Skip to main content
SpringerLink
Log in

Synthesis, antiplatelet aggregation activity, and molecular modeling study of novel substituted-piperazine analogues

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

New carbamoylpyridine and carbamoylpiperidine analogues containing nipecotic acid scaffold were designed, synthesized, and evaluated for their platelet aggregation inhibitory activity. Molecular modeling investigation was performed and the impact of lipophilicity on activity was also discussed. Structure activity relationship among this series was obtained. N 1-[1-(4-bromobenzyl)-3-piperidino-carbonyl]-N 4-(2-chlorophenyl)-piperazine hydrobromide (20), and 1,4-bis-[3-[N 4-(2-chlorophenyl)-N 1-(piperazino-carbonyl)]-piperidin-1-yl-methyl]-benzene dibromide (30) are the most active antiplatelet aggregating compounds in this study, both at concentration of 0.06 μM.

Graphical Abstract

 

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Chart 1

Similar content being viewed by others

References

  • Antithrombotic Trialists’ Collaboration (2002) Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 324:71–86

    Article  Google Scholar 

  • Banner DW, Hadvary P (1991) Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors. J Biol Chem v266:20085–20093

    Google Scholar 

  • Berger PB (1999) The thienopyridines in coronary artery disease. Curr Cardiol Rep 1:192–198

    Article  PubMed  CAS  Google Scholar 

  • Binisti C, Assogba L, Touboul E, Mounier C, Huet J, Ombetta J-E, Dong CZ, Redeuilh C, Heymans F, Godfroid J-J (2001) Structure–activity relationships in platelet-activating factor (PAF). 11-From PAF-antagonism to phospholipase A2 inhibition: syntheses and structure–activity relationships in 1-arylsulfamido-2-alkylpiperazines. Eur J Med Chem 36:809–828

    Article  PubMed  CAS  Google Scholar 

  • Budin N, Majeux N, Caflisch A (2001) Fragment-based flexible ligand docking by evolutionary optimization. Biol Chem 382:1365–1372

    Article  PubMed  CAS  Google Scholar 

  • Chatelain P, Massingham R (1997) Cardiac ischaemia: possibilities for future drug therapy. Eur J Med Chem 32:687–707

    Article  CAS  Google Scholar 

  • Cody WL, Cai C, Doherty AM, Edmunds JJ, He JX, Narasimhan LS, Plummer JS, Rapundalo ST, Rubin JR, Van Huis CA, St-Denis Y, Winocour PD, Siddiqui MA (1999) The design of potent and selective inhibitors of thrombin utilizing a piperazinedione template: part 1. Bioorg Med Chem Lett 9:2497–2502

    Article  PubMed  CAS  Google Scholar 

  • De Candia M, Fossa P, Cellamare S, Mosti L, Carotti A, Altomare C (2005) Insights into structure-activity relationships from lipophilicity profiles of pyridine-2(1H)-one analogs of the cardiotonic agent milrinone. Eur J Pharm Sci 26:78–86

    Article  PubMed  Google Scholar 

  • De Marco A, de Candia M, Carroti A, Cellamare S, De Candia E, Altomare C (2004) Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides. Eur J Pharm Sci 22:153–164

    Article  PubMed  Google Scholar 

  • Dillingham EO, Lasslo A, Carter-Burks G, Bond SE, Gollamudi R (1989) Relationships between chemical structure and inhibition of ADP-stimulated human thrombocyte release of serotonin and platelet factor 4. Biochim Biophys Acta 990:128–132

    PubMed  CAS  Google Scholar 

  • Dogné J-M, de Leval X, Benoit P, Delarge J, Masereel B, David J-L (2001) Recent advances in antiplatelet agents. Curr Med Chem 9:577–589

    Article  Google Scholar 

  • Feng Z, Gollamudi R, Dillingham EO, Bond SE, Lyman BA, Purcell WP, Hill RJ, Korfmacher WA (1992) Molecular determinants of the platelet aggregation inhibitory activity of carbamoylpiperidines. J Med Chem 35:2952–2958

    Article  PubMed  CAS  Google Scholar 

  • Fuster V, Badimon L, Badimon JJ, Chesebro JH (1992) The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 326:242–250

    Article  PubMed  CAS  Google Scholar 

  • Gachet C (2001) ADP receptors of platelets and their inhibition. Thromb Haemost 86:222–232

    PubMed  CAS  Google Scholar 

  • Gader AMA, Bahakim HM, Jabbar FA, Lambourne AL, Gaafar TH, Edrees YB (1988) Dose-response aggregometry in maternal/neonatal platelets. Thromb Haemostat 60:314–318

    CAS  Google Scholar 

  • Heath JA, Mehrotra MM, Chi S, Yu J-C, Hutchaleelaha A, Hollenbach SJ, Giese NA, Scarborough RM, Pandey A (2004) Corrigendum to “Identification of 4-piperazin-1-yl-quinazoline template based aryl and benzyl thioureas as potent, selective, and orally bioavailable inhibitors of platelet-derived growth factor (PDGF) receptor. Bioorg Med Chem Lett 14:6133–6142

    CAS  Google Scholar 

  • Hyperchem (1999) Molecular Modeling System, Hypercube, Inc., Release 6, Florida, USA

