationship studies for a new imidazole series of J774 macrophage specific acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors. J Med Chem 38:1067–1083

    Article  CAS  PubMed  Google Scholar 

  • Makita A, Isobe Y, Tomizawa H, Chiba S, Sasaki M (2000) Preparation of 3-nitrogen-containing 5-membered heterocyclylthio-1,2-propanediols and cytosolic phospholipase A2 inhibitors. Jpn Kokai Tokkyo Koho JP 2000038380

  • Mekhfi H, El Haouari M, Legssyer A, Bnouham M, Aziz M, Atmani F, Remmal A, Ziyyat A (2004) Platelet anti-aggregant property of some Moroccan medicinal plants. J Ethnopharmacol 94:317–322

    Article  PubMed  Google Scholar 

  • Mosa RA, Oyedeji AO, Shode FO, Singh M, Opoku AR (2011) Triterpenes from the stem bark of Protorhus longifolia exhibit anti-platelet aggregation activity. Afr J Pharm Pharmacol 5:2698–2714

    CAS  Google Scholar 

  • Muccioli GG, Fazio N, Scriba GKE, Poppitz W, Cannata F, Poupaert JH, Wouters J, Lambert DM (2006) Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates. J Med Chem 49:417–425

    Article  CAS  PubMed  Google Scholar 

  • Parekh PJ, Merrell J, Brush JE, Johnson DA (2014) Clinical review: pharmacology of traditional and modern anticoagulant and antiplatelet therapy. In: Alesci JP, Victorino A (eds) Clopidogrel. Nova Science Publishers, New York, pp 1–52

    Google Scholar 

  • Saeed A, Batool M (2007) Synthesis and bioactivity of some new 1-tolyl-3-aryl-4-methylimidazole-2-thiones. Med Chem Res 16:143–154

    Article  CAS  Google Scholar 

  • Savjani JK, Gajjar AK (2011) Pharmaceutical importance and synthetic strategies for imidazolidine-2-thione and imidazole-2-thione derivatives. Pak J Biol Sci 14:1076–1089

    Article  CAS  PubMed  Google Scholar 

  • Selig R, Schattel V, Goettert M, Schollmeyer D, Albrecht W, Laufer S (2011) Conformational effects on potency of thioimidazoles and dihydrothiazolines. Med Chem Commun 2:261–269

    Article  CAS  Google Scholar 

  • Sharpe TR, Cherkofsky SC, Hewes WE, Smith DH, Gregory WA, Haber SB, Leadbetter MR, Whitney JG (1985) Preparation and antiarthritic and analgesic activity of 4,5-diaryl-2-(substituted thio)-1H-imidazoles and their sulfoxides and sulfones. J Med Chem 28:1188–1194

    Article  CAS  PubMed  Google Scholar 

  • Skvortsova GG, Abramova ND, Trzhtsinskaya BV (1974) Synthesis and some properties of N,S-divinyl-2-mercaptobenzimidazole. Chem Heterocycl Compd 10:1217–1220

    Article  Google Scholar 

  • Tang J, Fang Y, Han Y, Bai X, Yan X, Zhang Y, Lai R, Zhang Z (2014) YY-39, a tick anti-thrombosis peptide containing RGD domain. Peptides. doi:10.1016/j.peptides.2014.08.008

    Google Scholar 

  • Tomita T, Umegaki K, Hayashi E (1983) Basic aggregation properties of washed rat platelets: correlation between aggregation, phospholipid degradation, malondialdehyde, and thromboxane formation. J Pharmacol Methods 10:31–44

    Article  CAS  PubMed  Google Scholar 

  • Trzhtsinskaya BV, Abramova ND (1991) Imidazole-2-thiones: synthesis, structure, properties. Sulfur Reports 10:389–430

    Article  CAS  Google Scholar 

  • Trzhtsinskaya BV, Aleksandrova AE, Abramova ND, Andriyankova LV, Vinogradova TI, Shchegoleva RA (1992) Synthesis and tuberculostatic activity of imidazole-2-thione derivatives. Khim-Farm Zh 4:57–60

    Google Scholar 

  • Tsuji M, Inoue T, Ikesue K, Fujimoto N, Noda K (1989) Preparation of (heterocyclylalkylthio-or-sulfinyl)diphenylimidazoles as antiulcer and antiinflammatory agents. Jpn Kokai Tokkyo Koho JP 01040467

  • Yasser ML, El-Badawi MA, El-Barbary AA, Pedersen EB, Nielsen C (2003) Synthesis of 2-methylsulfanyl-1H-imidazoles as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs). Arch Pharm 336:175–180

    Article  Google Scholar 

  • Zhang H, Hollenberg PF (2014) From mechanism to therapeutics: overcoming inter-individual variability in clopidogrel therapy. In: Alesci JP, Victorino A (eds) Clopidogrel. Nova Science Publishers, New York, pp 121–147

    Google Scholar 

Download references

Acknowledgments

This research was supported by grants from the National Research Foundation (NRF), South Africa and was supported by the South African Research Chairs Initiative of the Department of Science and Technology. We thank Dr Hong Su from the University of Cape Town for X-Ray analysis.

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Authors and Affiliations

  1. School of Chemistry, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, South Africa

    Mehbub I. K. Momin & Neil A. Koorbanally

  2. School of Chemical Engineering, University of KwaZulu-Natal, Durban, 4041, South Africa

    Deresh Ramjugernath

  3. Department of Biochemistry and Microbiology, University of Zululand, Private Bag X1001, Kwadlangezwa, 3886, South Africa

    Rebamang A. Mosa & Andrew R. Opoku

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  1. Mehbub I. K. Momin
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  2. Deresh Ramjugernath
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  3. Rebamang A. Mosa
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  5. Neil A. Koorbanally
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Correspondence to Neil A. Koorbanally.

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Momin, M.I.K., Ramjugernath, D., Mosa, R.A. et al. Synthesis and in vitro antiplatelet aggregation screening of novel fluorinated diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate derivatives. Med Chem Res 24, 2075–2084 (2015). https://doi.org/10.1007/s00044-014-1284-6

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  • DOI: https://doi.org/10.1007/s00044-014-1284-6

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