Synthesis of 4-methoxy-1,3-benzenediolylhydrazones and evaluation of their anti-platelet aggregation activity

Document Type : Research article


1 School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China.

2 Tianjin Key Laboratory of Organic Solar Cells and Photochemical Conversion, School of Chemistry and Chemical Engineering Tianjin University of Technology, Tianjin 300384, China.


In our present investigation, a series of novel 4-methoxy-1,3-benzenediolyl-hydrazones were designed and synthesized, and their ability to inhibit platelet aggregation was evaluated by adenosine diphosphate (ADP) and arachidonic acid (AA). The structures of the synthesized compounds were confirmed by spectral data. Results demonstrated that the activities of all compounds excelled the positive drug Picotamide (25.1 % inhibition rate) and seven compounds (PNN01, PNN03, PNN05, PNN07, PNN09, PNN12, PNN14) have efficiently inhibited platelet aggregation even higher than Clopidogrel (37.6 % inhibition rate) induced by AA. Among them, PNN07 (39.8 % inhibition rate) was considered as the most potent analogue. Evaluation of cytotoxic activity of the compounds against L929 cell line revealed that none of the compounds have significant cytotoxicity. Thus, diolylhydrazones derives are potential to be antiplatelet aggregation inhibitors and maybe working in AA-induced selectively.


