A Deep Overview of Anticoagulant Drugs: Recent Synthesis and Their Activity Assay


Engrid Juni Astuti(1), Slamet Ibrahim(2), Muhammad Ali Zulfikar(3), Sophi Damayanti(4*)

(1) Pharmacochemistry Research Group, School of Pharmacy, Institut Teknologi Bandung, Jl. Ganesha No. 10, Bandung 40132, Indonesia; Department of Pharmacy, Faculty of Health Sciences, Universitas Muhammadiyah Malang, Jl. Bendungan Sutami No. 188, Malang 65145, Indonesia
(2) Faculty of Pharmacy, Universitas Jenderal Achmad Yani, Jl. Terusan Jenderal Sudirman, Cimahi 40633, Indonesia
(3) Division on Analytical Chemistry, Faculty of Mathematics and Natural Sciences, Institut Teknologi Bandung, Jl. Ganesha No. 10, Bandung 40132, Indonesia
(4) Pharmacochemistry Research Group, School of Pharmacy, Institut Teknologi Bandung, Jl. Ganesha No. 10, Bandung 40132, Indonesia; University Center of Excellence on Artificial Intelligence for Vision, Natural Language Processing & Big Data Analysis (U-CoE AI-VLB), Institut Teknologi Bandung, Jl. Ganesha No. 10, Bandung 40132, Indonesia
(*) Corresponding Author


During the unprecedented COVID-19 pandemic, anticoagulant drugs have emerged as a crucial component of treatment alongside antivirus medications. Patients with severe COVID-19 frequently have critical conditions marked by blood clot development, necessitating the administration of anticoagulants. This review aims to provide a comprehensive overview of various anticoagulant drugs, their synthesis methods, and assays employed to predict their anticoagulant activity. Notable anticoagulant categories frequently utilized include oral anticoagulants heparin, non-vitamin K antagonists, and vitamin K antagonists. In recent years, the development of new anticoagulants has seen a shift towards a multifaceted approach that combines in silico prediction with in vitro and in vivo assays. In silico prediction techniques play a pivotal role in the initial screening process. This integrated approach has yielded promising results, paving the way for the synthesis of novel anticoagulant candidates, as substantiated by a battery of in vitro, in vivo, and ex-vivo tests.


anticoagulant, prediction, synthesis, anticoagulant activity

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[1] Hussain, Z., Cooke, A.J., Neelamkavil, S., Brown, L., Carswell, E., Geissler, W.M., Guo, Z., Hawes, B., Kelly, T.M., Kiyoi, Y., Lai, K., Lesburg, C., Pow, E., Zang, Y., Wood, H.B., Edmondson, S.D., and Liu, W., 2020, Design and synthesis of novel proline based factor XIa selective inhibitors as leads for potential new anticoagulants, Bioorg. Med. Chem. Lett., 30 (16), 127072.

[2] Lu, D., Jin, Y., Wang, X., Xie, L., Liu, Q., Chen, Y., Wang, H., and Lei, Z., 2021, Heparin-like anticoagulant polypeptides with tunable activity: Synthesis, characterization, anticoagulative properties and clot solubilities in vitro, Mater. Sci. Eng., C, 129, 112405.

[3] Araújo, C.C.B., Simon, A., Honório, T.S., da Silva, S.V.C., Valle, I.M.M., da Silva, L.C.R.P., Rodrigues, C.R., de Sousa, V.P., Cabral, L.M., Sathler, P.C., and do Carmo, F.A., 2021, Development of rivaroxaban microemulsion-based hydrogel for transdermal treatment and prevention of venous thromboembolism, Colloids Surf., B, 206, 111978.

[4] Santana, A.G., Gracher, A.H.P., Rüdiger, A.L., Zanchin, N.I.T., Carvalho, P.C., Cipriani, T.R., and de Arruda Campos Brasil de Souza, T., 2017, Identification of potential targets for an anticoagulant pectin, J. Proteomics, 151, 243–250.

[5] Imran, M., Sajwan, M., Alsuwayt, B., and Asif, M., 2020, Synthesis, characterization and anticoagulant activity of chitosan derivatives, Saudi Pharm. J., 28 (1), 25–32.

[6] Santinon, C., Ochi, D., Beppu, M.M., and Vieira, M.G.A., 2022, Chemical modifications in the structure of seaweed polysaccharides as a viable antimicrobial application: A current overview and future perspectives, Algal Res., 66, 102796.

[7] Sun, X., Hong, Z., Liu, M., Guo, S., Yang, D., Wang, Y., Lan, T., Gao, L., Qi, H., Gong, P., and Liu, Y., 2017, Design, synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity, Bioorg. Med. Chem., 25 (10), 2800–2810.

