Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Design, Synthesis and Biological Evaluation of Novel Triazolothiadiazoles Derived from NSAIDs as Anticancer Agents

Author(s): Peri Aytaç, Irem Durmaz Sahin, Rengül Çetin Atalay and Birsen Tozkoparan*

Volume 22, Issue 7, 2022

Published on: 23 June, 2021

Page: [1340 - 1347] Pages: 8

DOI: 10.2174/1871520621666210623093550

Price: $65


Background: Although transplantation, surgical resection, and tumor ablation are treatment options available following early diagnosis of HCC, poor prognosis and high recurrence rates restrict the efficacy of these approaches. Hence, small molecules with high selectivity and bioactivity are urgently required.

Objective: This study presents the synthesis of a series of new triazolothiadiazole derivatives (1a-3j) with NSAID moieties and their cytotoxic bioactivities.

Methods: The new synthetic derivatives (1-3; 1a-3j) and NSAIDs ibuprofen, naproxen, and flurbiprofen that commonly used in clinics were screened against human liver (Huh7), breast (MCF7), and colon (HCT116) carcinoma cell lines under in vitro conditions via NCI-sulforhodamine B assay.

Results: The 4-methoxyphenyl substituted condensed derivatives 1h, 2h, and 3h were the most active compounds. Based on its high potency, compound 3h was selected for the further biological evaluation of hepatocellular carcinoma cell lines, and the mechanisms underlying cell death induced by 3h were determined. The results revealed that compound 3h induced apoptosis and cell cycle arrest in the sub G1 phase in human liver cancer cells.

Conclusion: These new small molecules may be used for the development of new lead compounds.

Keywords: Novel triazolothiadiazoles, NSAIDs, liver cancer, cytotoxicity, SRB, anticancer.

