Login Register Cart 0
Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Design, Synthesis, Molecular Docking Study and Anti-Hepatocellular Carcinoma Evaluation of New Bis-Triazolothiadiazines

Author(s): Sobhi M. Gomha, Zeinab A. Muhammad*, Elham Ezz El-Arab, Amira M. Elmetwally, Abdelaziz A. El-Sayed and Islam K. Matar

Volume 20, Issue 9, 2020

Page: [788 - 800] Pages: 13

DOI: 10.2174/1389557519666191015130037

Price: $65

Abstract

Objective: The reaction of bis(4-amino-4H-1,2,4-triazole-3-thiol) with hydrazonoyl halides and α-halo-ketones gave a new series of bis-1,2,4-triazolo[3,4-b]thiadiazine derivatives.

Methods: The structure of the new products was established on the basis of their elemental and spectral data (mass, 1H NMR, 13C NMR and IR) and an alternate method.

Results: Several of the synthesized products were subjected to in vitro anticancer screening against human hepatocellular carcinoma (HepG-2) and the results showed that compounds 16, 14 and 12 have promising activities (IC50 value of 24.8±9.1, 28.3±0.5, and 31±2.9μM, respectively) compared with Harmine reference drug (IC50 value of 22.4±1.11 μM).

Conclusion: Moreover, molecular docking studies were performed to analyze the binding modes of the discovered hits into the active site of DYRK1A using iGEMDOCK.

Keywords: 1, 4-dihydropyridines, triazolo-thiadiazines, hydrazonoyl halides, molecular docking, antitumor activities, in vitro.

« Previous Next »
Graphical Abstract

[1]
Radadiya, A.; Khedkar, V.; Bavishi, A.; Vala, H.; Thakrar, S.; Bhavsar, D.; Shah, A.; Coutinho, E. Synthesis and 3D-QSAR study of 1,4-dihydropyridine derivatives as MDR cancer reverters. Eur. J. Med. Chem., 2014, 74, 375-387.
[http://dx.doi.org/10.1016/j.ejmech.2014.01.011] [PMID: 24486418]
[2]
Hunter, A.M.; LaCasse, E.C.; Korneluk, R.G. The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis, 2007, 12(9), 1543-1568.
[http://dx.doi.org/10.1007/s10495-007-0087-3] [PMID: 17573556]
[3]
Shekari, F.; Sadeghpour, H.; Javidnia, K.; Saso, L.; Nazari, F.; Firuzi, O.; Miri, R. Cytotoxic and multidrug resistance reversal activities of novel 1,4-dihydropyridines against human cancer cells. Eur. J. Pharmacol., 2015, 746, 233-244.
[http://dx.doi.org/10.1016/j.ejphar.2014.10.058] [PMID: 25445037]
[4]
UniProt: the universal protein knowledgebase. Nucleic Acids Res., 2017, 45(D1), D158-D169.
[http://dx.doi.org/10.1093/nar/gkw1099] [PMID: 27899622]
[5]
Ogawa, Y.; Nonaka, Y.; Goto, T.; Ohnishi, E.; Hiramatsu, T.; Kii, I.; Yoshida, M.; Ikura, T.; Onogi, H.; Shibuya, H.; Hosoya, T.; Ito, N.; Hagiwara, M. Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A. Nat. Commun., 2010, 1, 86.
[http://dx.doi.org/10.1038/ncomms1090] [PMID: 20981014]
[6]
Soundararajan, M.; Roos, A.K.; Savitsky, P.; Filippakopoulos, P.; Kettenbach, A.N.; Olsen, J.V.; Gerber, S.A.; Eswaran, J.; Knapp, S.; Elkins, J.M. Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. Structure, 2013, 21(6), 986-996.
[http://dx.doi.org/10.1016/j.str.2013.03.012] [PMID: 23665168]
[7]
Alexeeva, M.; Åberg, E.; Engh, R.A.; Rothweiler, U. The structure of a dual-specificity tyrosine phosphorylation-regulated kinase 1A-PKC412 complex reveals disulfide-bridge formation with the anomalous catalytic loop HRD(HCD) cysteine. Acta Crystallogr. D Biol. Crystallogr., 2015, 71(Pt 5), 1207-1215.
[http://dx.doi.org/10.1107/S1399004715005106] [PMID: 25945585]
[8]
Hadizadeh, F.; Hassanabad, Z.F.; Bamshad, M.; Poorsoghat, H.; Hassanabad, M.F. Synthesis and antihypertensive activity of new 1,4-dihydropyridine. Indian J. Chem., 2005, 44B, 2343.
[9]
Jorjani, M.; Rastegar, H.; Roshanzamir, F.; Varmazyari, M.; Abdollahi, M.; Zarghi, A. Synthesis and biological evaluation of new 1, 4-dihydropyridines as antihypertensives agents. Iran. J. Pharm. Res., 2003, 2, 43.
[10]
Vijesh, A.M.; Isloor, A.M.; Peethambar, S.K.; Shivananda, K.N.; Arulmoli, T.; Isloor, N.A. Hantzsch reaction: synthesis and characterization of some new 1,4-dihydropyridine derivatives as potent antimicrobial and antioxidant agents. Eur. J. Med. Chem., 2011, 46(11), 5591-5597.
[http://dx.doi.org/10.1016/j.ejmech.2011.09.026] [PMID: 21968373]
[11]
Abu-Melha, H. Synthesis, antibacterial and antifungal evaluation of novel 1,4-dihydropyridine derivatives. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2013, 113, 115-122.
[http://dx.doi.org/10.1016/j.saa.2012.12.069] [PMID: 23732618]
[12]
Fassihi, A.; Azadpour, Z.; Delbari, N.; Saghaie, L.; Memarian, H.R.; Sabet, R.; Alborzi, A.; Miri, R.; Pourabbas, B.; Mardaneh, J.; Mousavi, P.; Moeinifard, B.; Sadeghi-Aliabadi, H. Synthesis and antitubercular activity of novel 4-substituted imidazolyl-2,6-dimethyl-N3,N5-bisaryl-1,4-dihydropyridine-3,5-dicarboxamides. Eur. J. Med. Chem., 2009, 44(8), 3253-3258.
[http://dx.doi.org/10.1016/j.ejmech.2009.03.027] [PMID: 19371979]
[13]
Khoshneviszadeh, M.; Edraki, N.; Javidnia, K.; Alborzi, A.; Pourabbas, B.; Mardaneh, J.; Miri, R. Synthesis and biological evaluation of some new 1,4-dihydropyridines containing different ester substitute and diethyl carbamoyl group as anti-tubercular agents. Bioorg. Med. Chem., 2009, 17(4), 1579-1586.
[http://dx.doi.org/10.1016/j.bmc.2008.12.070] [PMID: 19162489]
[14]
Pandey, V.P.; Bisht, S.S.; Mishra, M.; Kumar, A.; Siddiqi, M.I.; Verma, A.; Mittal, M.; Sane, S.A.; Gupta, S.; Tripathi, R.P. Synthesis and molecular docking studies of 1-phenyl-4-glycosyl-dihydropyridines as potent antileishmanial agents. Eur. J. Med. Chem., 2010, 45(6), 2381-2388.
[http://dx.doi.org/10.1016/j.ejmech.2010.02.018] [PMID: 20199824]
[15]
Reimão, J.Q.; Scotti, M.T.; Tempone, A.G. Anti-leishmanial and anti-trypanosomal activities of 1,4-dihydropyridines: In vitro evaluation and structure-activity relationship study. Bioorg. Med. Chem., 2010, 18(22), 8044-8053.
[http://dx.doi.org/10.1016/j.bmc.2010.09.015] [PMID: 20934347]
[16]
Kumar, A.; Maurya, R.A.; Sharma, S.; Kumar, M.; Bhatia, G. Synthesis and biological evaluation of N-aryl-1,4-dihydropyridines as novel antidyslipidemic and antioxidant agents. Eur. J. Med. Chem., 2010, 45(2), 501-509.
[http://dx.doi.org/10.1016/j.ejmech.2009.10.036] [PMID: 19962217]
[17]
Miri, R.; Javidnia, K.; Amirghofran, Z.; Salimi, S.H.; Sabetghadam, Z.; Meili, S.; Mehdipour, A.R. Cytotoxic effect of some 1, 4-dihydropyridine derivatives containing nitroimidazole moiety. Iran. J. Pharm. Res., 2011, 10(3), 497-503.
[PMID: 24250381]
[18]
Zarrin, A.; Mehdipour, A.R.; Miri, R. Dihydropyridines and multidrug resistance: previous attempts, present state, and future trends. Chem. Biol. Drug Des., 2010, 76(5), 369-381.
[http://dx.doi.org/10.1111/j.1747-0285.2010.01025.x] [PMID: 20925689]
[19]
Karegoudar, P.; Prasad, D.J.; Ashok, M.; Mahalinga, M.; Poojary, B.; Holla, B.S. Synthesis, antimicrobial and anti-inflammatory activities of some 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines bearing trichlorophenyl moiety. Eur. J. Med. Chem., 2008, 43(4), 808-815.
[http://dx.doi.org/10.1016/j.ejmech.2007.06.026] [PMID: 17804121]
[20]
Holla, B.S.; Poojary, K.N.; Rao, B.S.; Shivananda, M.K. New bis-aminomercaptotriazoles and bis-triazolothiadiazoles as possible anticancer agents. Eur. J. Med. Chem., 2002, 37(6), 511-517.
[http://dx.doi.org/10.1016/S0223-5234(02)01358-2] [PMID: 12204477]
[21]
Witkoaski, J.T.; Robins, R.K.; Sidwell, R.W.; Simon, L.N. Synthesis of 1-p-chlorobenzyl-7-azaindole-3-alpha-piperidylmethanol as a potential antimalarial agent. J. Med. Chem., 1972, 15, 150.
[22]
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]
[23]
Skoumbourdis, A.P.; Leclair, C.A.; Stefan, E.; Turjanski, A.G.; Maguire, W.; Titus, S.A.; Huang, R.; Auld, D.S.; Inglese, J.; Austin, C.P.; Michnick, S.W.; Xia, M.; Thomas, C.J. Exploration and optimization of substituted triazolothiadiazines and triazolopyridazines as PDE4 inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(13), 3686-3692.
[http://dx.doi.org/10.1016/j.bmcl.2009.01.057] [PMID: 19464886]
[24]
Kaur, R.; Dwivedi, A.R.; Kumar, B.; Kumar, V. Recent developments on 1,2,4-triazole nucleus in anticancer compounds: A review. Anticancer. Agents Med. Chem., 2016, 16(4), 465-489.
[http://dx.doi.org/10.2174/1871520615666150819121106] [PMID: 26286663]
[25]
Kharb, R.; Sharma, P.C.; Yar, M.S. Pharmacological significance of triazole scaffold. J. Enzyme Inhib. Med. Chem., 2011, 26(1), 1-21.
[http://dx.doi.org/10.3109/14756360903524304] [PMID: 20583859]
[26]
Gomha, S.M.; Farghaly, T.A.; Sayed, A.R. Design, Synthesis, and characterization of bis-thiazoles based on bis-hydrazonoyl chlorides. J. Heterocycl. Chem., 2017, 54, 1537.
[http://dx.doi.org/10.1002/jhet.2741]
[27]
Gomha, S.M.; Abbas, I.M.; Elaasser, M.M.; Mabrouk, B.K.A. Synthesis, molecular docking and pharmacological study of pyrimido-thiadiazinones and its bis-derivatives. Lett. Drug Des. Discov., 2017, 14, 434.
[http://dx.doi.org/10.2174/1570180813666160815125409]
[28]
Gomha, S.M.; Edrees, M.M.; El-Arab, E.E. Synthesis and preliminary in-vitro cytotoxic evaluation of some novel bis-heterocycles incorporating thienothiophene. J. Heterocycl. Chem., 2017, 54, 641.
[http://dx.doi.org/10.1002/jhet.2636]
[29]
Abdelrazek, F.M.; Gomha, S.M.; Metz, P. Synthesis of some novel 1,4-phenylene-bis-thiazolyl derivatives and their anti-hypertensive α-blocking activity screening. J. Heterocycl. Chem., 2017, 54, 618.
[http://dx.doi.org/10.1002/jhet.2633]
[30]
Gomha, S.M.; Kheder, N.A.; Abdelhamid, A.O.; Mabkhot, Y.N. One pot single step synthesis and biological evaluation of some novel bis(1,3,4-thiadiazole) derivatives as potential cytotoxic agents. Molecules, 2016, 21(11), 1532.
[http://dx.doi.org/10.3390/molecules21111532] [PMID: 27854300]
[31]
Sayed, A.R.; Gomha, S.M.; Farghaly, T.A. Synthesis and characterization of bis-imidazoles, bistriazoles, bis-thiadiazoles and bis-thiazoles from novel bis-hydrazonoyl dichlorides. J. Heterocycl. Chem., 2016, 53, 255.
[http://dx.doi.org/10.1002/jhet.2320]
[32]
Gomha, S.M.; Badrey, M.G.; Edrees, M.M. Heterocyclization of a bis-thiosemicarbazone of 2,5-diacetyl-3,4-disubstituted-thieno[2,3-b]thiophene, bis-thiosemicarbazones leading to bis-thiazoles and bis-1,3,4-thiadiazoles as anti-breast cancer agents. J. Chem. Res., 2016, 40, 120.
[http://dx.doi.org/10.3184/174751916X14537182696214]
[33]
Gomha, S.M.; Abdelrazek, F.M.; Abdelrahman, A.H.; Peter, M. Synthesis of some novel thiazole, thiadiazole and 1,4-phenylene-bis-thiazole derivatives. Heterocycles, 2016, 92, 954.
[http://dx.doi.org/10.3987/COM-16-13443]
[34]
Gomha, S.M.; Riyadh, S.M.; Abdalla, M.M. Solvent-drop grinding method: Efficient synthesis, DPPH radical scavenging and anti-diabetic activities of chalcones, bis-chalcones, azolines, and bis-azolines. Curr. Org. Synth., 2015, 12, 220.
[http://dx.doi.org/10.2174/1570179412666150122230447]
[35]
Gomha, S.M.; Khalil, K.D.; El-Zanate, A.M.; Riyadh, S.M. A Facile green synthesis and anti-cancer activity of bis-arylhydrazononitriles, triazolo[5,1-c][1,2,4]triazine, and 1,3,4-thiadiazoline. Heterocycles, 2013, 87, 1109.
[http://dx.doi.org/10.3987/COM-13-12696]
[36]
Gomha, S.M.; Edrees, M.M.; Altalbawy, F.M.A. Synthesis and characterization of some new bis-pyrazolyl-thiazoles incorporating the thiophene moiety as potent anti-tumor agents. Int. J. Mol. Sci., 2016, 17(9), 1499.
[http://dx.doi.org/10.3390/ijms17091499] [PMID: 27618013]
[37]
Gomha, S.M.; Farghaly, T.A.; Abbas, E.M.; Nadia, H.; Alqurashi, T. Terephthalaldehyde: An effecient key precursor for novel synthesis of some intresting bis-thiazoles and bis-triazolopyrimidinones. J. Heterocycl. Chem., 2018, 55, 750.
[http://dx.doi.org/10.1002/jhet.3100]
[38]
Kotb, E.R.; Abbas, H.S.; Flefel, E.M.; Sayed, H.H.; Abdelwahed, N.A.M. Utility of Hantzsch ester in synthesis of some 3,5-bis-dihydropyridine derivatives and studying their biological evaluation. J. Heterocycl. Chem., 2015, 52, 1531.
[http://dx.doi.org/10.1002/jhet.1848]
[39]
Shawali, S.; Gomha, S.M. A New entry for short and regioselective synthesis of [1,2,4]triazolo[4,3-b][1,2,4]-triazin-7(1H)-one. Adv. Synth. Catal., 2000, 342, 599.
[40]
Gfeller, D.; Michielin, O.; Zoete, V. Shaping the interaction landscape of bioactive molecules. Bioinformatics, 2013, 29(23), 3073-3079.
[http://dx.doi.org/10.1093/bioinformatics/btt540] [PMID: 24048355]
[41]
Adayev, T.; Wegiel, J.; Hwang, Y.W. Harmine is an ATP-competitive inhibitor for dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A). Arch. Biochem. Biophys., 2011, 507(2), 212-218.
[http://dx.doi.org/10.1016/j.abb.2010.12.024] [PMID: 21185805]
[42]
Gomha, S.M.; Riyadh, S.M.; Mahmmoud, E.A.; Elaasser, M.M. Synthesis and anticancer activities of thiazoles, 1,3-thiazines, and thiazolidine using chitosan-grafted-poly(vinylpyridine) as basic catalyst. Heterocycles, 2015, 91, 1227.
[http://dx.doi.org/10.3987/COM-15-13210]
[43]
Gomha, S.M.; Edrees, M.M.; Muhammad, Z.A.; El-Reedy, A.A.M. 5-(Thiophen-2-yl)-1,3,4-thiadiazole derivatives: synthesis, molecular docking and in vitro cytotoxicity evaluation as potential anticancer agents. Drug Des. Devel. Ther., 2018, 12, 1511-1523.
[http://dx.doi.org/10.2147/DDDT.S165276] [PMID: 29881258]
[44]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[45]
Hsu, K.C.; Chen, Y.F.; Lin, S.R.; Yang, J.M. iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC Bioinformatics, 2011, 12(Suppl. 1), S33.
[http://dx.doi.org/10.1186/1471-2105-12-S1-S33] [PMID: 21342564]
[46]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform., 2011, 3, 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]

Rights & Permissions Print Cite
Article Metrics
12
© 2024 Bentham Science Publishers | Privacy Policy