Chemical Papers

, Volume 73, Issue 4, pp 987–994 | Cite as

Design and synthesis of novel 3,4-diaminobenzoyl derivatives as antithrombotic agents with improved solubility

  • Guangqu Liu
  • Jiabin Yang
  • Bolang Su
  • Ruizhu Liao
  • Wei ZhouEmail author
  • Li ChenEmail author
Original Paper


To obtain a highly selective, direct coagulation factor Xa (FXa) inhibitor with excellent antithrombotic activity and improved solubility, a series of novel 3,4-diaminobenzoyl derivatives were designed and synthesized based on reported structure–activity relationship analysis of FXa inhibitors. Preliminary solubility test showed that the decrease of intramolecular hydrogen bonds and the change of rigid structure could effectively improve physicochemical property of compounds. The synthesized compound 7ab could significantly prolong prothrombin time at a concentration of 40 nM compared with Apixaban. Docking investigation of 7ab with FXa protein revealed that the several groups could form multiple hydrogen bonds with amino acid residues ALA-190, ASP-189 and GLY-216. These results indicated that compound 7ab might serve as a potential anticoagulant agent.


Anticoagulant Synthesis Improved solubility FXa inhibitor PT Docking 

Supplementary material

11696_2018_645_MOESM1_ESM.docx (1.9 mb)
Supplementary material 1 (DOCX 1969 kb)


  1. Al-Horani RA, Mehta AY, Desai UR (2012) Potent direct inhibitors of factor Xa based on the tetrahydroisoquinoline scaffold. Eur J Med Chem 54:771–783. CrossRefGoogle Scholar
  2. Bijak M, Bobrowski M, Borowiecka M, Podsędek A, Golański J, Nowak P (2011) Anticoagulant effect of polyphenols-rich extracts from black chokeberry and grape seeds. Fitoterapia 82:811–817. CrossRefGoogle Scholar
  3. Bijak M, Ponczek MB, Nowak P (2014) Polyphenol compounds belonging to flavonoids inhibit activity of coagulation factor X. Int J Biol Macromol 65:129–135. CrossRefGoogle Scholar
  4. Bijak M, Saluk J, Szelenberger R, Nowak P (2016) Popular naturally occurring antioxidants as potential anticoagulant drugs. Chem Biol Interact 257:35–45. CrossRefGoogle Scholar
  5. Davie EW, Ratnoff OD (1964) Waterfall sequence for intrinsic blood clotting. Science 145:1310–1312. CrossRefGoogle Scholar
  6. de Candia M et al (2013) Synthesis and biological evaluation of direct thrombin inhibitors bearing 4-(piperidin-1-yl)pyridine at the P1 position with potent anticoagulant activity. J Med Chem 56:8696–8711. CrossRefGoogle Scholar
  7. Evano G, Blanchard N, Toumi M (2008) Copper-mediated coupling reactions and their applications in natural products and designed biomolecules synthesis. Chem Rev 108:3054–3131. CrossRefGoogle Scholar
  8. Imaeda Y et al (2008) Discovery of imidazo[1,5-c]imidazol-3-ones: weakly basic, orally active factor Xa inhibitors. J Med Chem 51:3422–3436. CrossRefGoogle Scholar
  9. Kleanthous S et al (2010) Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs. Bioorg Med Chem Lett 20:618–622. CrossRefGoogle Scholar
  10. Kohrt JT et al (2006) The discovery of glycine and related amino acid-based factor Xa inhibitors. Bioorg Med Chem 14:4379–4392. CrossRefGoogle Scholar
  11. Kohrt JT et al (2007) The discovery of (2R,4R)-N-(4-chlorophenyl)-N-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor. Chem Biol Drug Des 70:100–112. CrossRefGoogle Scholar
  12. Lee YK et al (2008) 7-Fluoroindazoles as potent and selective inhibitors of factor Xa. J Med Chem 51:282–297. CrossRefGoogle Scholar
  13. Macfarlane RG (1964) An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature 202:498. CrossRefGoogle Scholar
  14. Matter H et al (2002) Design and quantitative structure-activity relationship of 3-amidinobenzyl-1H-indole-2-carboxamides as potent, nonchiral, and selective inhibitors of blood coagulation factor Xa. J Med Chem 45:2749–2769CrossRefGoogle Scholar
  15. Nagahara T et al (1994) Dibasic (amidinoaryl)propanoic acid derivatives as novel blood coagulation factor Xa inhibitors. J Med Chem 37:1200–1207CrossRefGoogle Scholar
  16. Nazare M et al (2005) Probing the subpockets of factor Xa reveals two binding modes for inhibitors based on a 2-carboxyindole scaffold: a study combining structure–activity relationship and X-ray crystallography. J Med Chem 48:4511–4525. CrossRefGoogle Scholar
  17. Pruitt JR et al (2000) Isoxazolines and isoxazoles as factor Xa inhibitors. Bioorg Med Chem Lett 10:685–689CrossRefGoogle Scholar
  18. Qiao JX et al (2007) SAR and X-ray structures of enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and cyclohexyldiamine derivatives as inhibitors of coagulation Factor Xa. Bioorg Med Chem Lett 17:4419–4427. CrossRefGoogle Scholar
  19. Trott O, Olson JA (2009) Software news and update AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. Google Scholar
  20. Van Huis CA et al (2009) Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent, orally active factor Xa inhibitors with extended duration of action. Bioorg Med Chem 17:2501–2511. CrossRefGoogle Scholar
  21. Yang J, Su G, Ren Y, Chen Y (2015) Synthesis of 3,4-diaminobenzoyl derivatives as factor Xa inhibitors. Eur J Med Chem 101:41–51. CrossRefGoogle Scholar
  22. Young RJ et al (2006) Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs. Bioorg Med Chem Lett 16:5953–5957. CrossRefGoogle Scholar
  23. Young RJ et al (2011) Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs. Bioorg Med Chem Lett 21:1582–1587. CrossRefGoogle Scholar
  24. Zhao Y et al (2015) Design, synthesis and structure–activity relationship of oxazolidinone derivatives containing novel S4 ligand as FXa inhibitors. Eur J Med Chem 96:369–380. CrossRefGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2018

Authors and Affiliations

  1. 1.Department of PharmaceuticsChina Pharmaceutical UniversityNanjingPeople’s Republic of China
  2. 2.Department of Natural Medicinal Chemistry, School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjingPeople’s Republic of China
  3. 3.Nanjing Zhongrui Pharmaceutical Co., Ltd.NanjingPeople’s Republic of China

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