[8] Wang, F., Ren, Y.J., and Dong, M.H., 2016, Molecular design, synthesis and anticoagulant activity evaluation of fluorinated dabigatran analogues, Bioorg. Med. Chem., 24 (12), 2739–2753.

[9] Khadse, A.N., Savsani, H.H., Chikhale, R.V., Ghuge, R.B., Prajapati, D.R., Kureshi, G., Murumkar, P.R., Patel, K.V., Rajput, S.J., and Yadav, M.R., 2022, Design, synthesis and biological evaluation of piperazinylanthranilamides as potential factor Xa inhibitors, J. Mol. Struct., 1270, 133974.

[10] Ayan, S., Dogan, Ö., Ivantcova, P.M., Datsuk, N.G., Shulga, D.A., Chupakhin, V.I., Zabolotnev, D.V., and Kudryavtsev, K.V., 2013, Asymmetric synthesis and molecular docking study of enantiomerically pure pyrrolidine derivatives with potential antithrombin activity, Tetrahedron: Asymmetry, 24 (13-14), 838–843.

[11] Krishnan, H., Gopinath, S.C.B., Zulhaimi, H.I., Md Arshad, M.K., and Subramaniam, S., 2021, In silico structural analysis of truncated 2’ fluoro-RNA aptamer: Elucidating EGF-1 and EGF-2 binding domains on factor IX protein, Process Biochem., 111 (P2), 124–131.

[12] Gao, X., Wang, X., Tie, S., Cui, H., Shen, J., Wang, P.G., and Zhao, W., 2016, An efficient anticoagulant candidate: Characterization, synthesis and in vivo study of a fondaparinux analogue Rrt1.17, Eur. J. Med. Chem., 126, 1039–1055.

[13] Colodi, F.G., Ducatti, D.R.B., Noseda, M.D., de Carvalho, M.M., Winnischofer, S.M.B., and Duarte, M.E.R., 2021, Semi-synthesis of hybrid ulvan-kappa-carrabiose polysaccharides and evaluation of their cytotoxic and anticoagulant effects, Carbohydr. Polym., 267, 118161.

[14] Ouerghemmi, S., Dimassi, S., Tabary, N., Leclercq, L., Degoutin, S., Chai, F., Pierlot, C., Cazaux, F., Ung, A., Staelens, J.N., Blanchemain, N., and Martel, B., 2018, Synthesis and characterization of polyampholytic aryl-sulfonated chitosans and their in vitro anticoagulant activity, Carbohydr. Polym., 196 (8), 8–17.

[15] Cronin, M.T.D., Belfield, S.J., Briggs, K.A., Enoch, S.J., Firman, J.W., Frericks, M., Garrard, C., Maccallum, P.H., Madden, J.C., Pastor, M., Sanz, F., Soininen, I., and Sousoni, D., 2023, Making in silico predictive models for toxicology FAIR, Regul. Toxicol. Pharm., 140, 105385.

[16] Askri, S., Edziri, H., Ben Hamouda, M., Mchiri, C., Gharbi, R., Abd El-Gawad, H.H., and El-Tahawy, M.M.T., 2022, Synthesis, biological evaluation, density functional calculation and molecular docking analysis of novel spiropyrrolizidines derivatives as potential anti-microbial and anti-coagulant agents, J. Mol. Struct., 1250, 131688.

[17] Anwaar, M.U., Adnan, F., Abro, A., Khan, R.A., Rehman, A.U., Osama, M., Rainville, C., Kumar, S., Sterner, D.E., Javed, S., Jamal, S.B., Baig, A., Shabbir, M.R., Ahsan, W., Butt, T.R., and Assir, M.Z., 2022, Combined deep learning and molecular docking simulations approach identifies potentially effective FDA approved drugs for repurposing against SARS-CoV-2, Comput. Biol. Med., 141, 105049.

[18] Ceccato, A., Camprubí-Rimblas, M., Campaña-Duel, E., Areny-Balagueró, A., Morales-Quinteros, L., and Artigas, A., 2022, Anticoagulant treatment in severe ARDS COVID-19 patients, J. Clin. Med., 11 (10), 2695.

[19] Egunsola, O., Li, J.W., Mastikhina, L., Akeju, O., Dowsett, L.E., and Clement, F., 2022, A qualitative systematic review of facilitators of and barriers to community pharmacists–led anticoagulation management service, Ann. Pharmacother., 56 (6), 704–715.

