Abstract
Background: In this investigation, 2-cyano-N-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) acetamide (3) reacts with dimethylformamide dimethyl acetal (DMF-DMA) to afford the corresponding (E)- 2-cyano-3-(dimethylamino)-N-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acrylam-ide (4) utilizing microwave irradiation. The condensation reactions of acrylamide derivative 4 with hydrazine derivatives obtain pyrazole derivatives 6a and 6b; respectively. The synthesized compounds demonstrate in vitro antitumor activity against liver tumor cell line HepG2. Furthermore, additional studies were carried out on the most effective compound 6b to evaluate the potential interaction against 4hdq synthase complex with ΔE= -4.5Kcal/mol and with short distance = 1.727Å and 2.027Å, respectively. The comprehensive theoretical studies of compounds 6a and 6b is based on bond length, bond angles and energy gap HOMO-LUMO. In addition, the vibrational frequencies of optimized compounds 6a and 6b were examined through DFT/B3LYP/6+31G(d) basis set.
Methods: In this research, synthesis of novel pyrimidiopyrazole derivatives calculated the computational studies to find suitable drug-receptor interactions and biological activity.
Results and Discussion: The synthesized pyrimidiopyrazole derivative 6b exhibited high antitumor activity IC50 =12.6 μg/ml and interacted it with 4hdq synthase complex with ΔE=-4.5Kcal/mol and with short distance = 1.727Å and 2.027Å. Furthermore, the optimized compounds utilize Gaussian 09W.
Conclusion: In the optimized pyrimidiopyrazole derivatives, 6b showed better antitumor activity HeG-2 against 5-flurouracil due to its energy and confirmed more potent of hydrogen bond interaction with protein pocket.
Keywords: Enaminonitrile, aminopyrazole, antitumor activity, molecular docking, 4hdq synthase complex, computational study, FT-IR analysis.
Graphical Abstract
[1]
(a) Fahim, A.M.; Shalaby, M.A.; Ibrahim, M.A. Microwaveassisted
synthesis of novel 5-aminouracil-based compound with
DFT calculations J. Mol. Struct., 2019, 1194, 211-226.
[http://dx.doi.org/10.1016/j.molstruc.2019.04.078]
(b) Farag, A.M.; Fahim, A.M. Synthesis, biological evaluation and DFT calculation of novel pyrazole and pyrimidine derivatives. J. Mol. Struct., 2019, 1179, 304-314.
[http://dx.doi.org/10.1016/j.molstruc.2018.11.008]
[http://dx.doi.org/10.1016/j.molstruc.2019.04.078]
(b) Farag, A.M.; Fahim, A.M. Synthesis, biological evaluation and DFT calculation of novel pyrazole and pyrimidine derivatives. J. Mol. Struct., 2019, 1179, 304-314.
[http://dx.doi.org/10.1016/j.molstruc.2018.11.008]
[2]
Fahim, A.M.; Shalaby, M.A. Synthesis, biological evaluation, molecular docking and DFT calculations of novel benzenesulfonamide derivatives. J. Mol. Struct., 2019, 1176, 408-421.
[http://dx.doi.org/10.1016/j.molstruc.2018.08.087]
[http://dx.doi.org/10.1016/j.molstruc.2018.08.087]
[3]
Fahim. A.M, Farag.A.M, Shabban.M.R, Ragab.E.A, Synthesis and DFT studyof novel pyrazole, thiophene, 1, 3-thiazole and 1, 3, 4-thiadiazole derivatives. Eureopan. J. Chem., 2018, 9, 30-38.
[4]
Fahim, A.M. Microwave assisted regioselective synthesis and biological evaluation of pyrano[2,3-c]pyridine derivatives utilizing DMAP as a catalyst. Online J. Biol. Sci., 2017, 17, 394-403.
