A New Synthesis of Poly Heterocyclic Compounds Containing [1,2,4]triazolo and [1,2,3,4]tetrazolo Moieties and their DFT Study as Expected Anti-cancer Reagents

Author(s): El-sayed M. Abdelrehim*, Doaa S. El-Sayed

Journal Name: Current Organic Synthesis

Volume 17 , Issue 3 , 2020

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Abstract:

Background: 2-amino-3-cyanopyridines are good starting reagents that have been used in synthesis of many heterocyclic compounds such as pyridopyrimidines, [1,2,4]triazolo and [1,2,3,4] tetrazolo derivatives which have biological activities as anti-microbial and cytotoxic activities. Meanwhile [1,2,4]triazolo and [1,2,3,4]tetrazolo derivatives are well known to possess many physiological activities, such as anticancer , antifungal, muscle relaxant, hypnotic, anti-inflammatory, diuretic and antihypertensive activities. A broad class of heterocyclic compounds has been studied to demonstrate their biological activity on the structures of DNA and RNA. Several of important functions make Tankyrases acts as targets in potential drug.

Objective: The article focuses on synthesis of [1,2,4]triazolo and [1,2,3,4]tetrazolo derivatives and their theoretical calculations that suggest they are anti-cancer substances.

Materials and Methods: DFT and computational studies were performed on the structural properties of experimental molecules experimentally, and significant theoretical calculations were performed based on density functional theory (DFT) with Becke’s three-parameter exchange function21-22 of correlation functional Lee Yang Parr (B3LYP) with the basis set 6-31G (d,p) using Gaussian 03 software23. Geometrical parameters of the optimized structures were calculated and also the charge on each atom (Mulliken charge). Chemcraft program24 was used to visualize the optimized structure and ChemBio3D ultra 12.0 was used to visualize the highest occupied and lowest unoccupied molecular orbitals.

Results: Preliminary screening in five studied ligands acts as inhibitors for different active sites along the target. The molecular docking study also revealed that the compound 6c was the most effective compounds in inhibiting Tankyrase I enzyme (2rf5), this result can help strongly in inhibition of carcinogenic cells and cancer treatment.

Conclusion: We have described a new practical cyclocondensation synthesis for a series of [1,2,4]triazolo[4,3- c]pyrido[3,2-e] pyrimidine and pyrido[2',3':4,5] pyrimido[6,1-c][1,2,4] triazine from 2-amino-3-cyano-4.6- diarylpyridines. Also polyheterocyclic compounds containing [1,2,4]triazolo and [1,2,3,4]tetrazolo moieties were also synthesized through the reactions of 3-hydrazino-8,10-diaryl [1,2,4]triazolo[4,3-c]pyrido[3,2- e]pyrimidine with both formic acid and the formation of diazonuim salt respectively. Newly synthesized heterocycles structures were confirmed using elemental analysis, IR, 1H-NMR, 13C-NMR and mass spectral data. DFT and computational studies were carried out on five of the synthesized poly heterocyclic compounds to show their structural and geometrical parameters involved in the study. Molecular docking using Tankyrase I enzyme as a target showed how the studied heterocyclic compounds act as a ligand interacting most of active sites on Tankyrase I with a type of interactions specified for H-bonding and VDW. We investigated that the five studied ligands act as inhibitors for different active sites along the target. The molecular docking study also revealed that the compound 6c was the most effective compounds in inhibiting Tankyrase I enzyme (2rf5), this result can help strongly in inhibition of carcinogenic cells and cancer treatment.

Keywords: Polyheterocyclic compounds, [1, 3, 4]triazolo, [1, 2, 3, 4] tetrazolo, DFT, computational calculation, molecular docking.