[20] Toma, M.M., Bungau, S.G., Tit, D.M., Moisi, M.I., Bustea, C., Vesa, C.M., Behl, T., Stoicescu, M., Brisc, C.M., Purza, L.A., Gitea, D., and Diaconu, C.C., 2022, Use of anticoagulant drugs in patients with atrial fibrillation. Does adherence to therapy have a prognostic impact?, Biomed. Pharmacother., 150, 113002.

[21] Becattini, C., Pace, U., Pirozzi, F., Donini, A., Avruscio, G., Rondelli, F., Boncompagni, M., Chiari, D., De Prizio, M., Visonà, A., De Luca, R., Guerra, F., Muratore, A., Portale, G., Milone, M., Castagnoli, G., Righini, M., Martellucci, J., Persiani, R., Frasson, S., Dentali, F., Delrio, P., Campanini, M., Gussoni, G., Vedovati, M.C., and Agnelli, G., 2022, Rivaroxaban vs placebo for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer, Blood, 140 (8), 900–908.

[22] Kluge, K.E., Seljeflot, I., Arnesen, H., Jensen, T., Halvorsen, S., and Helseth, R., 2022, Coagulation factors XI and XII as possible targets for anticoagulant therapy, Thromb. Res., 214, 53–62.

[23] DeWald, T.A., Washam, J.B., and Becker, R.C., 2018, Anticoagulants: Pharmacokinetics, Mechanisms of Action, and Indications, Neurosurg. Clin. N. Am., 29 (4), 503–515.

[24] Li, A., Li, M.K., Crowther, M., and Vazquez, S.R., 2020, Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: A systematic review, Thromb. Res., 194, 240–245.

[25] Dobesh, P.P., Bhatt, S.H., Trujillo, T.C., and Glaubius, K., 2019, Antidotes for reversal of direct oral anticoagulants, Pharmacol. Ther., 204, 107405.

[26] Cho, M.S., Kim, M., Lee, S., Lee, S., Kim, D.H., Kim, J., Song, J.M., Nam, G.B., Kim, S.J., Kang, D.H., and Choi, K.J., 2022, Comparison of dabigatran versus warfarin treatment for prevention of new cerebral lesions in valvular atrial fibrillation, Am. J. Cardiol., 175, 58–64.

[27] Park, I.H., Park, J.W., Chung, H., Kim, J.M., Lee, S., Kim, K.A., and Park, J.Y., 2021, Development and validation of LC–MS/MS method for simultaneous determination of dabigatran etexilate and its active metabolites in human plasma, and its application in a pharmacokinetic study, J. Pharm. Biomed. Anal., 203, 114220.

[28] Grover, S.P., Coughlin, T., Fleifil, S.M., Posma, J.J.N., Spronk, H.H.M., Heitmeier, S., Owens, A.P., and Mackman, N., 2022, Effect of combining aspirin and rivaroxaban on atherosclerosis in mice, Atherosclerosis, 345, 7–14.

[29] Xu, J., Chang, D., Chui, J., Cao, J., and Negus, J., 2022, The efficacy and cost-effectiveness of enoxaparin versus rivaroxaban in the prevention of venous thromboembolism following total hip or knee arthroplasty: A meta-analysis, J. Orthop., 30, 1–6.

[30] Marston, X.L., Wang, R., Yeh, Y.C., Zimmermann, L., Ye, X., Gao, X., Brüggenjürgen, B., and Unverdorben, M., 2022, Comparison of clinical outcomes of edoxaban versus apixaban, dabigatran, rivaroxaban, and vitamin K antagonists in patients with atrial fibrillation in Germany: A real-world cohort study, Int. J. Cardiol., 346, 93–99.

[31] Di Minno, A., Frigerio, B., Spadarella, G., Ravani, A., Sansaro, D., Amato, M., Kitzmiller, J.P., Pepi, M., Tremoli, E., and Baldassarre, D., 2017, Old and new oral anticoagulants: Food, herbal medicines and drug interactions, Blood Rev., 31 (4), 193–203.

[32] Gouveia, F., Bicker, J., Gonçalves, J., Alves, G., Falcão, A., and Fortuna, A., 2019, Liquid chromatographic methods for the determination of direct oral anticoagulant drugs in biological samples: A critical review, Anal. Chim. Acta, 1076, 18–31.

[33] Dobesh, P.P., and Trevarrow, B.J., 2019, Betrixaban: Safely reducing venous thromboembolic events with extended prophylaxis, Am. J. Med., 132 (3), 307–311.

[34] Røed-Undlien, H., Schultz, N.H., Lunnan, A., Husebråten, I.M., Wollmann, B.M., Molden, E., and Bjørnstad, J.L., 2022, In vitro apixaban removal by CytoSorb whole blood adsorber: an experimental study, J. Cardiothorac. Vasc. Anesth., 36 (6), 1636–1644.