[http://dx.doi.org/10.3844/ojbsci.2017.394.403]
[http://dx.doi.org/10.3844/ojbsci.2017.394.403]
[5]
Zayed, E.M.; Zayed, M.A.; Fahim, A.M.; El-Samahy, F.A. Synthesis
of novel macrocyclic Schiff’s-base and its complexes having
N2O2 group of donor atoms. Characterization and anticancer
screening are studied Appl. Organomet. Chem.,, 2017. 31e3694
[http://dx.doi.org/10.1002/aoc.3694]
[http://dx.doi.org/10.1002/aoc.3694]
[6]
Fahim, A.M.; Farag, A.M.; Yakout, E.M.A.; Nawwar, G.A.M.; Ragab, E.A. Sun degradation and synthesis of new antimicrobial and antioxidant utilising poly(ethylene terephthalate) waste. Int. J. Environ. Waste Manag., 2018, 22, 239-259.
[http://dx.doi.org/10.1504/IJEWM.2018.094111]
[http://dx.doi.org/10.1504/IJEWM.2018.094111]
[7]
Fahim, A.M. Regioselective synthesis of novel fused sulphonamide derivatives utilizing microwave irradiation. Curr. Microw. Chem., 2018, 5(1), 4-12.
[http://dx.doi.org/10.2174/2213335604666171110172524]
[http://dx.doi.org/10.2174/2213335604666171110172524]
[8]
Fahim, A.M.; Farag, A.M.; Shabban, M.R.; Ragab, E.A. Regio selective synthesis and DFT study of novel fused heterocyclic utilizing thermal heating and microwave irradiation. Afinidad, 2018, 75, 148-159.
[9]
Fahim, A.M.; Farag, A.M.; Yakout, E.M.A.; Nawwar, G.A.M.; Ragab, E.A. Synthesis,biological evaluation of 1,3,4-oxadiazole, triazole and uracil derivatives from poly (ethylene terephthalate) waste. Egypt. J. Chem., 2016, 59, 285-303.
[http://dx.doi.org/10.21608/ejchem.2016.1048]
[http://dx.doi.org/10.21608/ejchem.2016.1048]
[10]
Fahim, A.M.; Yakout, E.A.M.; Nawwar, G.A. Facile synthesis of in-vivo insecticidal and antimicrobial evaluation of bis heterocyclic moiety from pet waste. Online J. Biol. Sci., 2014, 14, 196-208.
[http://dx.doi.org/10.3844/ojbsci.2014.196.208]
[http://dx.doi.org/10.3844/ojbsci.2014.196.208]
[11]
Fahim.A.M, Farag.A.M, Nawwar.G.A.M, PET waste recycling as chemical feedstock: synthesis and antimicrobial activity of new compounds with anticipated industrial use. J. Appl. Chem., 2013, 2, 502-510.
[12]
Fahim.A.M, Farag.A.M, Shaaban.M.R, Ragab.E.A, Microwave Assisted Synthesis of Pyrazolo [1, 5-a] pyrimidine, Triazolo [1, 5-a] pyrimidine, Pyrimido [1, 2-a] benzimdazole, Triazolo [5, 1-c][1, 2, 4] triazine and imidazo[2,1-c][1,2,4]triazine. Curr. Microw. Chem., 2018, 5, 111-119.
[13]
Fahim, A.M.; Farag, A.M. Synthesis, antimicrobial evaluation, molecular docking and theoretical calculations of novel pyrazolo[1,5-a]pyrimidine derivatives. J. Mol. Struct., 2020, 1199127025
[http://dx.doi.org/10.1016/j.molstruc.2019.127025]]
[http://dx.doi.org/10.1016/j.molstruc.2019.127025]]
[14]
Fahim, A.M.; Ismael, E.H. Synthesis, antimicrobial activity and quantum calculations of Novel sulphonamide derivatives. Egypt. J. Chem., 2019, 62(8), 1427-1440.
[http://dx.doi.org/10.21608/ejchem.2019.6870.1575]
[http://dx.doi.org/10.21608/ejchem.2019.6870.1575]
[15]
Chimenti, F.; Bolasco, A.; Manna, F.; Secci, D.; Chimenti, P.; Befani, O.; Turini, P.; Giovannini, V.; Mondovì, B.; Cirilli, R.; La Torre, F. Synthesis and selective inhibitory activity of 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives against monoamine oxidase. J. Med. Chem., 2004, 47(8), 2071-2074.
[http://dx.doi.org/10.1021/jm031042b] [PMID: 15056004]
[http://dx.doi.org/10.1021/jm031042b] [PMID: 15056004]
[16]
Darweesh, A.F.; Mekky, A.E.M.; Salman, A.A.; Farag, A.M. Efficient, microwave-mediated synthesis of benzothiazole- and benzimidazole-based heterocycles. Res. Chem. Intermed., 2016, 42, 4341-4358.
[http://dx.doi.org/10.1007/s11164-015-2279-8]
[http://dx.doi.org/10.1007/s11164-015-2279-8]
[17]
Eldebss, T.M.A.; Jing, Y.X.; Farag, A.M.; Khedr, A.A.; Abdu, M.M.; Mabkhot, Y.N. Synthesis of new pyrazolone-based heterocycles as inhibitors of monoamine oxidase enzymes. J. Indian Chem. Soc., 2018, 15(8), 1785-1800.
[18]
Fahim, A.M.; Farag, A.M.; Yakout, E.M.A.; Nawwar, G.A.M.; Ragab, E.A. Chemistry of terephthalate derivatives. Int. J Envir Waste Manag., 2019, 24(3), 273-301.
[19]
Dawood, K.M.; Shaaban, M.R.; Elamin, M.B.; Farag, A.M. Catalytic activity of some oxime- based Pd (II)- complexes in Suzuki coupling of aryl and heteroaryl bromides in water. Arab. J. Chem., 2017, 2017(10), 473-479.
[http://dx.doi.org/10.1016/j.arabjc.2013.06.004]
[http://dx.doi.org/10.1016/j.arabjc.2013.06.004]
[20]
Abbate, F.; Casini, A.; Owa, T.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX. Bioorg. Med. Chem. Lett., 2004, 14(1), 217-223.
[http://dx.doi.org/10.1016/j.bmcl.2003.09.062] [PMID: 14684331]
[http://dx.doi.org/10.1016/j.bmcl.2003.09.062] [PMID: 14684331]
[21]
Dawood, K.M.; Moghazy, S.M.; Farag, A.M. Convenient synthesis of azolopyrimidine, azolotriazine, azinobenzimidazole and 1,3,4-thiadiazole derivatives. Arab. J. Chem., 2017, 10, S2782-S2789.
[http://dx.doi.org/10.1016/j.arabjc.2013.10.029]
[http://dx.doi.org/10.1016/j.arabjc.2013.10.029]
[22]
Dawood, K.M.; Elamin, M.B.; Farag, A.M. Microwave-assisted synthesis of arylated pyrrolo[2,1-a]isoquinoline derivatives via sequential [3+2] cycloadditions and suzuki-miyaura cross-couplings in aqueous medium. J. Heterocycl. Chem., 2016, 53, 1928-1934.
[http://dx.doi.org/10.1002/jhet.2508]
[http://dx.doi.org/10.1002/jhet.2508]
[23]
Fahim, A.M.; Farag, A.M.; Yakout, E.M.A.; Nawwar, G.A.M.; Ragab, E.A. Synthesis, reactions and DFT calculations of aza-
Michael additions of α,β-unsaturated ketones from Poly(methyl
methacrylate) Waste International journal of environmental and
waste management, 2019, 24(4).
[24]
Gingras, A.R.; Puzon-McLaughlin, W.; Ginsberg, M.H. The structure of the ternary complex of Krev interaction trapped 1 (KRIT1) bound to both the Rap1 GTPase and the heart of glass (HEG1) cytoplasmic tail. J. Biol. Chem., 2013, 288(33), 23639-23649.
[http://dx.doi.org/10.1074/jbc.M113.462911] [PMID: 23814056]
[http://dx.doi.org/10.1074/jbc.M113.462911] [PMID: 23814056]
[25]
Ghorab, M.M.; Ragab, F.A.; Heiba, H.I.; Soliman, A.M. Design and synthesis of some novel 4-Chloro-N-(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl) benzenesulfonamide derivatives as anticancer and radiosensitizing agents. Eur. J. Med. Chem., 2016, 117, 8-18.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.009] [PMID: 27085944]
[http://dx.doi.org/10.1016/j.ejmech.2016.04.009] [PMID: 27085944]
[26]
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; Nakatsuji, H.; Caricato, M.; Hratchian, X.; Li, H.P.; Izmaylov, A.F.; Bloino, J.; Zheng, G.; Sonnenberg, J.L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J.A.; Peralta, J.E.; Ogliaro, F.; Bearpark, M.; Heyd, J.J.; Brothers, E.; Kudin, K.N.; Staroverov, V.N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J.C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.M.; Klene, M.; Knox, J.E.; Cross, J.B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Martin, R.L.; Morokuma, K.; Zakrzewski, V.G.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Dapprich, S.; Daniels, A.D.; Farkas, O.; Foresman, J.B.; Ortiz, J.V.; Cioslowski, J.; Fox, D.J. Gaussian 09, Revision a. 1; Gaussian, Inc.: Wallingford, CT, 2009.