Graphical Abstract
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A.C.A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J. Clin, 2018, 68(6), 394-424.
Mauer, K.; O’Kelley, R.; Podda, N.; Flanagan, S.; Gadani, S. New treatment modalities for hepatocellular cancer. Curr. Gastroenterol. Rep., 2015, 17(5), 442.
[] [PMID: 25869473]
Portolani, N.; Coniglio, A.; Ghidoni, S.; Giovanelli, M.; Benetti, A.; Tiberio, G.A.M.; Giulini, S.M. Early and late recurrence after liver resection for hepatocellular carcinoma: Prognostic and therapeutic implications. Ann. Surg., 2006, 243(2), 229-235.
[] [PMID: 16432356]
Gurpinar, E.; Grizzle, W.E.; Piazza, G.A. NSAIDs inhibit tumorigenesis, but how? Clin. Cancer Res., 2014, 20(5), 1104-1113.
[] [PMID: 24311630]
Guadagni, F.; Ferroni, P.; Palmirotta, R.; Del Monte, G.; Formica, V.; Roselli, M. Non-steroidal anti-inflammatory drugs in cancer prevention and therapy. Anticancer Res., 2007, 27(5A), 3147-3162.
[PMID: 17970056]
Cuzick, J.; Otto, F.; Baron, J.A.; Brown, P.H.; Burn, J.; Greenwald, P.; Jankowski, J.; La Vecchia, C.; Meyskens, F.; Senn, H.J.; Thun, M. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: An international consensus statement. Lancet Oncol., 2009, 10(5), 501-507.
[] [PMID: 19410194]
Khan, I.; Zaib, S.; Ibrar, A.; Rama, N.H.; Simpson, J.; Iqbal, J. Synthesis, crystal structure and biological evaluation of some novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines. Eur. J. Med. Chem., 2014, 78, 167-177.
[] [PMID: 24681981]
Feng, C.; Wang, L.; Yan, Y.; Liu, J.; Li, S. Synthesis and antitumor evaluation of some 1,3,4-oxadiazole-2(3H)-thione and 1,2,4-triazole-5(1H)-thione derivatives. Med. Chem. Res., 2012, 21(3), 315-320.
Kamel, M.M.; Megally Abdo, N.Y. Synthesis of novel 1,2,4-triazoles, triazolothiadiazines and triazolothiadiazoles as potential anticancer agents. Eur. J. Med. Chem., 2014, 86, 75-80.
[] [PMID: 25147148]
Joshi, S.D.; More, Y.; Vagdevi, H.M.; Vaidya, V.P.; Gadaginamath, G.S.; Kulkarni, V.H. Synthesis of new 4-(2,5-dimethylpyrrol-1-yl)/4-pyrrol-1-yl benzoic acid hydrazide analogs and some derived oxadiazole, triazole and pyrrole ring systems: a novel class of potential antibacterial, antifungal and antitubercular agents. Med. Chem. Res., 2013, 22(3), 1073-1089.
Khan, I.; Ibrar, A.; Zaib, S.; Ahmad, S.; Furtmann, N.; Hameed, S.; Simpson, J.; Bajorath, J.; Iqbal, J. Active compounds from a diverse library of triazolothiadiazole and triazolothiadiazine scaffolds: Synthesis, crystal structure determination, cytotoxicity, cholinesterase inhibitory activity, and binding mode analysis. Bioorg. Med. Chem., 2014, 22(21), 6163-6173.
[] [PMID: 25257911]
Husain, A.; Rashid, M.; Shaharyar, M.; Siddiqui, A.A.; Mishra, R. Benzimidazole clubbed with triazolo-thiadiazoles and triazolo-thiadiazines: New anticancer agents. Eur. J. Med. Chem., 2013, 62, 785-798.
[] [PMID: 23333063]
Zhao, P-L.; Duan, A-N.; Zou, M.; Yang, H-K.; You, W-W.; Wu, S-G. Synthesis and cytotoxicity of 3,4-disubstituted-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazoles and novel 5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives bearing 3,4,5-trimethoxyphenyl moiety. Bioorg. Med. Chem. Lett., 2012, 22(13), 4471-4474.
[] [PMID: 22647723]
Ilango, K.; Valentina, P.; Valentina, P. Facile synthesis and cytotoxic activity of 3,6-disubstituted 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles. Eur. J. Chem., 2010, 1(1), 50-53.
LaPorte, M.G.; Wang, Z.; Colombo, R.; Garzan, A.; Peshkov, V.A.; Liang, M.; Johnston, P.A.; Schurdak, M.E.; Sen, M.; Camarco, D.P.; Hua, Y.; Pollock, N.I.; Lazo, J.S.; Grandis, J.R.; Wipf, P.; Huryn, D.M. Optimization of pyrazole-containing 1,2,4-triazolo-[3,4-b]thiadiazines, a new class of STAT3 pathway inhibitors. Bioorg. Med. Chem. Lett., 2016, 26(15), 3581-3585.
[] [PMID: 27381083]
Baburajeev, C.P.; Mohan, C.D.; Rangappa, S.; Mason, D.J.; Fuchs, J.E.; Bender, A.; Barash, U.; Vlodavsky, I. Basappa; Rangappa, K. S. Efficient T3P® mediated synthesis, differential cytotoxicity and apoptosis induction by indolo-triazolo-thiadiazoles in human breast adenocarcinoma cells. BMC Cancer, 2017, 17(1), 235.
[] [PMID: 28359266]
Xu, Q.; Bao, K.; Sun, M.; Xu, J.; Wang, Y.; Tian, H.; Zuo, D.; Guan, Q.; Wu, Y.; Zhang, W. Design, synthesis and structure-activity relationship of 3,6-diaryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines as novel tubulin inhibitors. Sci. Rep., 2017, 7(1), 11997.
[] [PMID: 28931885]
Kamath, P.R.; Sunil, D.; Das, S.; Abdul Salam, A.A.; Rao, B.S.S. Efficient T3P® mediated synthesis, differential cytotoxicity and apoptosis induction by indolo-triazolo-thiadiazoles in human breast adenocarcinoma cells. Chem. Biol. Interact., 2017, 268, 53-67.
[] [PMID: 28235427]
Liu, Z.; Lang, B.; Gao, M.; Chang, X.; Guan, Q.; Xu, Q.; Wu, D.; Li, Z.; Zuo, D.; Zhang, W.; Wu, Y.J. 3-(3-Methoxyphenyl)-6-(3-amino-4-methoxyphenyl)-7H-[1,2,4] triazolo [3,4-b][1,3,4] thiadiazine, a novel tubulin inhibitor, evokes G2/M cell cycle arrest and apoptosis in SGC-7901 and HeLa cells. Cell. Biochem, 2020, 121(3), 2184-2196.
Aytaç, P.S.; Durmaz, I.; Houston, D.R.; Çetin-Atalay, R.; Tozkoparan, B. Novel triazolothiadiazines act as potent anticancer agents in liver cancer cells through Akt and ASK-1 proteins. Bioorg. Med. Chem., 2016, 24(4), 858-872.
[] [PMID: 26810835]
Tozkoparan, B.; Peri Aytac, S.; Gursoy, S.; Gunal, S.; Aktay, G. Novel 1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazole Derivatives as Dual Analgesic/Anti-inflammatory and Antimicrobial Agents. Lett. Drug Des. Discov., 2012, 9(2), 204-212.
Gundoğdu, G.; Karayel, A.; Aytaç, S.P.; Tozkoparan, B.; Kaynak, F.B. Synthesis and structural characterization of 3-[1-[4-(2-methylpropyl)phenyl]ethyl]-6-(4-fluorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole. Powder Diffr., 2019, 34(4), 325-330.
Gundoğdu, G.; Aytaç, S.P.; Muller, M.; Tozkoparan, B.; Kaynak, F.B. Structure determination of two structural analogs, named 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-fluorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C23H16F2N4S) and 3-[1-(2-fluoro-4-biphenyl) ethyl]-6-(4-chlorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C23H16ClFN4S) by synchrotron X-ray powder diffraction. Powder Diffr., 2017, 32(4), 279-289.
Sujith, K.V.; Kalluraya, B.; Adhikari, A.; Vijayanarayana, K. Microwave-mediated synthesis of triazolothiadiazoles as anti-inflammatory, analgesic, and anti-oxidant agents. Med. Chem. Res., 2012, 21(5), 543-551.
Amir, M.; Kumar, H.; Javed, S.A. Condensed bridgehead nitrogen heterocyclic system: Synthesis and pharmacological activities of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid. Eur. J. Med. Chem., 2008, 43(10), 2056-2066.
[] [PMID: 18023930]
Amir, M.; Kumar, H.; Javed, S.A. Synthesis and pharmacological evaluation of condensed heterocyclic 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives of naproxen. Bioorg. Med. Chem. Lett., 2007, 17(16), 4504-4508.
[] [PMID: 17576062]
Metwally, K.A.; Yaseen, S.H.; Lashine, E.S.; El-Fayomi, H.M.; El-Sadek, M.E. Non-carboxylic analogues of arylpropionic acids: Synthesis, anti-inflammatory activity and ulcerogenic potential. Eur. J. Med. Chem., 2006, 42(2), 152-160.
[PMID: 17052805]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy