Novel N-substituted indole hydrazones as potential antiplatelet agents: synthesis, biological evaluations, and molecular docking studies

Navid Tavili , Shaya Mokhtari, Hafezeh Salehabadi, Marjan Esfahanizadeh, Shohreh Mohebbi


Background and purpose: Antiplatelet agents can diminish the chance of coronary heart diseases due to the prevention of unusual clotting in the arteries by inhibiting platelet aggregation and avoiding the formation of a blood clot. This mechanism can help to prevent ischemic stroke likewise. To improve the activity of these drugs and reduce their side effects, further studies are required.

Experimental approach: Based on the previous studies representing the promising antiplatelet activity of indole hydrazones, a series of their homologs containing twenty-one compounds were prepared in two steps. First, alkylation reaction on the nitrogen of the indole ring, and second, chiff base formation by condensation of a primary amine and N-substituted indole-3 carbaldehyde. Consequently, their platelet anti-aggregation activity was evaluated based on the Born turbidimetric method.

Findings/Results: Most of the compounds exhibited noticeable activity against platelet aggregation induced by arachidonic acid. Amongst them, two compounds 2e and 2f showed higher activity with IC50 values that made comparable to indomethacin and acetylsalicylic acid as standard drugs and had no toxicity on platelets.

Conclusion and implications: The synthesized compounds exhibited promising activity against arachidonic acid-induced aggregation; however, none of them showed noticeable antiplatelet activity induced by adenosine di-phosphate. Chemical structure comparison of the prepared derivatives indicated the existence of a lipophilic medium-sized group on the phenyl ring increased their activity. In addition, the docking studies confirmed this hydrophobic interaction in the lipophilic pocket of cyclooxygenase-1 enzyme suggesting that hydrophobicity of this region plays a pivotal role in the anti-platelet activity of these compounds. To prove this finding, the enzymatic evaluation with the target enzyme is required.




Keywords: Antiplatelet aggregation; Indole; Synthesis; Turbidimetric assay.

Full Text:



Mendis S, Puska P, Norrving B. Global Atlas on Cardiovascular Disease Prevention and Control. Geneva: World Health Organization; 2011. pp: 3-12.

Stegner D, Klaus V, Nieswandt B. Platelets as modulators of cerebral ischemia/reperfusion injury. Front Immunol. 2019;10:2505,1-10.

DOI: 10.3389/fimmu.2019.02505.

Hall R, Mazer CD. Antiplatelet drugs: a review of their pharmacology and management in the perioperative period. Anesth Analg. 2011;112(2):292-318.

DOI: 10.1213/ane.0b013e318203f38d.

Guthrie R. Review and management of side effects associated with antiplatelet therapy for prevention of recurrent cerebrovascular events. Adv Ther. 2011;28:473-482.

DOI: 10.1007/s12325-011-0026-0.

Chelucci RC, Dutra LA, Lopes Pires ME, De Melo TRF, Bosquesi PL, Chung MC, et al. Antiplatelet and antithrombotic activities of non-steroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit. Molecules. 2014;19(2):2089-2099.

DOI: 10.3390/molecules19022089.

Khalid W, Badshah A, Khan AU, Nadeem H, Ahmed S. Synthesis, characterization, molecular docking evaluation, antiplatelet and anticoagulant actions of 1,2,4 triazole hydrazone and sulphonamide novel derivatives. Chem Cent J. 2018;12(1):11-26.

DOI: 10.1186/s13065-018-0378-5.

Ramzan A, Nazeer A, Irfan A, Al-Sehemi A, Verpoort F, Khatak Z, et al. Synthesis and antiplatelet potential evaluation of 1,3,4-oxadiazoles derivatives. Z Phys Chem. 2019;233(12):1741-1759.

DOI: 10.1515/zpch-2018-1316.

Silva GA, Costa LMM, Brito FCF, Miranda ALP, Barreiro EJ, Fraga CA. New class of potent antinociceptive and antiplatelet 10H-phenothiazine-1-acylhydrazone derivatives. Bioorg Med Chem. 2004;12(12):3149-3158.

DOI: 10.1016/j.bmc.2004.04.009.

Mashayekhi V, Tehrani KHME, Amidi S, Kobarfard F. Synthesis of novel indole hydrazine derivatives and evaluation of their antiplatelet aggregation activity. Chem Pharm Bull (Tokyo). 2013;61(2): 144-150.

DOI: 10.1248/cpb.c12-00597.

Lima LA, Frattani FS, Dos Santos JL, Castro HC, Fraga CA, Zingali RB, et al. Synthesis and anti-platelet activity of novel arylsulfonate-acylhydrazone derivatives, designed as antithrombotic candidates. Eur J Med Chem. 2008;43(2):348-356.

DOI: 10.1016/j.ejmech.2007.03.032.

