Biopolym. Cell. 2018; 34(1):59-71.
Bioorganic Chemistry
Synthesis and antitumor activities of new N-(5-benzylthiazol-2-yl)-2-(heteryl-5-ylsulfanyl)-acetamides
1Ostapiuk Yu. V., 1Frolov D. A., 2Vasylyschyn R. Ya., 1Matiychuk V. S.
  1. Ivan Franko National University of Lviv
    4, Hrushevskoho Str., Lviv, Ukraine, 79005
  2. Enamine Ltd
    78, Chervonotkatska Str., Kyiv, Ukraine, 02094


Aim. Synthesis of series of new N-(5-benzyl-thiazol-2-yl)-2-(heteryl-5-ylsulfanyl)-acetamides and study on their anticancer activity. Methods. Organic synthesis, analytical and spectral meth-ods, pharmacological screening. Results. [2-chloro-N-(5-aryl-1,3-thiazol-2-yl)acetamides 3a-h have been prepared in good yields] by the reaction of 2-amino-5-(R-benzyl)thiazoles with chloroacetyl chloride. The obtained compounds react with 1-phenyl-1H-tetrazole-5- 4, 4-allyl-5-phenyl-4H-[1,2,4]triazole-3- 5a, 4-allyl-5-furan-2-yl-4H-[1,2,4]triazole-3- 5b thioles, pyrimidine-2- 6a and 4,6-dimethyl-pyrimidine-2- thioles 6b to form series of novel N-(5-benzyl-thiazol-2-yl)-2-(heterylsulfanyl)acetamides with yields 65-96%. These compounds have been evaluated for their anticancer activity against 60 cancer cell lines in the concentration of 10 µM. The human tumour cell lines were derived from nine different cancer types: leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers. The synthesized compounds displayed moder-ate activity in the in vitro screening with the tested cell lines. However, it was observed a selective influence of some compounds on several cancer cell lines. Compounds 7c, 8a, 8d and 9c-g have been found to be active and highly selective towards the] HOP-92 Non-Small Cell Lung Cancer cell line (GP = 39.45 – 65.63%), whereas 2-(4,6-R1-pyrimidin-2-ylsulfanyl)-N-[(5-R-benzyl)-thiazol-2-yl]-acetamides 9c-h are active towards the UO-31 Renal Cancer cell line (GP = 34.43 – 60.58%). Compounds 7c possessed significant activity towards the SNB-75 CNS Cancer cell line (GP = -3.83 %), 7f – on the OVCAR-4 Ovarian Cancer cell line (GP = 14.66 %), 8d – on the HS 578T Breast Cancer cell line (GP = 11.09%), 9g – on the NCI-H226 Non-Small Cell Lung Can-cer (GP = 9.75%) and UO-31 Renal Cancer cell lines (GP = 16.35%). Conclusions. A series of new 2-amino-5-arylmetylthiazole derivatives was synthesized. It was established that these com-pounds are promising in the search for innovative anti-cancer agents.
Keywords: organic synthesis, arylation, 2-amino-5-arylmetylthiazole, anticancer activity.


[1] Nevagi RJ. Biological and medicinal significance of 2-aminothiazoles. Pharm Let. 2014;6(5):134–50.
[2] Das D, Sikdar P, Bairagi M. Recent developments of 2-aminothiazoles in medicinal chemistry. Eur J Med Chem. 2016;109:89-98.
[3] Girish K G, Vinod K. Thiazole: A privileged scaffold in drug discovery. In: Chemical Drug Design. Walter de Gruyter GmbH & Co KG, 2016. 297 p.
[4] Chhabria MT, Patel S, Modi P, Brahmkshatriya PS. Thiazole: A Review on Chemistry, Synthesis and Therapeutic Importance of its Derivatives. Curr Top Med Chem. 2016;16(26):2841-2862.
[5] Ahmed A, Molvi KI, Nazim S,Shaikh A A. A Review on Thiazole: Recent Developments and Biological Activities. Inventi Impact: Med Chem. 2015;3:51–70.
[6] Siddiqui N, Faiz Arshad M, Ahsan W, Alam MS. Thiazoles: a valuable insight into the recent advances and biological activities. Int J Pharma Sci Drug Res. 2009;1(3):136–43.
[7] Obushak ND, Matiichuk VS, Vasylyshin RYa, Ostapyuk YuV. Heterocyclic syntheses on the basis of arylation products of unsaturated compounds: X. 3-aryl-2-chloropropanals as reagents for the synthesis of 2-amino-1,3-thiazole derivatives. Russ J Org Chem. 2004;40(3):383–9.
