Design, synthesis, cytotoxicity evaluation and docking studies of 1,2,4-triazine derivatives bearing different arylidene-hydrazinyl moieties as potential mTOR inhibitors

Sara Ranjbar, Najmeh Edraki, Mahsima Khoshneviszadeh, Alireza Foroumadi, Ramin Miri, Mehdi Khoshneviszadeh


Mammalian target of rapamycin (mTOR) is a phosphoinositide 3-kinase-related protein kinase which controls cell growth and is frequently deregulated in many cancers. Therefore, mTOR inhibitors are used as antineoplastic agents for cancer treatment. In this study, 1,2,4-triazine derivatives containing different arylidene-hydrazinyl moieties were designed and synthesized. Cytotoxicity of the compounds was evaluated on HL-60 and MCF-7 cell lines by MTT assay. S1, S2 and S3 exhibited good cytotoxic activity on both cell lines with an IC50 range of 6.42 - 20.20 μM. In general, substitution of a five-membered heterocyclic ring containing NO2, such as 5-nitrofuran-2-yl, resulted in the best potency. Molecular docking analysis was performed to study the possible interactions and binding modes of all the triazine derivatives with mTOR receptor. The most promising compound, S1, was well accommodated within the active site and had the least estimated free energy of binding (even less than the inherent ligand of the protein, PDB ID: 4JT6). It is concluded from both MTT assay and docking studies that the arylidene moiety linked to the hydrazinyl part of the structure had a prominent role in cytotoxicity and mTOR inhibitory activity.


Cancer; mTOR inhibitor; 1,2,4-Triazines; Docking; MTT

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Mathers CD, Loncar D. Updated projections of global mortality and burden of disease, 2002-2030: data sources, methods and results. Geneva: World Health Organization. 2005.

Hosseinzadeh L, Aliabadi A, Kalantari M, Mostafavi A, Khajouei MR. Synthesis and cytotoxicity evaluation of some new 6-nitro derivatives of thiazole-containing 4-(3H)-quinazolinone. Res Pharm Sci. 2016;11:210-218.

Sarvmeili N, Jafarian-Dehkordi A, Zolfaghari B. Cytotoxic effects of Pinus eldarica essential oil and extracts on HeLa and MCF-7 cell lines. Res Pharm Sci. 2016;11:476-483.

Abnous K, Manavi H, Mehri S, Alibolandi M, Kamali H, Ghandadi M, et al. In vitro evaluation of dihydropyridine-3-carbonitriles as potential cytotoxic agents through PIM-1 protein kinase inhibition. Res Pharm Sci. 2017;12:196-203.

Vosooghi M, Yahyavi H, Divsalar K, Shamsa H, Kheirollahi A, Safavi M, et al. Synthesis and In vitro cytotoxic activity evaluation of (E)-16-(substituted benzylidene) derivatives of dehydroepiandrosterone. DARU. 2013;21:34.

Dienstmann R, Rodon J, Serra V, Tabernero J. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther. 2014;13:1021-1031.

Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer cell. 2007;12:9-22.

Chiarini F, Evangelisti C, McCubrey JA, Martelli AM. Current treatment strategies for inhibiting mTOR in cancer. Trends Pharmacol Sci. 2015;36:124-135.

Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6: 729-734.

Zhan P, Li X, Li Z, Chen X, Tian Y, Chen W, et al. Structure-based bioisosterism design, synthesis and biological evaluation of novel 1, 2, 4-triazin-6-ylthioacetamides as potent HIV-1 NNRTIs. BioorgMed Chem Lett. 2012;22:7155-7162.

Ashour HM, Shaaban OG, Rizk OH, El-Ashmawy IM. Synthesis and biological evaluation of thieno [2′, 3′: 4, 5] pyrimido [1, 2-b][1, 2, 4] triazines and thieno [2, 3-d][1, 2, 4] triazolo [1, 5-a] pyrimidines as anti-inflammatory and analgesic agents. Eur J Med Chem. 2013;62:341-351.