[27]
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, 1107-1112.
[28]
Alsulaili, A.; Fahim, A.M. Oil removal from produced water by
agriculture waste adsorbents Int. J. Envir. Waste Manag, 25(1)
[http://dx.doi.org/10.1504/IJEWM.2020.104345]
[http://dx.doi.org/10.1504/IJEWM.2020.104345]
[29]
Kooistra, M.R.; Dubé, N.; Bos, J.L. Rap1: a key regulator in cell-cell junction formation. J. Cell Sci., 2007, 120(Pt 1), 17-22.
[http://dx.doi.org/10.1242/jcs.03306] [PMID: 17182900]
[http://dx.doi.org/10.1242/jcs.03306] [PMID: 17182900]
[30]
Pannekoek, W.; Kooistra, R.H.; Zwartkruis, M.; Bos, F. Cell-cell junction formation: the role of Rap1 and Rap1 guanine nucleotide exchange factors, 2009, 1178, 790-796.
[31]
Akl, E.; Dacrory, S.; Kamel, M.; Fahim, A.M. Preparation and characterization of novel antibacterial blended films based on modified carboxymethyl cellulose/phenolic compounds. Polym. Bull., 2020.
[http://dx.doi.org/10.1007/s00289-020-03148-w]
[http://dx.doi.org/10.1007/s00289-020-03148-w]
[32]
Gingras, A.R. Structural basis of the junctional anchorage of the cerebral cavernous malformations complex. Journal of cell biology, 2012, 199, 1, 39-48.
[33]
Trilleras, J. Quiroga, J.; Low, J.N.; Cobo, J.; Glidewell, C. 2-(4-Chlorophenyl)-5-(4-nitrophenyl)-4,7-dihydropyrazolo(1,5-a)pyrimidine-3,6-dicarbaldehyde. Acta Crystallogr. C, 2008, 64, o341.
[http://dx.doi.org/10.1107/S0108270108014509]
[http://dx.doi.org/10.1107/S0108270108014509]
[34]
Bassoude, I.; Berteina-Raboin, S.; Essassi, M.; Guillaumet, G.; El Ammari, L. 7-Chloro-5-methyl-2-phenyl-pyrazolo-[1,5-a]pyrimidine. Acta Crystallogr. Sect. E Struct. Rep. Online, 2013, 69(Pt 5), o749.
[http://dx.doi.org/10.1107/S1600536813009896] [PMID: 23723898]
[http://dx.doi.org/10.1107/S1600536813009896] [PMID: 23723898]
[35]
Takazawa, H.; Ohba, S.; Saito, Y. Structure of monoclinic o-aminobenzoic acid. Acta Crystallogr. C, 1986, 42, 1880.
[http://dx.doi.org/10.1107/S0108270186090182]
[http://dx.doi.org/10.1107/S0108270186090182]
[36]
Fukui, K. Role of frontier orbitals in chemical reactions. Science, 1982, 218(4574), 747-754.
[http://dx.doi.org/10.1126/science.218.4574.747] [PMID: 17771019]
[http://dx.doi.org/10.1126/science.218.4574.747] [PMID: 17771019]
[38]
Zielinski, T.J.; Rein, R. Optimum geometries and relative energies for cytosine, thymine, uracil, the imino tautomer of cytosine, the enol tautomer of thymine, and the enol tautomer of uracil by the MINDO/2 SCF MO method. Int. J. Quantum Chem., 1978, 1978(14), 851-860.