[8] Matiichuk VS, Potopnyk MA, Obushak ND. Molecular design of pyrazolo[3,4-d]pyridazines. Russ J Org Chem. 2008;44(9):1352–61.
[9] Matiychuk VS, Naskrent M, Gzella AK. A convenient method for the synthesis of 2-[(5-benzyl-1,3-thiazol-2-yl) imino]-1,3-thiazolidin-4-one derivatives. Tetrahedron Lett. 2012;53(5):543–5.
[10] Khalil A, Edwards JA, Rappleye CA, Tjarks W. Design, synthesis, and biological evaluation of aminothiazole derivatives against the fungal pathogens Histoplasma capsulatum and Cryptococcus neoformans. Bioorg Med Chem. 2015;23(3):532-47.
[11] Zimenkovskii BS, Kutsyk RV, Lesyk RB, Matyichuk VS, Obushak ND, Klyufinska TI. Synthesis and antimicrobial activity of 2,4-dioxothiazolidine-5-acetic acid amides. Pharm Chem J. 2006;40(6):303–6.
[12] Servi S, Genc M, Gür S, Koca M. The synthesis and antimicrobial activity of some new methyl N-arylthiocarbamates, dimethyl N-aryldithiocarbonimidates and 2-arylamino-2-imidazolines. Eur J Med Chem. 2005;40(7):687-93.
[13] rasavin M, Karapetian R, Konstantinov I, Gezentsvey Y, Bukhryakov K, Godovykh E, Soldatkina O, Lavrovsky Y, Sosnov AV, Gakh AA. Discovery and potency optimization of 2-amino-5-arylmethyl-1,3-thiazole derivatives as potential therapeutic agents for prostate cancer. Arch Pharm (Weinheim). 2009;342(7):420-7.
[14] Pokhodylo N, Shyyka O, Matiychuk V. Synthesis and anticancer activity evaluation of new 1,2,3-triazole-4-carboxamide derivatives. Med Chem Res. 2014;23(5):2426–38.
[15] Park CM, Sun C, Olejniczak ET, Wilson AE, Meadows RP, Betz SF, Elmore SW, Fesik SW. Non-peptidic small molecule inhibitors of XIAP. Bioorg Med Chem Lett. 2005;15(3):771-5.
[16] Radi M, Crespan E, Falchi F, Bernardo V, Zanoli S, Manetti F, Schenone S, Maga G, Botta M. Design and synthesis of thiadiazoles and thiazoles targeting the Bcr-Abl T315I mutant: from docking false positives to ATP-noncompetitive inhibitors. ChemMedChem. 2010;5(8):1226-31.
[17] Choi MJ, Jung KH, Kim D, Lee H, Zheng HM, Park BH, Hong SW, Kim MH, Hong S, Hong SS. Anti-cancer effects of a novel compound HS-113 on cell growth, apoptosis, and angiogenesis in human hepatocellular carcinoma cells. Cancer Lett. 2011;306(2):190-6.
[18] Schiedel M, Rumpf T, Karaman B, Lehotzky A, Oláh J, Gerhardt S, Ovádi J, Sippl W, Einsle O, Jung M. Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study. J Med Chem. 2016;59(4):1599-612.
[19] Finiuk NS, Hreniuh VP, Ostapiuk YuV, Matiychuk VS, Frolov DA, Obushak MD, Stoika RS, Babsky AM. Anti-neoplastic activity of novel thiazole derivatives. Biopolym Cell. 2017;33(2):135–46.
[20] Fizer M, Sidey V, Tupys A, Ostapiuk Y, Tymoshuk O, Bazel Y. On the structure of transition metals complexes with the new tridentate dye of thiazole series: Theoretical and experimental studies. J Mol Struct. 2017;1149:669–82.
[21] Bazel Y, Tupys A, Ostapiuk Y, Tymoshuk O, Matiychuk V. A green cloud-point microextraction method for spectrophotometric determination of Ni(II) ions with 1-[(5-benzyl-1,3-thiazol-2-yl)diazenyl]naphthalene-2-ol. J Mol Liq. 2017;242:471–7.
[22] Tupys A, Kalembkiewicz J, Ostapiuk Y, Matiichuk V, Tymoshuk O, Woźnicka E, Byczyński Ł. ynthesis, structural characterization and thermal studies of a novel reagent 1-[(5-benzyl-1,3-thiazol-2-yl)diazenyl]naphthalene-2-ol. J Therm Anal Calorim. 2017;127(3):2233–42.
