Pyrimidinone Associated Triazole Carboxamides: Synthesis, Characterization, Cytotoxicity and DNA Binding Studies

Author(s): Prakash Bhaskar, Suresha K. Tholappanavara*, Bhuvanesh S. Kalal, Vasantha Kumar, Ananda K.C. Siddegowda, Sowmya H.B. Vijaykumar, Vinitha R. Pai, Sujan Ganapathy

Journal Name: Current Bioactive Compounds

Volume 16 , Issue 6 , 2020


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Abstract:

Background: Pyrimidinones and its derivatives are present in many anti-cancer agents. It has been reported that these substances were proven to have significant activities against different types of human cancers. The incorporation of [1,2,3]-triazole, a nitrogen-rich unit not only increases the efficacy but also increases the lipophilicity of the drug molecule. As our research was to synthesize newer molecules of effective cytotoxicity, we focused on pyrimidinone and [1,2,3]-triazoles systems, as important scaffolds with the expectation of potential cytotoxic properties.

Methods: Novel series of [1,2,3]-triazole carboxamides (5a-j) were synthesized, starting from 3-(2- chloroethyl)-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one. The structure of all the synthesized compounds was elucidated based on IR, 1H-NMR, 13C-NMR and LC-MS data. Compounds were focused for their in vitro cytotoxicity against A375 melanoma cancer cell lines, MDA-MB-231 breast cancer cell lines and HEK 293-Human embryonic kidney cell lines using colorimetric MTT assay. The potent compound was evaluated for the DNA binding studies.

Results: Most of the Pyrimidinone conjugated [1,2,3]-triazole carboxamides found to be selective towards melanoma cancer cell lines than breast cancer cell lines. Compounds 5d, 5i and 5b were effective against A375 cancer cell lines and are found to be non-toxic against HEK 293-Human embryonic kidney cell lines. The potent compound 5d showed good intrinsic binding constant (Kb) value 3.12 x 103 M-1 in UV based DNA titration.

Conclusion: Newly synthesized Pyrimidinone conjugated [1,2,3]-triazole carboxamide derivatives showed the significant cytotoxicity and the potent compound showed good intrinsic binding constant in UV based DNA titration.

Keywords: 1, 2, 3-triazole, Pyrimidinone, cytotoxicity, A375 melanoma cancer cell lines, MDA-MB-231 cell lines, HEK 293- Human embryonic kidney cell lines, DNA binding.