[http://dx.doi.org/10.1002/qua.560140615]
[http://dx.doi.org/10.1002/qua.560140615]
[39]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[40]
Ditchfield.R, The Molecular orbital theory of magnetic shielding and magnetic susceptibility. J. Chem. Phys., 1972, 56, 5688-5691.
[http://dx.doi.org/10.1063/1.1677088]
[http://dx.doi.org/10.1063/1.1677088]
[41]
Dennington.R, Keith.T, Millam.J, GaussView, Version 5; Semichem Inc.: Shawnee Mission, KS, 2009.
[42]
Borowski, P. An evaluation of scaling factors for multiparameter scaling procedures based on DFT force fields. J. Phys. Chem. A, 2012, 116(15), 3866-3880.
[http://dx.doi.org/10.1021/jp212201f] [PMID: 22372987]
[http://dx.doi.org/10.1021/jp212201f] [PMID: 22372987]
[43]
Jamróz, M.H. Vibrational energy distribution analysis (VEDA): scopes and limitations. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2013, 114, 220-230.
[http://dx.doi.org/10.1016/j.saa.2013.05.096] [PMID: 23778167]
[http://dx.doi.org/10.1016/j.saa.2013.05.096] [PMID: 23778167]
[44]
Dacrory, S.; Fahim, A.M. Synthesis, anti-proliferative activity, computational studies of tetrazole cellulose utilizing different homogenous catalyst. Carbohydr. Polym., 2020, 229115537
[http://dx.doi.org/10.1016/j.carbpol.2019.115537] [PMID: 31826405]
[http://dx.doi.org/10.1016/j.carbpol.2019.115537] [PMID: 31826405]
[45]
Scott.A.P, Radom.L, Harmonic vibrational frequencies: an evaluation of hartree-fock, møller−plesset, quadratic configuration interaction, density functional theory, and semiempirical scale factors. J. Phys. Chem., 1996, 100, 16502-16513.
[http://dx.doi.org/10.1021/jp960976r]
[http://dx.doi.org/10.1021/jp960976r]
[46]
Pouysségur, J.; Dayan, F.; Mazure, N.M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature, 2006, 441(7092), 437-443.
[http://dx.doi.org/10.1038/nature04871] [PMID: 16724055]
[http://dx.doi.org/10.1038/nature04871] [PMID: 16724055]
[47]
Morris.G.M, Huey.R, Lindstrom.W, Sanner.M., Belew M. F, Goodsell. R. K, and A.J Olson, Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. J. Comput. Chem., 2009, 16, 2785-2791.
[48]
Fahim, A.M.; Wasiniak, B.; Łukaszewicz, J.P. Molecularly imprinted polymer and computational study of (e)-4-(2- cyano-3-(dimethylamino)acryloyl)benzoic acid from poly(ethylene terephthalate) plastic waste. Curr. Anal. Chem., 2020, 16(2), 119-137.
[http://dx.doi.org/10.2174/1573411015666190131123843]
[http://dx.doi.org/10.2174/1573411015666190131123843]
[49]
Arthur, W.T.; Quilliam, L.A.; Cooper, J.A. Rap1 promotes cell spreading by localizing Rac guanine nucleotide exchange factors. J. Cell Biol., 2004, 167(1), 111-122.
[http://dx.doi.org/10.1083/jcb.200404068] [PMID: 15479739]
[http://dx.doi.org/10.1083/jcb.200404068] [PMID: 15479739]
[50]
Schlegel, B. Optimization of equilibrium geometries and transition structures. J. Comput. Chem., 1982, 3, 214-218.
[http://dx.doi.org/10.1002/jcc.540030212]
[http://dx.doi.org/10.1002/jcc.540030212]
[51]
Peng, C.; Ayala, P.Y.; Schlegel, H.B.; Frisch, M.J. Using redundant internal coordinates to optimize equilibrium geometries and transition states. J. Comput. Chem., 1996, 17, 49-56.
[http://dx.doi.org/10.1002/(SICI)1096-987X(19960115)17:1<49::AI D-JCC5>3.0.CO;2-0]
[http://dx.doi.org/10.1002/(SICI)1096-987X(19960115)17:1<49::AI D-JCC5>3.0.CO;2-0]
Article Metrics
19