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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Synthesis, In Silico and In Vivo Evaluation of Novel 1, 3, 4-Thiadiazole Analogues as Novel Anticancer Agents

Author(s): Swathi Krishna, Byran Gowramma*, Manal Mohammed, Rajagopal Kalirajan, Lakshman Kaviarasan and Thaggikuppe Krishnamurthy Praveen*

Volume 17, Issue 4, 2020

Page: [434 - 444] Pages: 11

DOI: 10.2174/1570180816666190710145939

Price: $65

Abstract

Background: 1,3,4-thiadiazole is a lead molécule which is versatile for a wide variety of biological activities and in continuation of our interest in establishing some novel heterocyclic compounds for antitumor activity.

Objective: The objective of the study was to synthesize series of 5-(1,3-benzodioxol-5-yl)-1,3,4- thiadiazol-2-amine derivative and evaluated for their possible in vitro and in vivo anticancer activity.

Methods: The synthesis of 2-aminonaphthoxy-1,3,4-thiadiazole and 5-(1,3-benzodioxol-5-yl)-1,3,4- thiadiazol-2-amine as intermediates were carried out by cyclization method. A mixture of thiosemicarbazide and naphthoxyacetic acid/piperonylic acid and phosphoryl chloride were subjected to cyclization with phosphorous oxychloride to obtain compound 3. Further compounds 1 and 3 were reacted with different aromatic aldehydes in methanol to form compounds 2a-e and 4a-e. The compounds 2a-e and 4a-e were characterized for the melting points, IR, Proton NMR and Mass spectra. The compounds were further evaluated for their anticancer activity. The docking study was performed using Discovery studio 4.1 (Accelrys) software against DNA-binding domain of STAT3. The compounds were analyzed for the ligand-protein binding interaction(s) by molecular docking into the active site of STAT3β using the CDOCKER protocol of Discovery studio (v4.1).

Results: The title compounds were screened for in vitro anticancer on human breastadenocarcinoma cells (MCF-7 and Vero). Compounds 4c, 4d and 2d against MCF 7 and 4d against Vero cell lines were found to be the most active dérivatives with IC50 values of 1.03, 2.81 and 3.45 µg/ml against MCF 7 and 31.81 µg/ml against Vero cell lines, respectively.

Conclusion: From the in vivo anticancer studies, it was concluded that the synthesized compounds 4c and 4d displayed anticancer activity comparable to the standard drug, while the rest of the compounds demonstrated mild potency for anticancer studies.

Keywords: 1, 3, 4-Thiadiazole, molecular docking, STAT3, IC50, MCF-7, Vero, in vitro and in vivo anticancer activity.