Sangshetti JN, Shinde DB. One pot synthesis and SAR of some novel 3-substituted 5, 6-diphenyl-1, 2, 4-triazines as antifungal agents. Bioorg Med Chem Let. 2010;20:742-745.

El-Sayed Ali T. Synthesis of some novel pyrazolo [3, 4-b] pyridine and pyrazolo [3, 4-d] pyrimidine derivatives bearing 5, 6-diphenyl-1, 2, 4-triazine moiety as potential antimicrobial agents. Eur J Med Chem. 2009;44:4385-4392.

Irannejad H, Amini M, Khodagholi F, Ansari N, Tusi SK, Sharifzadeh M, et al. Synthesis and in vitro evaluation of novel 1, 2, 4-triazine derivatives as neuroprotective agents. Bioorg Med Chem. 2010;18:4224-4230.

Shaikh BM, Chobe SS, Konda SG, Khandare NT, Chavan SA, Dawane BS. An efficient synthesis and in vitro antimicrobial activity of 1, 2, 4-triazin-6-(5H)-one derivatives. Der Chemica Sinica. 2010;1:86-91.

Bakharev V, Gidaspov A, Yakunina N, Bulychev YN. Synthesis and cytotoxic activity of trinitromethyl derivatives of 1, 3, 5-triazine. Pharm Chem J. 2008;42:241-244.

Sztanke K, Rzymowska J, Niemczyk M, Dybała I, Kozioł AE. Synthesis, crystal structure and anticancer activity of novel derivatives of ethyl 1-(4-oxo-8-aryl-4, 6, 7, 8-tetrahydroimidazo [2, 1-c][1, 2, 4] triazin-3-yl) formate. J Med Chem. 2006;41:539-547.

Gucký T, Fryšová I, Slouka J, Hajdúch M, Džubák P. Cyclocondensation reaction of heterocyclic carbonyl compounds, Part XIII: Synthesis and cytotoxic activity of some 3, 7-diaryl-5-(3, 4, 5-trimethoxyphenyl) pyrazolo [4, 3-e][1, 2, 4] triazines. Eur J Med Chem. 2009;44:891-900.

Yurttaş L, Demirayak Ş, Ilgın S, Atlı Ö. In vitro antitumor activity evaluation of some 1, 2, 4-triazine derivatives bearing piperazine amide moiety against breast cancer cells. Bioorg Med Chem. 2014;22:6313-6323.

Karczmarzyk Z, Wysocki W, Urbańczyk-Lipkowska Z, Kalicki P, Bielawska A, Bielawski K, et al. Synthetic Approaches for Sulfur Derivatives Containing 1, 2, 4-Triazine Moiety: Their Activity for in Vitro Screening towards Two Human Cancer Cell Lines. Chem Pharm Bull. 2015;63:531-537.

Zhang X, Fryknäs M, Hernlund E, Fayad W, De Milito A, Olofsson MH, et al. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat Commun. 2014;5:3295.

Sutherlin DP, Sampath D, Berry M, Castanedo G, Chang Z, Chuckowree I, et al. Discovery of

(thienopyrimidin-2-yl) aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer. J Med Chem. 2010;53: 1086-1097.

Zhu W, Chen C, Sun C, Xu S, Wu C, Lei F, et al. Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTOR/PI3Kα inhibitors. Eur J Med Chem. 2015;93:64-73.

Menear KA, Gomez S, Malagu K, Bailey C, Blackburn K, Cockcroft X-L, et al. Identification and optimisation of novel and selective small molecular weight kinase inhibitors of mTOR. Bioorg Med Chem Let. 2009;19:5898-5901.

Khoshneviszadeh M, Ghahremani MH, Foroumadi A, Miri R, Firuzi O, Madadkar-Sobhani A, et al. Design, synthesis and biological evaluation of novel

anti-cytokine 1, 2, 4-triazine derivatives. Bioorg Med Chem. 2013;21:6708-6017.

Bag S, Vaze VV, Degani MS. Microwave assisted benzoin condensation using thiamine as catalyst. J Chem Res. 2006;2006:267-269.


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