[1]
Elsaedany, S.K.; Zein, M.A.; Abdelrehim, E.M.; Keshk, R.M. Synthesis, anti-microbial, and cytotoxic activities evaluation of some new pyrido[2,3-d]pyrimidines. J. Hetrocyclic Chem., 2016, 53, 1534.
[2]
Abdelrehim, E.M.; Zein, M.A. Synthesis of some novel pyrido[2,3-d]pyrimidine and pyrido[3,2-e][1,3,4]triazolo and tetrazolo[1,5-c]pyrimidine derivatives as potential antimicrobial and anticancer agents. J. Hetrocyclic Chem., 2018, 55, 419.
[3]
Kurumurthy, C.; Sambasiva, P.; Veera Swamy, B.; Santhosh Kumar, G.; Shanthan, P.; Narsaiah, B.; Velatooru, L.R.; Pamanji, R.; , Venkateswara Synthesis of novel alkyltriazole tagged pyrido[2,3-d]pyrimidine derivatives and their anticancer activity. Eur. J. Med. Chem., 2011, 46(8), 3462-3468.[Available from.
[http://dx.doi.org/10.1016/j.ejmech.2011.05.011] [PMID: 21632155]
[4]
Li, F.; Feng, Y.; Meng, Q.; Li, W.; Wang, Q.; Tao, F. An efficient construction of quinazolin-4 (3H)-ones under microwave irradiation. ARKIVOC, 2007, 1, 40.
[5]
Abdel-Rahman, R.M.; Morsy, J.M.; Hanafy, F.; Amene, H.A. Synthesis of heterobicyclic nitrogen systems bearing the 1,2,4-triazine moiety as anti-HIV and anticancer drugs: Part I. Pharmazie, 1999, 54(5), 347-351.
[PMID: 10368828]
[6]
Kang, T.S.; Wang, W.; Zhong, H.J.; Dong, Z.Z.; Huang, Q.; Mok, S.W.; Leung, C.H.; Wong, V.K.; Ma, D.L. An anti-prostate cancer benzofuran-conjugated iridium(III) complex as a dual inhibitor of STAT3 and NF-κB. Cancer Lett., 2017, 396, 76-84.[Available from.
[http://dx.doi.org/10.1016/j.canlet.2017.03.016] [PMID: 28323031]
[7]
Yang, C.; Wang, W.; Chen, L.; Liang, J.; Lin, S.; Lee, M.Y.; Ma, D.L.; Leung, C.H. Discovery of a VHL and HIF1α interaction inhibitor with in vivo angiogenic activity via structure-based virtual screening. Chem. Commun. (Camb.), 2016, 52(87), 12837-12840.[Available from.
[http://dx.doi.org/10.1039/C6CC04938A] [PMID: 27709157]
[8]
Ibrahim, M.A.; Abdelrahman, R.M.; Ibrahim, S.S.; Alimony, H.A. Synthesis and antifungal activity of novel polyheterocyclic compounds containing fused 1,2,4-triazine moiety. ARKIVOC, 2008, (xvi), 202-215.
[9]
Wong, W. Enzymes in Synthetic Organic Chemistry, 1st ed; Enzymes In Synthetic Organic Chemistry. , 1994.
[10]
Du, X.; Li, Y.; Xia, Y.L.; Ai, S.M.; Liang, J.; Sang, P.; Ji, X.L.; Liu, S.Q. Insights into Protein-Ligand Interactions: Mechanisms, Models, and Methods. Int. J. Mol. Sci., 2016, 17(2), 144.[Available from.
[http://dx.doi.org/10.3390/ijms17020144] [PMID: 26821017]
[11]
Lehtiö, L.; Chi, N.W.; Krauss, S. Tankyrases as drug targets. FEBS J., 2013, 280(15), 3576-3593.[Available from.
[http://dx.doi.org/10.1111/febs.12320] [PMID: 23648170]
[12]
Riffell, J.L.; Lord, C.J.; Ashworth, A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat. Rev. Drug Discov., 2012, 11(12), 923-936.[Available from.
[http://dx.doi.org/10.1038/nrd3868] [PMID: 23197039]
[13]
Kim, M.K. Novel insight into the function of tankyrase. Oncol. Lett., 2018, 16(6), 6895-6902.[Available from.
[http://dx.doi.org/10.3892/ol.2018.9551] [PMID: 30546421]
[14]
Nkizinkiko, Y.; Desantis, J.; Koivunen, J.; Haikarainen, T.; Murthy, S.; Sancineto, L.; Massari, S.; Ianni, F.; Obaji, E.; Loza, M.I.; Pihlajaniemi, T.; Brea, J.; Tabarrini, O.; Lehtiö, L. 2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors. Sci. Rep., 2018, 8(1), 1680.[Available from.
[http://dx.doi.org/10.1038/s41598-018-19872-3] [PMID: 29374194]
[15]
Haikarainen, T.; Krauss, S.; Lehtiö, L. Tankyrases: structure, function and therapeutic implications in cancer. Curr. Pharm. Des., 2014, 20(41), 6472-6488.[Available from.