[35] Zhang, T., Liu, X., Li, H., Wang, Z., Chi, L., Li, J.P., and Tan, T., 2019, Characterization of epimerization and composition of heparin and dalteparin using a UHPLC-ESI-MS/MS method, Carbohydr. Polym., 203, 87–94.

[36] Wu, F., Dong, K., Zhu, M., Zhang, Q., Xie, B., Li, D., Gan, H., Linhardt, R.J., and Zhang, Z., 2019, Development of a method to analyze the complexes of enoxaparin and platelet factor 4 with size-exclusion chromatography, J. Pharm. Biomed. Anal., 164, 668–671.

[37] Zhang, C., Qi, S., Meng, J., and Chen, X., 2021, Selective and efficient extraction of heparin by arginine-functionalized flowered mesoporous silica nanoparticles with high capacity, Sep. Purif. Technol., 276, 119321.

[38] Mycroft-West, C.J., Su, D., Pagani, I., Rudd, T.R., Elli, S., Gandhi, N.S., Guimond, S.E., Miller, G.J., Meneghetti, M.C.Z., Nader, H.B., Li, Y., Nunes, Q.M., Procter, P., Mancini, N., Clementi, M., Bisio, A., Forsyth, N.R., Ferro, V., Turnbull, J.E., Guerrini, M., Fernig, D.G., Vicenzi, E., Yates, E.A., Lima, M.A., and Skidmore, M.A., 2020, Heparin inhibits cellular invasion by SARS-CoV-2: Structural dependence of the interaction of the spike S1 receptor-binding domain with heparin, Thromb. Haemost., 120 (12), 1700–1715.

[39] Liu, X., St. Ange, K., Lin, L., Zhang, F., Chi, L., and Linhardt, R.J., 2017, Top-down and bottom-up analysis of commercial enoxaparins, J. Chromatogr. A, 1480, 32–40.

[40] Fu, L., Suflita, M., and Linhardt, R.J., 2016, Bioengineered heparins and heparan sulfates, Adv. Drug Delivery Rev., 97, 237–249.

[41] Yan, Y., Sun, Y., Wang, P., Zhang, R., Huo, C., Gao, T., Song, C., Xing, J., and Dong, Y., 2020, Mucoadhesive nanoparticles-based oral drug delivery systems enhance ameliorative effects of low molecular weight heparin on experimental colitis, Carbohydr. Polym., 246, 116660.

[42] Qiu, M., Huang, S., Luo, C., Wu, Z., Liang, B., Huang, H., Ci, Z., Zhang, D., Han, L., and Lin, J., 2021, Pharmacological and clinical application of heparin progress: An essential drug for modern medicine, Biomed. Pharmacother., 139, 111561.

[43] Permsuwan, U., Chaiyakunapruk, N., Nathisuwan, S., and Sukonthasarn, A., 2015, Cost-effectiveness analysis of fondaparinux vs enoxaparin in non-ST elevation acute coronary syndrome in Thailand, Heart, Lung Circ., 24 (9), 860–868.

[44] Shi, C., Wang, C., Wang, H., Yang, C., Cai, F., Zeng, F., Cheng, F., Liu, Y., Zhou, T., Deng, B., Vlodavsky, I., Li, J.P., and Zhang, Y., 2020, The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID-19 patients: A retrospective cohort study, Clin. Transl. Sci., 13 (6), 1087–1095.

[45] Kamel, A.M., Sobhy, M., Magdy, N., Sabry, N., and Farid, S., 2021, Anticoagulation outcomes in hospitalized Covid-19 patients: A systematic review and meta-analysis of case-control and cohort studies, Rev. Med. Virol., 31 (3), e2180.

[46] Vitiello, A., and Ferrara, F., 2021, Low molecular weight heparin, anti-inflammatory/immunoregulatory and antiviral effects, a short update, Cardiovasc. Drugs Ther., 37 (2), 277–281.

[47] Xie, L., Chen, Z., Wang, H., Zheng, C., and Jiang, J., 2020, Bibliometric and visualized analysis of scientific publications on atlantoaxial spine surgery based on web of science and VOSviewer, World Neurosurg., 137, 435–442.e4.

[48] Chen, Y., Sun, X., Shan, J., Tang, C., Hu, R., Shen, T., Qiao, H., Li, M., Zhuang, W., Zhu, C., and Ying, H., 2020, Flow synthesis, characterization, anticoagulant activity of xylan sulfate from sugarcane bagasse, Int. J. Biol. Macromol., 155, 1460–1467.

[49] Mao, J.Y., Lin, F.Y., Chu, H.W., Harroun, S.G., Lai, J.Y., Lin, H.J., and Huang, C.C., 2019, In situ synthesis of core-shell carbon nanowires as a potent targeted anticoagulant, J. Colloid Interface Sci., 552, 583–596.

[50] Venkatappa, M.M., Udagani, C., Hanumegowda, S.M., Pramod, S.N., Venkataramaiah, S., Rangappa, R., Achur, R., Alataway, A., Dewidar, A.Z., Al-Yafrsi, M., Mahmoud, E.A., Elansary, H.O., and Sannaningaiah, D., 2022, Effect of Biofunctional Green synthesized MgO-nanoparticles on oxidative-stress-induced tissue damage and thrombosis, Molecules, 27 (16), 5162.

[51] El-Waseif, A.A., Alshehrei, F., Al-Ghamdi, S.B., and El-Ghwas, D.E., 2022, Antioxidant and anticoagulant activity of microbial nano cellulose-ZnO-Ag composite components, Pak. J. Biol. Sci., 25 (6), 531–536.

[52] Ramesh, G., Sharath Kumar, N.M., Raghavendra Kumar, P., Suchetan, P.A., Devaraja, S., Sabine, F., and Nagaraju, G., 2020, Synthesis, characterisation, crystal structures, anticoagulant and antiplatelet activity studies of new 2,6-dipyrazinylpyridines with pendant trimethoxyphenyl, J. Mol. Struct., 1200, 127040.

[53] Debbabi, M., Nimbarte, V.D., Chekir, S., Chortani, S., Romdhane, A., and Ben jannet, H., 2019, Design and synthesis of novel potent anticoagulant and anti-tyrosinase pyranopyrimidines and pyranotriazolopyrimidines: Insights from molecular docking and SAR analysis, Bioorg. Chem., 82, 129–138.

[54] Skorik, Y.A., Kritchenkov, A.S., Moskalenko, Y.E., Golyshev, A.A., Raik, S.V., Whaley, A.K., Vasina, L.V., and Sonin, D.L., 2017, Synthesis of N-succinyl- and N-glutaryl-chitosan derivatives and their antioxidant, antiplatelet, and anticoagulant activity, Carbohydr. Polym., 166, 166–172.

[55] Cheng, S., Wu, D., Liu, H., Xu, X., Zhu, B., and Du, M., 2021, A novel anticoagulant peptide discovered from: Crassostrea gigas by combining bioinformatics with the enzymolysis strategy: Inhibitory kinetics and mechanisms, Food Funct., 12 (20), 10136–10146.

[56] Huang, S., Ren, Y., Peng, X., Qian, P., and Meng, L., 2019, Computer-aid drug design, synthesis, and anticoagulant activity evaluation of novel dabigatran derivatives as thrombin inhibitors, Eur. J. Pharm. Sci., 137, 104965.

[57] Syed, A.A., Venkatraman, K.L., and Mehta, A., 2019, An anticoagulant peptide from Porphyra yezoensis inhibits the activity of factor XIIa: In vitro and in silico analysis, J. Mol. Graph. Model., 89, 225–233.

[58] Kumari, R., and Nath, M., 2018, Synthesis and characterization of novel trimethyltin(IV) and tributylltin(IV) complexes of anticoagulant, WARFARIN: Potential DNA binding and plasmid cleaving agents, Inorg. Chem. Commun., 95, 40–46.

[59] Tu, M., Liu, H., Cheng, S., Mao, F., Chen, H., Fan, F., Lu, W., and Du, M., 2019, Identification and characterization of a novel casein anticoagulant peptide derived from: In vivo digestion, Food Funct., 10 (5), 2552–2559.

[60] Zhang, Y., Yang, R., Wang, L., Li, Y., Han, J., Yang, Y., Zheng, H., Lu, M., Shen, Y., and Yang, H., 2022, Purification and characterization of a novel thermostable anticoagulant protein from medicinal leech Whitmania pigra Whitman, J. Ethnopharmacol., 288, 114990.

[61] Dockal, M., Till, S., Zhang, Z., Knappe, S., Reutterer, S., Quinn, C., Redl, C., Ehrlich, H.J., Scheiflinger, F., and Szabo, C., 2012, Structure-activity relationship of pro- and anticoagulant effects of Fucus vesiculosus fucoidan, Blood, 120 (21), 3353–3353.

[62] Chandika, P., Heo, S.Y., Oh, G.W., Choi, I.W., Park, W.S., and Jung, W.K., 2020, Antithrombin III-mediated blood coagulation inhibitory activity of chitosan sulfate derivatized with different functional groups, Int. J. Biol. Macromol., 161, 1552–1558.