[23] Tupys A, Kalembkiewicz J, Bazel Y, Zapała L, Dranka M, Ostapiuk Y, Tymoshuk O, Woźnicka E. 1-[(5-Benzyl-1,3-thiazol-2-yl)diazenyl]naphthalene-2-ol: X-ray structure, spectroscopic characterization, dissociation studies and application in mercury(II) detection. J Mol Struct. 2017;1127:722–33.
[24] Basha NM, Lavanya G, Padmaja A, Padmavathi V. Synthesis and Antioxidant Activities of Acetamidomethylsul-fonyl Bis Heterocycles Oxazolyl/Thiazolyl/Imidazolyl-1,3,4-Oxadiazoles. Arch Pharm. 2013;346(7):511–20.
[25] Ramachandra P, Dandu R, Adivireddy S, Venkatapuram P, Padmavathi V, Krishna NS. Synthesis, antioxidant, and cytotoxic activities of bis(oxazolyl/thiazolyl/imidazolyl)amidomethanesulfonyl Acetamides. Med Chem Res. 2015;24(1):86–98.
[26] Altintop MD, Kaplancikli ZA, Ozdemir A, Turan-Zitouni G, Temel HE, Akalın G. Synthesis and anticholinesterase activity and cytotoxicity of novel amide derivatives. Arch Pharm (Weinheim). 2012;345(2):112-6.
[27] Ibrahim MK, Khaled EA, Zayed MF, Mahdy HA. Design, synthesis, docking, and biological evaluation of some novel 5-chloro-2-substituted sulfanylbenzoxazole derivatives as anticonvulsant agents. Med Chem Res. 2015:24(1):99–114.
[28] Siddiqui N, Alam MS, Sahu M, Naim MJ, Yar MS, Alam O. Design, synthesis, anticonvulsant evaluation and docking study of 2-[(6-substituted benzo[d]thiazol-2-ylcarbamoyl)methyl]-1-(4-substituted phenyl)isothioureas. Bioorg Chem. 2017;71:230-243.
[29] Prakash TB, Reddy LM, Padmaja A, Padmavathi V. Synthesis and antimicrobial activity of azole derivatives. Chem Pharm Bull (Tokyo). 2013;61(5):516-23.
[30] Tegley CM, Viswanadhan VN, Biswas K, Frohn MJ, Peterkin TA, Chang C, Bürli RW, Dao JH, Veith H, Rogers N, Yoder SC, Biddlecome G, Tagari P, Allen JR, Hungate RW. Discovery of novel hydroxy-thiazoles as HIF-alpha prolyl hydroxylase inhibitors: SAR, synthesis, and modeling evaluation. Bioorg Med Chem Lett. 2008;18(14):3925-8.
[31] Ozawa T, Kitagawa H, Yamamoto Y, Takahata S, Iida M, Osaki Y, Yamada K. Phenylimidazole derivatives as specific inhibitors of bacterial enoyl-acyl carrier protein reductase FabK. Bioor Med Chem. 2007;15(23):7325–36.
[32] Yan G, Hao L, Niu Y, Huang W, Wang W, Xu F, Liang L, Wang C, Jin H, Xu P. 2-Substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamides as BACE1 inhibitors: Synthesis, biological evaluation and docking studies. Eur J Med Chem. 2017;137:462-475.
[33] Piechowicz KA, Truong EC, Javed KM, Chaney RR, Wu JY, Phuan PW, Verkman AS, Anderson MO. Synthesis and evaluation of 5,6-disubstituted thiopyrimidine aryl aminothiazoles as inhibitors of the calcium-activated chloride channel TMEM16A/Ano1. J Enzyme Inhib Med Chem. 2016;31(6):1362-8.
[34] Xu Q, Huang L, Liu J, Ma L, Chen T, Chen J, Peng F, Cao D, Yang Z, Qiu N, Qiu J, Wang G, Liang X, Peng A, Xiang M, Wei Y, Chen L. Design, synthesis and biological evaluation of thiazole- and indole-based derivatives for the treatment of type II diabetes. Eur J Med Chem. 2012;52:70-81.
[35] Obushak ND, Lesyuk AI, Gorak YI, Matiichuk VS. Mechanism of Meerwein arylation of furan derivatives. Russ J Org Chem. 2009;45(9):1375–81.
[36] Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, et al. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst. 1991;83(11):757-66.
[37] Boyd MR, Paull KD. Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Dev Res. 1995;34(2):91–109.
[38] Boyd MR, Teicher BA. In: Cancer Drug Discovery and Development. Humana Press, 1997. Chap 2.:23–43.
[39] Shoemaker RH. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer. 2006;6(10):813-23.