[http://dx.doi.org/10.2174/1381612820666140630101525] [PMID: 24975604]
[16]
Narwal, M.; Haikarainen, T.; Fallarero, A.; Vuorela, P.M.; Lehtiö, L. Screening and structural analysis of flavones inhibiting tankyrases. J. Med. Chem., 2013, 56(9), 3507-3517.[Available from.
[http://dx.doi.org/10.1021/jm3018783] [PMID: 23574272]
[17]
Paine, H.A.; Nathubhai, A.; Woon, E.C.; Sunderland, P.T.; Wood, P.J.; Mahon, M.F.; Lloyd, M.D.; Thompson, A.S.; Haikarainen, T.; Narwal, M.; Lehtiö, L.; Threadgill, M.D. Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro. Bioorg. Med. Chem., 2015, 23(17), 5891-5908.[Available from.
[http://dx.doi.org/10.1016/j.bmc.2015.06.061] [PMID: 26189030]
[18]
Nkizinkiko, Y.; Suneel Kumar, B.V.; Jeankumar, V.U.; Haikarainen, T.; Koivunen, J.; Madhuri, C.; Yogeeswari, P.; Venkannagari, H.; Obaji, E.; Pihlajaniemi, T.; Sriram, D.; Lehtiö, L. Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics. Bioorg. Med. Chem., 2015, 23(15), 4139-4149.[Available from.
[http://dx.doi.org/10.1016/j.bmc.2015.06.063] [PMID: 26183543]
[19]
Kumpan, K.; Nathubhai, A.; Zhang, C.; Wood, P.J.; Lloyd, M.D.; Thompson, A.S.; Haikarainen, T.; Lehtiö, L.; Threadgill, M.D. Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases. Bioorg. Med. Chem., 2015, 23(13), 3013-3032.[Available from.
[http://dx.doi.org/10.1016/j.bmc.2015.05.005] [PMID: 26026769]
[20]
Dolzhenko, A.V.; Pastorin, G. Dolzhenko, A.V.; Chui, K. Y. 8-Methyl-2-[4-(trifluoromethyl)phenyl]-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine methanol disolvate. Tetrahedron Lett., 2009, 50, 5617.[Available from.
[http://dx.doi.org/10.1016/j.tetlet.2009.07.113]
[21]
Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B Condens. Matter, 1988, 37(2), 785-789.[Available from.
[http://dx.doi.org/10.1103/PhysRevB.37.785] [PMID: 9944570]
[22]
Becke, A.D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys., 1993, 98, 5648.[Available from.
[http://dx.doi.org/10.1063/1.464913]
[23]
Frisch, M.; Trucks, G.; Schlegel, H.; Scuseria, G.; Robb, M.; Cheeseman, J.; Montgomery, J.; Vreven, T.; Kudin, K. Burant, Inc., 2003.
[24]
Zhurko, G.A.; Zhurko, D.A. Chemcraft- Graphical software for visualization of quantum chemistry computations. 2011. Available from. http://www.chemcraftprog.com
[25]
Chen, Y-F.; Chen, Y-J. GEMDOCK: An Integrated Environment for Computer-aided Drug Desig and Its Applications 2007.
[26]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.[Available from.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[27]
Kosar, B.; Albayrak, C. Spectroscopic investigations and quantum chemical computational study of (E)-4-methoxy-2-[(p-tolylimino)methyl]phenol. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2011, 78(1), 160-167.[Available from.
[http://dx.doi.org/10.1016/j.saa.2010.09.016] [PMID: 20940104]
[28]
Foresman, J.B.; Frisch, A.E. Exploring Chemistry with Electronic Structure Methods, 2nd ed; Gaussian: Pittsburgh, PA, 1996.
[29]
Chang, R. Chemistry, 7th ed; McGraw-Hill Science/Engineering/Math: New York, 2001.
[30]
Parr, R.G.; Von Szentpàly, L.; Liu, S.B. Electrophilicity index. J. Am. Chem. Soc., 1999, 121, 1922-1924.[Available from.
[http://dx.doi.org/10.1021/ja983494x]


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Article Details

VOLUME: 17
ISSUE: 3
Year: 2020
Page: [211 - 223]
Pages: 13
DOI: 10.2174/1570179417666200226092516
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