[63] Fernández, P.V., Quintana, I., Cerezo, A.S., Caramelo, J.J., Pol-Fachin, L., Verli, H., Estevez, J.M., and Ciancia, M., 2013, Anticoagulant activity of a unique sulfated pyranosic (1→3)-β-L-arabinan through direct interaction with thrombin, J. Biol. Chem., 288 (1), 223–233.

[64] Koukab, S., Rashid, N., Ahmad, I., Nadeem, H., and Ismail, H., 2022, Synthesis, in-silico studies, and in-vitro bio-evaluation of new bi-thiacoumarins, J. Mol. Struct., 1262, 133040.

[65] Zhang, T., Liu, Q., and Ren, Y., 2020, Design, synthesis and biological activity evaluation of novel methyl substituted benzimidazole derivatives, Tetrahedron, 76 (13), 131027.

[66] Bora, B., Gogoi, D., Tripathy, D., Kurkalang, S., Ramani, S., Chatterjee, A., and Mukherjee, A.K., 2018, The N-terminal-truncated recombinant fibrin(ogen)olytic serine protease improves its functional property, demonstrates in vivo anticoagulant and plasma defibrinogenation activity as well as pre-clinical safety in rodent model, Int. J. Biol. Macromol., 111, 462–474.

[67] Ahmad, I., Sharma, S., Gupta, N., Rashid, Q., Abid, M., Ashraf, M.Z., and Jairajpuri, M.A., 2018, Antithrombotic potential of esculin 7,3′,4′,5′,6′-O-pentasulfate (EPS) for its role in thrombus reduction using rat thrombosis model, Int. J. Biol. Macromol., 119, 360–368.

[68] Ustyuzhanina, N.E., Bilan, M.I., Gerbst, A.G., Ushakova, N.A., Tsvetkova, E.A., Dmitrenok, A.S., Usov, A.I., and Nifantiev, N.E., 2016, Anticoagulant and antithrombotic activities of modified xylofucan sulfate from the brown alga Punctaria plantaginea, Carbohydr. Polym., 136, 826–833.

[69] Yang, H., Liu, Q., Gao, X., Ren, Y., and Gao, Y., 2017, Novel dabigatran derivatives with a fluorine atom at the C-2 position of the terminal benzene ring: Design, synthesis and anticoagulant activity evaluation, Eur. J. Med. Chem., 126, 799–809.

[70] Nanjundaswamy, S., Jayashankar, J., Renganathan, R.R.A., Karthik, C.S., Mallesha, L., Mallu, P., and Rai, V.R., 2022, Pyridine coupled pyrazole analogues as lethal weapon against MRSA: An in-vitro and in-silico approach, Microb. Pathog., 166, 105508.

[71] Tu, M., Liu, H., Cheng, S., Xu, Z., Wang, L.S., and M. Du, 2020, Identification and analysis of transepithelial transport properties of casein peptides with anticoagulant and ACE inhibitory activities, Food Res. Int., 138 (Part A), 109764.

[72] Ilin, I., Lipets, E., Sulimov, A., Kutov, D., Shikhaliev, K., Potapov, A., Krysin, M., Zubkov, F., Sapronova, L., Ataullakhanov, F., and Sulimov, V., 2019, New factor Xa inhibitors based on 1,2,3,4-tetrahydroquinoline developed by molecular modelling, J. Mol. Graphics Modell., 89, 215–224.

[73] Shi, Y., Sun, W., Pan, X., Hou, X., Wang, S., and Zhang, J., 2020, Establishment of thrombin affinity column (TAC)-HPLC-MS/MS method for screening direct thrombin inhibitors from radix Salviae miltiorrhiae, J. Chromatogr. B: Anal. Technol. Biomed. Life Sci., 1139, 121894.

[74] Rayani, R.H., Soni, J.Y., Parmar, D.R., Kusurkar, R.V., Eissae, I.H., Metwaly, A.M., Khalil, A., Zunjar, V., Battula, S., and Niazi, S., 2022, Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation, Results Chem., 4, 100355.

[75] Eranna, S.C., Panchangam, R.K., Kengaiah, J., Adimule, S.P., Foro, S., and Sannagangaiah, D., 2022, Synthesis, structural characterization, and evaluation of new peptidomimetic Schiff bases as potential antithrombotic agents, Monatsh. Chem., 153 (7), 635–650.

[76] Al-Horani, R.A., Abdelfadiel, E.I., Afosah, D.K., Morla, S., Sistla, J.C., Mohammed, B., Martin, E.J., Sakagami, M., Brophy, D.F., and Desai, U.R., 2019, A synthetic heparin mimetic that allosterically inhibits factor Xia and reduces thrombosis in vivo without enhanced risk of bleeding, J. Thromb. Haemost., 17 (12), 2110–2122.

[77] Khdhiri, E., Mnafgui, K., Ghazouani, L., Feriani, A., Hajji, R., Bouzanna, W., Allouche, N., Bazureau, J.P., Ammar, H., and Abid, S., 2020, (E)-N’-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide protecting rat heart tissues from isoproterenol toxicity: Evidence from in vitro and in vivo tests, Eur. J. Pharmacol., 881, 173137.

[78] Jeanne, A., Sarazin, T., Charlé, M., Kawecki, C., Kauskot, A., Hedtke, T., Schmelzer, C.E.H., Martiny, L., Maurice, P., and Dedieu, S., 2021, Towards the therapeutic use of thrombospondin 1/CD47 targeting TAX2 peptide as an antithrombotic agent, Arterioscler., Thromb., Vasc. Biol., 41 (1), e1–e17.

[79] Kardeby, C., Fälker, K., Haining, E.J., Criel, M., Lindkvist, M., Barroso, R., Påhlsson, P., Ljungberg, L.U., Tengdelius, M., Ed Rainger, G., Watson, S., Eble, J.A., Hoylaerts, M.F., Emsley, J., Konradsson, P., Watson, S.P., Sun, Y., and Grenegård, M., 2019, Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIba, Blood Adv., 3 (3), 275–287.

[80] Hogwood, J., Naggi, A., Torri, G., Page, C., Rigsby, P., Mulloy, B., and Gray, E., 2018, The effect of increasing the sulfation level of chondroitin sulfate on anticoagulant specific activity and activation of the kinin system, PLoS One, 13 (3), e0193482.

[81] Osunsanmi, F.O., Zaharare, G.E., Oyinloye, B.E., Mosa, R.A., Ikhile, M.I., Shode, F.O., Ogunyinka, I.B., and Opoku, A.R., 2018, Antithrombotic, anticoagulant and antiplatelet activity of betulinic acid and 3β-acetoxybetulinic acid from Melaleuca bracteata ‘revolution gold’ (Myrtaceae) Muell leaf, Trop. J. Pharm. Res., 17 (10), 1983–1989.

[82] Wang, Y., Chen, H., Zhang, X., Gui, L., Wu, J., Feng, Q., Peng, S., and Zhao, M., 2018, Dimethyl 2,2′-[2,2′-(ethane-1,1-diyl)bis(1H-indole-3,2-diyl)]-diacetate: A small molecule capable of nano-scale assembly, inhibiting venous thrombosis and inducing no bleeding side effect, Int. J. Nanomed., 13, 7835–7844.

[83] Gurevich, K.G., Urakov, A.L., Rozit, G.A., Klen, E., Samorodov, A.V., and Khaliullin, F.A., 2021, Synthesis and antiplatelet and anticoagulant activity of thietane-containing 2-(5-bromo-2,4-dihydro-3-oxo-1,2,4-triazolyl-4)acetate salts, Pharm. Chem. J., 55 (5), 417–422.

[84] Bogdanov, A., Tsivileva, O., Voloshina, A., Lyubina, A., Amerhanova, S., Burtceva, E., Bukharov, S., Samorodov, A., and Pavlov, V., 2022, Synthesis and diverse biological activity profile of triethyl-ammonium isatin-3-hydrazones, ADMET DMPK, 10 (2), 163–179.

[85] Platte, S., Korff, M., Imberg, L., Balicioglu, I., Erbacher, C., Will, J.M., Daniliuc, C.G., Karst, U., and Kalinin, D.V., 2021, Microscale parallel synthesis of acylated aminotriazoles enabling the development of factor XIIa and thrombin inhibitors, ChemMedChem, 16 (24), 3672–3690.

[86] dos Santos-Fidencio, G.C., Gonçalves, A.G., Noseda, M.D., Duarte, M.E.R., and Ducatti, D.R.B., 2019, Effects of carboxyl group on the anticoagulant activity of oxidized carrageenans, Carbohydr. Polym., 214, 286–293.

[87] Wang, Y., Chen, H., Sheng, R., Fu, Z., Fan, J., Wu, W., Tu, Q., and Guo, R., 2021, Synthesis and bioactivities of marine pyran-isoindolone derivatives as potential antithrombotic agents, Mar. Drugs, 19 (4), 218.