Tehrani KHME, Esfahanizadeh M, Mashayekhi V, Hashemi M, Kobarfard F, Gharebaghi F, et al. Synthesis, antiplatelet activity and cytotoxicity assessment of indole-based hydrazine derivatives. Iran J Pharm Res. 2015;14(4):1077-1086.

PMID: 26664374.

Kalhor N, Mardani M, Abdollahzadeh S, Vakof M, Esfahanizadeh M, Tehrani KHME, et al. Novel N-substituted ((1H-indol-3-yl)methylene) benzohydrazides and ((1H-indol-3-yl)methylene)-2-phenylhydrazines: synthesis and antiplatelet aggregation activity. Bull Korean Chem Soc. 2015;36(11):2632-2639.

DOI: 10.1002/bkcs.10531.

Esfahanizadeh M, Mohebbi S, Bozorg BD, Amidi S, Gudarzi A, Ayatollahi SA, et al. Synthesis and antiplatelet aggregation activity evaluation of some 2-aminopyrimidine and 2-substituted-4,6-diaminopyrimidine derivatives. Iran J Pharm Res. 2015;14(2):417-427.

PMID: 25901148.

Sum TJ, Sum TH, Galloway WRJD, Twigg DG, Ciardiello JJ, Spring DR. Synthesis of structurally diverse biflavonoids. Tetrahedron. 2018;74(38):5089-5101.

DOI: 10.1016/j.tet.2018.05.003.

Chemate S, Sekar N. Indole-based NLOphoric donor-π-acceptor styryl dyes: synthesis, spectral properties and computational studies. J Fluoresc. 2016;26(6):2063-2077.

DOI: 10.1007/s10895-016-1901-5.

Li W, Qi YY, Wang YY, Gan YY, Shao LH, Zhang LQ, et al. Design, synthesis, and biological evaluation of sorafenib derivatives containing indole (ketone) semicarbazide analogs as antitumor agents. J Heterocyclic Chem. 2020;57(6): 2548-2560.

DOI: 10.1002/jhet.3972.

Hassan M, Ghaffari R, Sardari S, Farahani YF, Mohebbi S. Discovery of novel isatin-based thiosemicarbazones: synthesis, antibacterial, antifungal, and antimycobacterial screening. Res Pharm Sci. 2020;15(3):281-290.

DOI: 10.4103/1735-5362.288435.

Rezaee Nasab R, Mansourian M, Hassanzadeh F. Synthesis, antimicrobial evaluation and docking studies of some novel quinazolinone Schiff base derivatives. Res Pharm Sci. 2018;13(3):213-221.

DOI: 10.4103/1735-5362.228942.

Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature. 1962;194:927-929.

DOI: 10.1038/194927b0.

Eskandariyan Z, Esfahanizadeh M, Tehrani KHME, Mashayekhi V, Kobarfard F. Synthesis of thioether derivatives of quinazoline-4-one-2-thione and evaluation of their antiplatelet aggregation activity. Arch Pharm Res. 2014;37(3):332-339.

DOI: 10.1007/s12272-013-0192-5.

Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785-2791.

DOI: 10.1002/jcc.21256.

Abbasi M, Sadeghi-Aliabadi H, Hassanzadeh F, Amanlou M. Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking, molecular dynamic simulation and virtual screening. J Mol Graph Model. 2015;61:186-195.

DOI: 10.1016/j.jmgm.2015.08.001.

Sander T, Freyss J, von Korff M, Rufener C. DataWarrior: an open-source program for chemistry aware data visualization and analysis. J Chem Inf Model. 2015;55(2):460-473.

DOI: 10.1021/ci500588j.

Moraes AdTO, Miranda MDS, Jacob ÍTT, Amorim CAdC, Moura ROd, Silva SASd, et al. Synthesis, in vitro and in vivo biological evaluation, COX-1/2 inhibition and molecular docking study of indole-N-acylhydrazone derivatives. Bioorg Med Chem. 2018;26(20):5388-5396.

DOI: 10.1016/j.bmc.2018.07.024.

Borges A, Casoti R, Silva MLA, Cunha NL, Rocha Pissurno AP, Kawano DF, et al. COX inhibition profiles and molecular docking studies of the lignan hinokinin and some synthetic derivatives. Mol Inform. 2018;37(12):e1800037.

DOI: 10.1002/minf.201800037.

Abdel-Aziz AAM, Abou-Zeid LA, ElTahir KEH, Mohamed MA, Abu El-Enin MA, El-Azab AS. Design, synthesis of 2,3-disubstitued 4(3H)-quinazolinone derivatives as anti-inflammatory and analgesic agents: COX-1/2 inhibitory activities and molecular docking studies. Bioorg Med Chem. 2016;24(16):3818-3828.

DOI: 10.1016/j.bmc.2016.06.026.


  • There are currently no refbacks.

Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.