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[1]
Bhat, K.S.; Poojary, B.; Prasad, D.J.; Naik, P.; Holla, B.S. Synthesis and antitumor activity studies of some new fused 1,2,4-triazole derivatives carrying 2,4-dichloro-5-fluorophenyl moiety. Eur. J. Med. Chem., 2009, 44(12), 5066-5070.
[http://dx.doi.org/10.1016/j.ejmech.2009.09.010] [PMID: 19822384]
[2]
Chawla, G.; Kumar, U.; Bawa, S.; Kumar, J. Syntheses and evaluation of anti-inflammatory, analgesic and ulcerogenic activities of 1,3,4-oxadiazole and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives. J. Enzyme Inhib. Med. Chem., 2012, 27(5), 658-665.
[http://dx.doi.org/10.3109/14756366.2011.606543] [PMID: 21899490]
[3]
el-Khawass, S.M.; Khalil, M.A.; Hazzaa, A.A.; Bassiouny, H.A.; Loutfy, N.F. Synthesis of some 1,2,4-triazolo [3,4-b] [1,3,4]thiadiazoles as potential anthelmintics. Farmaco, 1989, 44(7-8), 703-709.
[PMID: 2590368]
[4]
Pandey, V.K.; Tusi, Z.; Tandon, M. Synthesis of thiadiazolo-s-triazines for their antiviral activity based on QSAR studies. Indian J. Chem., 2003, 42, 2583.
[http://dx.doi.org/ 10.1002/chin.200404122]
[5]
Agarwal, V.R.; Nautiyal, S.R.; Mukerji, D.D. Synthesis of a new series of substituted-2-phenyl-3-[(2-sustituted anilinothiadiazolyl-5-(n ercaptophenyl)]quinazolin-4-one as antiviral and hypoglycemic agent. Indian Drugs., 1986, 23, 458.
[6]
Bano, Q.; Tiwari, N.; Giri, S. Nizamuddin. Anticancer, antibacterial and antifungal activites of some 2-substituted [1,3,4]-thiadiazolo [2,3-b]-tetrahydrobenzo (b) thieno [3,2-e] pyrimidines. Indian J. Chem., 1993, 32, 399.
[7]
Alagarswamy, V.; Pathak, U.S.; Rajasolomon, V.; Meena, S.; Ramseshu, K.V.; Rajesh, R. Synthesis and antimicrobial activity of some pyridyl and naphthyl substituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Indian J. Heterocycl. Chem., 2004, 13, 347.
[8]
Xia, J.Z.; Lu, H.L.; Gui, Y.J.; Zu, X.Z.; Agric, J. Synthesis, fungicidal activity, and 3D-QSAR of pyridazinone-substituted 1,3,4-oxadiazoles and 1,3,4-thiadiazoles. Food Chem., 2002, 50, 3757.
[http://dx.doi.org/10.1021/jf0201677]
[9]
Onkol, T.; Cakir, B.; Sahin, F.M. Synthesis and antinociceptive activity of 2-[(2-Oxobenzothiazolin-3-yl) methyl]-5-aminoalkyl/aryl-1,3,4-thiadiazole. Turk. J. Chem., 2002, 28, 461.
[10]
Sanmati, K.; Mishra, P. Preparation and evaluation of some 1,3,4-thiadiazoles as diuretic agents. Indian J. Chem., 2004, 43, 184.
[11]
Imtiaz, M. Husain; Vinay Kumar.; Synthesis and studies of 3 -[2-benzothiazolyl/benzimidazolyl/benzoxazolylthio) methyl]-1,2,4-triazolo [3,4-b] [1,3,4]-thiadiazole-6-yl substituted phenyl as possible anthelmintics. Indian J. Chem., 1992, 31, 673.
[12]
Mishra, P.; Ashok, K.S.; Agarwal, R.K.; Patnaik, G.K. Synthesis and biological activities of 2-(substituted -acetyl)-amino-5-alkyl-1,3,4-thiadiazoles as CNS depressants. J. Indian Chem. Soc., 1990, 67, 520.
[13]
Terzioglu, N.; Gürsoy, A. Synthesis and anticancer evaluation of some new hydrazone derivatives of 2,6-dimethylimidazo[2,1-b][1,3,4]thiadiazole-5-carbohydrazide. Eur. J. Med. Chem., 2003, 38(7-8), 781-786.
[http://dx.doi.org/10.1016/S0223-5234(03)00138-7] [PMID: 12932910]
[14]
Parkanyi, C.; Hui, L.Y.B.O.; Stromberg, H.E.; Ariella Evenzahar, J. Synthesis of 5 -Fluro -2 -methyl -3 -(2 - trifluromethyl -1,3,4 -thiadiazoles -5 -yl) -4 (3H) -quinazolinone and related compounds as potential anticancer agents. J. Heterocycl. Chem., 1992, 29, 749.
[http://dx.doi.org/10.1002/jhet.5570290411]
[15]
Tsukamoto, K.; Suno, M.; Igarashi, K.; Kozai, Y.; Sugino, Y. Mechanism of action of 2,2′-(methylenediimino)bis-1,3,4-thiadiazole (NSC 143019), an antitumor agent. Cancer Res., 1975, 35(10), 2631-2636.
[PMID: 125625]
[16]
Shaukath, A.K.; Sheena, S.; Belagur, S.S. A facile synthesis and antimicrobial activity of 3-(2-Aroylaryloxy)- methyl-5- mercapto-4-phenyl-4H-1,2,4-triazole and 2-(2-Aroylaryloxy)-methyl-5-N- phenylamino -1,3,4-thiadiazole analogues. Sci. Asia, 2003, 29, 383.
[http://dx.doi.org/10.2306/scienceasia1513-1874.2003.29.383]
[17]
Desai, K.; Baxi, A.J. Synthesis and antimicrobial activity of 5-(2′,4′- Dichloro phenoxy methyl)-2-(4”-aryl-3”-chloro-2”-azetidinone-1”-yl)-1,3,4-thiadiazole. Indian J. Pharm. Sci., 1992, 54, 183.
[18]
Dhiman, A.M.; Wadodkar, K.N. Synthesis and antimicrobial study of heterocycle substituted s-triazoles, 1,3,4-thiadiazoles, oxadiazoles and related heterocycles. Indian J. Chem., 2001, 40, 636.
[http://dx.doi.org/10.1002/chin.200141057]
[19]