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Wong ND. Epidemiological Studies of CHD and the
Evolution of Preventive Cardiology. Nat. Rev. Cardiol
(2014) 11: 276-89.
Lourenço AL, Salvador RRS, Silva LA, Saito MS,
Mello JFR and Cabral LM. Synthesis and mechanistic
evaluation of novelN-benzylidene-carbohydrazide1H-pyrazolo [3, 4-b] pyridine derivatives as nonanionic antiplatelet agents.Eur. J. Med. Chem. (2017)
135: 213-9.
Sakakura K, Nakano M, Otsuka F, Ladich E, Kolodgie
FD and Virmani R. Pathophysiology of Atherosclerosis
Plaque Progression. Heart Lung Circ. (2013) 22: 399-
Münzer P, Borst O, Walker B, Schmid E, Feijge MA H,
Cosemans JMEM, Chatterjee M, Eva-Maria, Schmidt
S, Towhid ST, Leibrock C, Elvers M, Schalle M,
Seizer P, Ferlinz K, May AE, Gulbins E, Heemskerk
Antiplatelet activity of benzenediolylhydrazones
JWM, Gawaz M and Lang F. Acid Sphingomyelinase
Regulates Platelet Cell Membrane Scrambling,
Secretion, and Thrombus Formation. Arterioscler.
Thromb. Vasc. Biol. (2014) 34: 61-71.
Nusca A and Patti G. Platelet Function and Inhibition
in Ischemic Heart Disease. Curr. Cardiol. Rep. (2012)
14: 457-67.
Eikelboom JW, Hirsh J, Spencer FA, Baglin TP and
Weitz JI. Antiplatelet Drugs:Antithrombotic Therapy
and Prevention of Thrombosis, 9th Ed: American
College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest (2012) 141 (2 Suppl):
Versteeg HH, Heemskerk JWM, Levi M and Reitsma,
PH. New Fundamentals in Hemostasis. Cardiovasc
Res. (2013) 93: 327-58.
Broos K, De Meyer SF, Feys HB, Vanhoorelbeke
K and Deckmyn H. Blood Platelet Biochemistry.
Thromb. Res. (2012) 129: 245-9.
Shah R, Keough LA, Belalcazar-Portacio A and
Ramanathan KB. Ticagrelor as an Alternative in
Clopidogrel-Associated Neutropenia. Platelets (2015)
26: 80-2.
de Almeida Chaves DS, Costa SS, de Almeida AP,
Frattani F, Assafim M and Zingali RB. Metabólitos
Secundários de Origem Vegetal: Uma Fonte Potencial
de Fármacos Antitrombóticos. Quim Nova. (2010) 33:
Angiolillo DJ, Datto C, Raines S and Yeomans ND.
Impact of Concomitant Low-Dose Aspirin on the
Safety and Tolerability of Naproxen and Esomeprazole
Magnesium Delayed-Release Tablets in Patients
Requiring Chronic Nonsteroidal Anti-Inflammatory
Drug Therapy: An Analysis from 5 Phase III Studies.
J. Thromb. Thrombolysis (2014) 38: 11-3.
Choi JT, Shin KA and Kim YK. Prevalence of Aspirin
Resistance and Clinical Characteristics in Patients
with Cerebral Infarction. Korean Soc. Biomed. Lab.
Sci. (2013) 3: 233-8.
Kunadian V, Sinclair H, Sutton A and Dangas G.
Aspirin, Platelet P2Y12 Receptor Inhibitors, and Other
Oral Antiplatelets: Comparative Pharmacology and
Role in Elective PCI. Interv. Cardiol. Clin. (2013) 2:
Reiter R A and Jilma B. Platelets and new antiplatelet
drugs. Therapy (2005) 2: 465-502.
Liu XJ, Wang CQ, Meng J, Shi XX, Yan YN and Liu
XG. Design, synthesis and biological evaluation of
4-methoxy diaryl isophthalates as antiplatelet agents.
Med. Chem. Res. (2017) 1: 1-7.
Cunha AC, Figueiredo JM, Tributino JLM, Miranda
ALP, Castro HC, Zingali RB, Fraga CAM, de Souza
MCBV, Ferreira VF and Barreiro EJ. Antiplatelet
properties of novel N-substituted-phenyl1,2,3-triazole-4-acylhydrazone derivatives. Bioorg.
Med. Chem. (2003) 11: 2051-9.
Silva GA, Costa LMM, Brito FCF, Miranda ALP,
Barreiro EJ and Fraga CAM. New class of potent
antinociceptive and antiplatelet 10H-phenothiazine1-acylhydrazone derivatives. Bioorg. Med. Chem.
(2004) 12: 3149-58.
Bezerra-Neto HJC, Lacerda DI, Miranda ALP,
Alves HM, Barreiro EJ and Fraga CAM. Design
and synthesis of 3,4-methylene-dioxy-6-
nitrophenoxyacetylhydrazone derivatives obtained
from natural safrole: new lead-agents with analgesic
and antipyretic properties. Bioorg. Med. Chem. (2006)
14: 7924-35.
Duarte CD, Tributino JLM, Lacerda DI, Martins
MV, Alexandre- Moreira MS, Dutra F, Bechara
EJH, De-Paula FS, Goulart MOF, Ferreira J, Calixto
JB, Nunes MP, Bertho AL, Miranda ALP, Barreiro
EJ and Fraga CAM. Synthesis, pharmacological
evaluation and electrochemical studies of novel
derivatives: discovery of LASSBio-881, a new ligand
of cannabinoid receptors. Bioorg. Med. Chem. (2007)
15: 2421-33.
Brito FCF, KummerleAE, LugnierC, Fraga
CAM, Barreiro EJ and Miranda AL. Novel
thienylacylhydrazone derivatives inhibit platelet
aggregation through cyclic nucleotides modulation
and thromboxane A2 synthesis inhibition. Eur. J.
Pharmacol. (2010) 638: 5-12.
Haj Mohammad Ebrahim Tehrani K, Sardari
S, Mashayekhi V, Esfahani Zadeh M, Azerang M
and Kobarfard F. One pot synthesis and biological
activity evaluation of novel Schiff bases derived from
2-hydrazinyl-1,3,4-thiadiazole. Chem. Pharm. Bull.
(2013) 61: 160-6.
Mirfazli S, Khoshneviszadeh M, Jeiroudi M,
Foroumadi A, Kobarfard F, Shafiee A. Design,
synthesis and QSAR study of arylidene indoles as
anti-platelet aggregation inhibitors. Med. Chem. Res.
(2016) 25: 1-18.
Born GVR. Aggregation of blood platelets by
adenosine diphosphate and its reversal. Nature (1962)
194: 927-9.
Xiong JW, Xiao H and Zhang ZX. An Experimental
Research on Different Detection Conditions between
MTT and CCK-8. Acta Laser. Biol. Sin. (2007) 16:
Syakaev V, Podyachev S, Buzykin B, Latypov
S, Habicher W and Konovalov A. NMR study
of conformation and isomer-ization of aryland heteroarylaldehyde 4-tert-butylphenoxyacetylhydrazones. J. Mol. Struct. (2006) 788: 55-62.
Unsal-Tan O, Ozden K, Rauk A and Balkan A.
Synthesis and cyclooxygenase inhibitory activities of
some N-acylhydrazone derivatives of isoxazolo [4,5-
d]pyridazin-4(5H)-ones. Eur. J. Med. Chem. (2010)
45: 2345-52.
Palla G, Predieri G, Domiano P, Vignali C and Turner
W. Conformational behavior and E/Z isomerization of
N-acyl and N-aroylhydrazones. Tetrahedron (1986)
42: 3649-54.
Liu XJ, Yan YN, Wang SQ, Li X and Liu XG. New
synthesis of 4-methoxyisophthalic acid. Russ. J. Org.
Chem. (2017) 53: 459-61.