[88] Ren, L., You, T., Li, Q., Chen, G., Liu, Z., Zhao, X., Wang, Y., Wang, L., Wu, Y., Tang, C., and Zhu, L., 2020, Molecular docking-assisted screening reveals tannic acid as a natural protein disulphide isomerase inhibitor with antiplatelet and antithrombotic activities, J. Cell. Mol. Med., 24 (24), 14257–14269.

[89] Ahmed, T., Khan, A.U., Abbass, M., Filho, E.R., Ud Din, Z., and Khan, A., 2018, Synthesis, characterization, molecular docking, analgesic, antiplatelet and anticoagulant effects of dibenzylidene ketone derivatives, Chem. Cent. J., 12 (1), 134.

[90] Varghese, M., Rokosh, R.S., Haller, C.A., Chin, S.L., Chen, J., Dai, E., Xiao, R., Chaikof, E.L., and Grinstaff, M.W., 2021, Sulfated poly-amido-saccharides (sulPASs) are anticoagulants: In vitro and in vivo, Chem. Sci., 12 (38), 12719–12725.

[91] Bogdanov, A.V., Sirazieva, A.R., Voloshina, A.D., Abzalilov, T.A., Samorodov, A.V., and Mironov, V.F., 2022, Synthesis and antimicrobial, antiplatelet, and anticoagulant activities of new isatin deivatives containing a hetero-fused imidazole fragment, Russ. J. Org. Chem., 58 (3), 327–334.

[92] Yang, Y.Y., Wu, Z.Y., Zhang, H., Yin, S.J., Xia, F.B., Zhang, Q., Wan, J.B., Gao, J.L., and Yang, F.Q., 2020, LC-MS-based multivariate statistical analysis for the screening of potential thrombin/factor Xa inhibitors from radix Salvia miltiorrhiza, Chin. Med., 15 (1), 38.

[93] Alshehri, B., Vijayakumar, R., Senthilkumar, S., Ismail, A., Abdelhadi, A., Choudhary, R.K., Albenasy, K.S., Banawas, S., Alaidarous, M.A., and Manikandan, P., 2022, Molecular target prediction and docking of anti-thrombosis compounds and its activation on tissue-plasminogen activator to treat stroke, J. King Saud Univ., Sci., 34 (1), 101732.

[94] Ren, Y., Ai, J., Liu, X., Liang, S., Zheng, Y., Deng, X., Li, Y., Wang, J., Deng, X., and Chen, L.L., 2020, Anticoagulant active ingredients identification of total saponin extraction of different Panax medicinal plants based on grey relational analysis combined with UPLC-MS and molecular docking, J. Ethnopharmacol., 260, 112955.

[95] Tu, M., Feng, L., Wang, Z., Qiao, M., Shahidi, F., Lu, W., and Du, M., 2017, Sequence analysis and molecular docking of antithrombotic peptides from casein hydrolysate by trypsin digestion, J. Funct. Foods, 32, 313–323.

[96] Du, K., Cui, Y., Chen, S., Yang, R., Shang, Y., Wang, C., Yan, Y., Li, J., and Chang, Y., 2022, An integration strategy combined progressive multivariate statistics with anticoagulant activity evaluation for screening anticoagulant quality markers in Chinese patent medicine, J. Ethnopharmacol., 287, 114964.

[97] Tang, Z., Ren, Y., and Liu, F., 2022, Identify thrombin inhibitor with novel skeleton based on virtual screening study, J. Biomol. Struct. Dyn., 40 (1), 499–507.

[98] Li, Q.Q., Yang, F.Q., Wang, Y.Z., Wu, Z.Y., Xia, Z.N., and Chen, H., 2018, Evaluation of thrombin inhibitory activity of catechins by online capillary electrophoresis-based immobilized enzyme microreactor and molecular docking, Talanta, 185, 16–22.

[99] Huang, X., Swanson, R., and Olson, S.T., 2022, Heparin activation of protein Z-dependent protease inhibitor (ZPI) allosterically blocks protein Z activation through an extended heparin-binding site, J. Biol. Chem., 298 (6), 102022.

[100] Zheng, X., Pu, P., Ding, B., Bo, W., Qin, D., and Liang, G., 2021, Identification of the functional food ingredients with antithrombotic properties via virtual screen and experimental studies, Food Chem., 362, 130237.

[101] Huang, J., Song, W., Hua, H., Yin, X., Huang, F., and Alolga, R.N., 2021, Antithrombotic and anticoagulant effects of a novel protein isolated from the venom of the Deinagkistrodon acutus snake, Biomed. Pharmacother., 138, 111527.

DOI: https://doi.org/10.22146/ijc.87252

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