Khosrow, Z.; Khalil, F.; Taraneh, T.; Mohammad, R.S. Synthesis and antimicrobial activity of some pyridyl and naphthyl substituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Turk. J. Chem., 2004, 28, 95.
[20]
Kokila, D.; Baxi, A.J. Synthesis and antimicrobial activity of 5-(2′,4′-dichlorophenoxymethyl)-2-(2′-aryl-5‘(H)-4’-thiazolidinone-1,3,4-thiadiazole. J. Indian Chem. Soc., 1992, 69, 212.
[21]
Sanmati, K.J.; Mishra, P. Synthesis of some 2-amino-5-aryl- 1, 3, 4-thiadiazoles. Asian J. Chem., 2000, 12, 1341.
[22]
Moorthy, N.S.H.N.; Karthikeyan, C.; Trivedi, P. Design, synthesis, cytotoxic evaluation, and QSAR study of some 6h-indolo[2,3-b]quinoxaline derivatives. J. Enzyme Inhib. Med. Chem., 2010, 25(3), 394-405.
[http://dx.doi.org/10.3109/14756360903190747] [PMID: 20233012]
[23]
Zuo, Y.; Yang, S.G.; Jiang, L.L.; Hao, G.F.; Wang, Z.F.; Wu, Q.Y.; Xi, Z.; Yang, G.F. Quantitative structure-activity relationships of 1,3,4-thiadiazol-2(3H)-ones and 1,3,4-oxadiazol-2(3H)-ones as human protoporphyrinogen oxidase inhibitors. Bioorg. Med. Chem., 2012, 20(1), 296-304.
[http://dx.doi.org/10.1016/j.bmc.2011.10.079] [PMID: 22130420]
[24]
Patel, K.; Karthikeyan, C.; Solomon, V.R.; Moorthy, N.S.H.N.; Lee, H.; Sahu, K.; Deora, G.S.; Trivedi, P. Synthesis of some coumarinyl chalcones and their antiproliferative activity against breast cancer cell lines. Lett. Drug Des. Discov., 2011, 8, 308.
[http://dx.doi.org/10.2174/157018011794839475]
[25]
Gowramma, B.; Praveen, T.K.; Kalirajan, R.; Babu, B. Synthesis of some novel 2-azetidinones/4-thiazolidinones bearing 1, 3, 4-thiadiazole nucleus and screening for its anti-inflammatory activity. Lett. Drug Des. Discov., 2016, 13(7), 6.
[http://dx.doi.org/10.2174/1570180813666151123235546]
[26]
Jatav, V.; Mishra, P.; Kashaw, S.; Stables, J.P. CNS depressant and anticonvulsant activities of some novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones. Eur. J. Med. Chem., 2008, 43(9), 1945-1954.
[http://dx.doi.org/10.1016/j.ejmech.2007.12.003] [PMID: 18222569]
[27]
Venu, M.N.; Srinivas, N.A.; Venkateswar, R.J.; Sarangapani, M. Synthesis of some new 1,3,4-thiadiazoles as antimicrobial agents. J. Pharm. Res., 2011, 4(5), 1396.
[28]
Cressier, D.; Prouillac, C.; Hernandez, P.; Amourette, C.; Diserbo, M.; Lion, C.; Rima, G. Synthesis, antioxidant properties and radioprotective effects of new benzothiazoles and thiadiazoles. Bioorg. Med. Chem., 2009, 17(14), 5275-5284.
[http://dx.doi.org/10.1016/j.bmc.2009.05.039] [PMID: 19502068]
[29]
Mahmoud, M.M.R.; Adel, A.H.; Abdel, R. Antimicrobial activity of newly synthesized 2,5-disubstituted1,3,4thiadiaozle derivatives. Bull. Korean Chem. Soc., 2011, 32(12), 4227.
[http://dx.doi.org/10.5012/bkcs.2011.32.12.4227]
[30]
Shashikant, R.P. Prajactkekare; Nachiket, S. D.; Sunil, A, N.; Deepak, S. M.; Smita, K, P.; Aarti, V. D.; Synthesis and biological evaluation of some 1, 3, 4-thiadiazoles. J. Chem. Pharm. Res., 2009, 1(1), 191.
[31]
Gowramma, B.; Praveen, T.K.; Gomathy, S.; Babu, B.; Kalirajan, R.; Krisnaveni, N. Synthesis of 2-(bis (2-chloroethyl) amino)-n′-(5-substitutedphenyl)- 1,3,4-thiadiazol-2-yl)acetohydrazide and evaluation of anticancer activity. Curr. Bioact. Compd., 2018, 14(3), 309.
[http://dx.doi.org/10.2174/1573407213666170428110528]
[32]
Gowramma, B.; Jubie, S.; Kalirajan, R.; Gomathy, S.; Elango, K. Synthesis and anticancer activity of some novel 1-(bis N,N-(chloroethyl)-amino acetyl)-3,5-disubstituted-1,2-pyrazolines. Int. J. Pharm. Tech. Res., 2009, 1(2), 347.
[33]
Liang, H.Z.; Qing, S.A.; Qing, C.J.; Qing , Zhong. Z.; Fei, Z.; Kui Cheng, Ying Yang.; Yu, C.; Yong, Q.; Hong Juan, Z.; Huan, Q. L.; Chang Fang, Z. Synthesis, biological evaluation and molecular docking studies of amide-coupled benzoic nitrogen mustard derivatives as potential antitumor agents. Bioorg. Med. Chem., 2010, 18, 880.
[http://dx.doi.org/10.1016/j.bmc.2009.11.037]
[34]
BIOVIA Ltd. (formerly Accelrys, Inc.). Discovery Studio version 4.0.. http://accelrys.com
[35]
Regulski, M.; Piotrowska-Kempisty, H.; Prukała, W.; Dutkiewicz, Z.; Regulska, K.; Stanisz, B.; Murias, M. Synthesis, in vitro and in silico evaluation of novel trans-stilbene analogues as potential COX-2 inhibitors. Bioorg. Med. Chem., 2018, 26(1), 141-151.
[http://dx.doi.org/10.1016/j.bmc.2017.11.027] [PMID: 29191502]
[36]
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82(13), 1107-1112.
[http://dx.doi.org/10.1093/jnci/82.13.1107] [PMID: 2359136]

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