  • Kunapuli SP (1998) Multiple P2 receptor subtypes on platelets: a new interpretation of their function. Trends Pharmacol Sci 19:391–394

    Article  PubMed  CAS  Google Scholar 

  • Leoncini G, Signorello MG, Roma G, Di Braccio M (1997) Effect of 2(1-piperazinyl)-4H-pyrido[1, 2-a]pyrimidin-4-one (AP155) on human platelets in vitro. Biochem Pharmacol 53:1667–1672

    Article  PubMed  CAS  Google Scholar 

  • Leoncini G, Signorello MG, Bruzzese D, Di Braccio M, Grossi GC, Roma G (2004) Mechanisms involved in the antiplatelet activity of 8-methyl-4-(1-piperazinyl)-7-(3-pyridinylmethoxy)-2H–1-benzopyran-2-one (RC414). Biochem Pharmacol 67:911–918

    Article  PubMed  CAS  Google Scholar 

  • Majerus W, Tollesfsen DM (2001) Anticoagulant, thrombolytic, and antiplatelet drugs. In: Goodman LS, Gilman AG, Limbird LE (eds) The Goodman Gilman’s pharmacological basis of therapeutics. McGraw-Hill, New York, pp 1519–1537

    Google Scholar 

  • McKee SA, Sane DC, Deliargyris EN (2002) Aspirin resistance in cardiovascular disease: a review of prevalence, mechanisms, and clinical significance. Thromb Haemost 88:711–715

    PubMed  CAS  Google Scholar 

  • Mills DC (1996) ADP receptors on platelets. Thromb Haemost 76:835–856

    PubMed  CAS  Google Scholar 

  • Papadopoulou C, Geronikaki A, Hadjipavlou-Litina D (2005) Synthesis and biological evaluation of new thiazolyl/benzothiazolyl-amides, derivatives of 4-phenylpiperazine. Farmaco 60:969–973

    Article  PubMed  CAS  Google Scholar 

  • Patrono C, Coller B, Dalen JE, FitzGerald GA, Fuster V, Gent M, Hirsh J, Roth G (2001) Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 119:39S–63S

    Article  PubMed  CAS  Google Scholar 

  • Sallem W, Serradji N, Dereuddre-Bosquet N, Dive G, Clayette P, Heymans F (2006) Structure–activity relationships in platelet-activating factor. Part 14: synthesis and biological evaluation of piperazine derivatives with dual anti-PAF and anti-HIV-1 activity. Bioorg Med Chem Lett 14:7999–8013

    Article  CAS  Google Scholar 

  • Slotboom AJ, Verheij HM, De Haas GH (1982) Specific transformations at the N-terminal region of phospholipase A2. In: Ansell GB (ed) Phospholipids. Elsevier, Amsterdam, pp 359–434

    Google Scholar 

  • Storey F (2001) The P2Y12 receptor as a therapeutic target in cardiovascular disease. Platelets 12:197–209

    Article  PubMed  CAS  Google Scholar 

  • Tucker TJ, Lumma WC, Mulichak AM, Naylor-Olsen AM, Lewis SD, Lucas R, Freidinger RM, Kuo LC (1997) Design of highly potent noncovalent thrombin inhibitors that utilize a novel lipophilic binding pocket in the thrombin active Site. J Med Chem 40:830–832

    Article  PubMed  CAS  Google Scholar 

  • Van De Graaff E, Steinhubl SR (2000) Antiplatelet medications and their indications in preventing and treating coronary thrombosis. Ann Med 32:561–571

    Article  Google Scholar 

  • Weksler BB (2000) Antiplatelet agents in stroke prevention. Combination therapy: present and future. Cerebrovasc Dis 10:41–48

    Article  PubMed  CAS  Google Scholar 

  • Youssef KM, Al-Shafie FS (1998) ADP-and arachidonic acid (AA)-induced platelet aggregation inhibitory activity of carbamoylpyridines and carbamoylpiperidines. Al-Azhar Bull Sci 9:569–582

    CAS  Google Scholar 

Download references

Acknowledgment

The financial support of King Abdulaziz City for Science and Technology, Project No. AR-25-50 is greatly appreciated.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University, 12311, Cairo, Egypt

    Khairia M. Youssef

  2. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia

    Mohamed A. Al-Omar, Hussein I. El-Subbagh & Nadia G. Haress

  3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt

    Laila A. Abou-zeid

  4. Department of Physiology, College of Medicine, King Saud University, Riyadh, 11451, Saudi Arabia

    Abdel-Galil M. Abdel-Gader & Ali S. Al-Tuwaijri

Authors
  1. Khairia M. Youssef
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohamed A. Al-Omar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hussein I. El-Subbagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laila A. Abou-zeid
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdel-Galil M. Abdel-Gader
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nadia G. Haress
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ali S. Al-Tuwaijri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Khairia M. Youssef.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Youssef, K.M., Al-Omar, M.A., El-Subbagh, H.I. et al. Synthesis, antiplatelet aggregation activity, and molecular modeling study of novel substituted-piperazine analogues. Med Chem Res 20, 898–911 (2011). https://doi.org/10.1007/s00044-010-9411-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-010-9411-5

Keywords

Search

Navigation