Synthesis and Evaluation of the Cytotoxicity of a Series of 1,3,4-Thiadiazole Based Compounds as Anticancer Agents

Document Type: Original Article

Authors

1 Department of Medicinal Chemistry, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran

2 Department of Medicinal Chemistry, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran 2 Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran

3 Department of Pharmacology, Toxicology and Medical Services, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran

Abstract

 




Objective(s):
Nowadays, cancer is an important public health problem in all countries. Limitations of current chemotherapy for neoplastic diseases such as severe adverse reactions and tumor resistance to the chemotherapeutic drugs have been led to a temptation for focusing on the discovery and development of new compounds with potential anticancer activity.
 
Materials and Methods:
A new series of 1,3,4-thiadiazole-derived compounds (3a-3l) were synthesized. N-(5-Mercapto-1,3,4-thiadiazol-2-yl)-2-(4-methoxyphenyl) acetamide (2) was prepared through direct amidation of 4-methoxyphenylacetic acid (2) with 5-amino-1,3,4-thiadiazole-2-thiol using EDC (N-Ethyl-N-dimethylaminopropyl carbodiimide) and HOBt (Hydroxybenzotriazole). Then, various derivatives of benzyl chloride containing electron withdrawing and electron donating moieties were reacted with compound 2 to prepare compounds 3a-3l. In vitro cytotoxicity assessment using MTT method was applied and results are presented as IC50.
Results:
All the synthesized compounds were characterized by 1H-NMR and IR spectroscopy. Some of the synthesized compounds were also characterized using MS spectroscopy. Related melting points were also recorded. According to the obtained data from MTT assay, all compounds (3a-3l) demonstrated a higher cytotoxic activity against MDA-MB-231 breast cancer cell line in comparison with other cell lines.
Conclusion:
It is notable that four synthesized compounds 3h (IC50= 11 ± 0.18 μM), 3j (IC50= 10 ± 0.39 μM), 3k (IC50= 11 ± 0.77 μM) and 3l (IC50= 8 ± 0.69 μM) exhibited higher cytotoxic activity against MDA-MB-231 cell line compared to imatinib (IC50= 20 ± 0.69 μM) as the reference drug.

Keywords


 

1.

Bhuva HA, Kini SJ. Synthesis, anticancer activity and docking of some substituted benzothiazoles as

Cytotoxicity of 1,3,4-Thiadiazole Based Compounds Aliabadi et al

Iran J Basic Med Sci, Vol. 16, No. 11, Nov 2013

 

1138

 

tyrosine kinase inhibitors. J Mol Graph Model 2010; 29:32-37.

2.

Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18:581-592.

3.

Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer Statistics, 2006. Cancer J Clin 2006; 56:106-130.

4.

Rafael Sierra J, Cepero V, Giordano S. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy. Mol Cancer 2010; 9:75-87.

5.

Arora A, Scholar EM. Role of tyrosine Kknase inhibitors in cancer therapy. J Pharmacol Exp Ther 2005; 3:971-979.

6.

Mousavi SH, Tayarani-Najaran Z, Hersey P. Apoptosis: from Signalling Pathways to Therapeutic Tools. Iran J Basic Med Sci 2008; 11:121-142.

7.

Hadizadeh F, Hosseinzadeh H, Kalantari M, Kiasat R, Mehrabi M. Synthesis and anticonvulsant effects of 2-(2-alkylthio-1-benzyl-5-imidazolyl)-2,3,4-trihydro-1,3,4-thiadiazoles in mice. Iran J Basic Med Sci 2003; 6:168-173.

8.

Dalip Kumar, Reddy Vaddula B, Kuei-Hua Chang KH, Shah K. One-pot synthesis and anticancer studies of 2-arylamino-5-aryl-1,3,4-thiadiazoles. Bioorg Med Chem Lett 2011; 21:2320-2323.

9.

Farshori NN, Banday RM, Ahmad A, Khan AU, Rauf A. Synthesis, characterization, and in vitro antimicrobial activities of 5-alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and thiadiazoles. Bioorg Med Chem Lett 2010; 20:1933-1938.

10.

Yang XH, Wen Q, Zhao TT, Sun J, Li X, Xing M, et al. Synthesis, biological evaluation, and molecular docking studies of cinnamic acyl 1,3,4-thiadiazole amide derivatives as novel antitubulin agents. Bioorg Med Chem 2012; 20:1181-1187.

11.

Matysiak J, Opolski A. Synthesis and antiproliferative activity of N-substituted 2-amino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles. Bioorg Med Chem 2006; 14:4483-4489.

12.

Radi M, Crespan E, Botta G, Falchi F, Maga G, Manetti F, et al. Discovery and SAR of 1,3,4-thiadiazole derivatives as potent Abl tyrosine kinase inhibitors and cytodifferentiating agents. Bioorg Med Chem Lett 2008; 18:1207-1211.

13.

Yusuf M, Payal Jain P. Synthesis and biological significances of 1,3,4-thiadiazolines and related heterocyclic compounds. Arab J Chem 2011, in press.

14.

Crespan E, Radi M, Zanoli S, Schenone S, Botta M, Maga G. Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms. Bioorg Med Chem 2010; 18:3999-4008.

15.

Sun J, Yang YS, Li W, Zhang YB, Wang XL, Tang JF, et al. Synthesis, biological evaluation and molecular docking studies of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan as potential antitumor agents. Bioorg Med Chem Lett 2011; 21:6116-6121.

16.

Rzeski W, Matysiakb J, Kandefer-Szerszen M. Anticancer, neuroprotective activities and computational studies of 2-amino-1,3,4-thiadiazole based compound. Bioorg Med Chem 2007; 15:3201-3207.

17.

Chou JY, Lai SY, Pan SL, Jow GM, Chern JW, Guh JH. Investigation of anticancer mechanism of thiadiazole-based compound in human non-small cell lung cancer A549 cells. Biochem Pharmacol 2003; 66:115-124.

18.

Aliabadi A, Shamsa F, Ostad SN, Emami S, Shafiee A, Davoodi J, et al. Synthesis and biological evaluation of 2-Phenylthiazole-4-carboxamide derivatives as anticancer agents. Eur J Med Chem 2010; 11:5384-5389.