[1]
Rashad, A.E.; Shamroukh, A.H.; Yousif, N.M.; Salama, M.A.; Ali, H.S.; Ali, M.M.; Mahmoud, A.E.; El-Shahat, M. New pyrimidinone and fused pyrimidinone derivatives as potential anticancer chemotherapeutics. Arch. Pharm. (Weinheim), 2012, 345(9), 729-738.
[http://dx.doi.org/10.1002/ardp.201200119] [PMID: 22674829]
[2]
De Oliveira, M.G.; Figueredo, A.S.; De Aquino, G.L.B.; Leo-poldino, A.M.; Da Silva, V.B.; Taft, C.A.; De Paula da Silva, C.H.T. In silico design of phenylbenzamide derivatives coupled to pyrimidines as novel hnRNP K ligands against Cancer. Curr. Bioact. Compd., 2014, 10, 158-162.
[http://dx.doi.org/10.2174/157340721003141013142614]
[3]
Sun, W.; Haller, D. UFT in the treatment of colorectal and breast cancer. Oncology (Williston Park), 2001, 15(1)(Suppl. 2), 49-56.
[PMID: 11219978]
[4]
Chai, B.; Wang, S.; Yu, W.; Li, H.; Song, C.; Xu, Y.; Liu, C.; Chang, J. Synthesis of novel strobilurin-pyrimidine derivatives and their antiproliferative activity against human cancer cell lines. Bioorg. Med. Chem. Lett., 2013, 23(12), 3505-3510.
[http://dx.doi.org/10.1016/j.bmcl.2013.04.045] [PMID: 23664877]
[5]
Holla, B.S.; Rao, B.S.; Sarojini, B.K.; Akberali, P.M. One pot synthesis of thiazolodihydropyrimidinones and evaluation of their anticancer activity. Eur. J. Med. Chem., 2004, 39(9), 777-783.
[http://dx.doi.org/10.1016/j.ejmech.2004.06.001] [PMID: 15337290]
[6]
El-Sayed, N.S.; El-Bendary, E.R.; El-Ashry, S.M.; El-Kerdawy, M.M. Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a]pyrimidines. Eur. J. Med. Chem., 2011, 46(9), 3714-3720.
[http://dx.doi.org/10.1016/j.ejmech.2011.05.037] [PMID: 21705114]
[7]
Fares, M.; Abou-Seri, S.M.; Abdel-Aziz, H.A.; Abbas, S.E.; Youssef, M.M.; Eladwy, R.A. Synthesis and antitumor activity of pyrido [2,3-d]pyrimidine and pyrido[2,3-d] [1,2,4]triazolo[4,3-a]pyrimidine derivatives that induce apoptosis through G1 cell-cycle arrest. Eur. J. Med. Chem., 2014, 83, 155-166.
[http://dx.doi.org/10.1016/j.ejmech.2014.06.027] [PMID: 24956552]
[8]
Brands, M.; Grande, Y.C.; Endermann, R.; Gahlmann, R.; Krüger, J.; Raddatz, S. Pyrimidinone antibiotics-heterocyclic analogues with improved antibacterial spectrum. Bioorg. Med. Chem. Lett., 2003, 13(16), 2641-2645.
[http://dx.doi.org/10.1016/S0960-894X(03)00578-X] [PMID: 12873484]
[9]
Devender, P.; Neha, S. Synthesis of some newer pyrimidi-none derivatives as potential analgesics and anti-inflammatory agents. J. Pharm. Res., 2012, 11, 71-75.
[http://dx.doi.org/10.18579/jpcrkc/2012/11/2/79353]
[10]
Sharma, M.; Chaturvedi, V.; Manju, Y.K.; Bhatnagar, S.; Srivastava, K.; Puri, S.K.; Chauhan, P.M.S. Substituted quinolinyl chalcones and quinolinyl pyrimidines as a new class of anti-infective agents. Eur. J. Med. Chem., 2009, 44(5), 2081-2091.
[http://dx.doi.org/10.1016/j.ejmech.2008.10.011] [PMID: 19028410]
[11]
Kotaiah, Y.; Harikrishna, N.; Nagaraju, K.; Venkata Rao, C. Synthesis and antioxidant activity of 1,3,4-oxadiazole tagged thieno[2,3-d]pyrimidine derivatives. Eur. J. Med. Chem., 2012, 58, 340-345.
[http://dx.doi.org/10.1016/j.ejmech.2012.10.007] [PMID: 23149297]
[12]
Sharma, R.; Gawande, D.Y.; Mohan, C.; Goel, R.K. Synthesis and anticonvulsant activities of functionalized 5-(isoindole-1,3-dione)-pyrimidinones. Med. Chem. Res., 2016, 25, 1420-1424.
[http://dx.doi.org/10.1007/s00044-016-1580-4]
[13]
Danta, C.C.; Sahu, S.B.; Swain, T.R. 2D Pharmacophoric design and synthesis of novel Pyrimidine derivatives as anti-convulsants. Curr. Bioact. Compd., 2017, 13, 130-136.
[http://dx.doi.org/10.2174/1573407212666160527104556]
[14]
Figarella, K.; Marsiccobetre, S.; Galindo-Castro, I.; Urdaneta, N.; Herrera, J.C.; Canudas, N.; Galarraga, E. Antileishmanial and antitrypanosomal activity of synthesized hydrazones, pyrazoles, pyrazolo[1,5-a]-pyrimidines and pyrazolo[3,4-b]-pyridine. Curr. Bioact. Compd., 2018, 14, 234-239.
[http://dx.doi.org/10.2174/1573407213666170405121810]
[15]
Agalave, S.G.; Maujan, S.R.; Pore, V.S. Click chemistry: 1,2,3-triazoles as pharmacophores. Chem. Asian J., 2011, 6(10), 2696-2718.
[http://dx.doi.org/10.1002/asia.201100432] [PMID: 21954075]
[16]
Pibiri, I.; Buscemi, S. Recent portrait of bioactive triazoles. Curr. Bioact. Compd., 2010, 6, 208-242.
[http://dx.doi.org/10.2174/157340710793237281]
[17]
Wang, X-L.; Wan, K.; Zhou, C-H. Synthesis of novel sulfanilamide derived 1,2,3-triazoles and their evaluation for antibacterial and antifungal activities. Eur. J. Med. Chem., 2010, 45(10), 4631-4639.
[http://dx.doi.org/10.1016/j.ejmech.2010.07.031] [PMID: 20708826]
[18]
Gill, C.; Jadhav, G.; Shaikh, M.; Kale, R.; Ghawalkar, A.; Nagargoje, D.; Shiradkar, M. Clubbed [1,2,3] triazoles by fluorine benzimidazole: A novel approach to H37Rv inhibitors as a potential treatment for tuberculosis. Bioorg. Med. Chem. Lett., 2008, 18(23), 6244-6247.
[http://dx.doi.org/10.1016/j.bmcl.2008.09.096] [PMID: 18930654]
[19]
Sambasiva Rao, P.; Kurumurthy, C.; Veeraswamy, B. San-thosh Kumar, G.; Poornachandra, Y.; Ganesh Kumar, C.; Vasamsetti, S.B.; Kotamraju, S.; Narsaiah, B. Synthesis of novel 1,2,3-triazole substituted-N-alkyl/aryl nitrone derivatives, their anti-inflammatory and anticancer activity. Eur. J. Med. Chem., 2014, 80, 184-191.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.052] [PMID: 24780595]
[20]
Khazir, J.; Hyder, I.; Gayatri, J.L.; Prasad Yandrati, L.; Nalla, N.; Chasoo, G.; Mahajan, A.; Saxena, A.K.; Alam, M.S.; Qazi, G.N.; Sampath Kumar, H.M. Design and synthesis of novel 1,2,3-triazole derivatives of coronopilin as anti-cancer compounds. Eur. J. Med. Chem., 2014, 82, 255-262.
[http://dx.doi.org/10.1016/j.ejmech.2014.05.053] [PMID: 24910974]
[21]
Sharma, G.V.M.; Kumar, K.S.; Reddy, S.V.; Nagalingam, A. Cunningham.; Ummanni, R.; Hugel, H.; Sharma, D.; Malhotra, S.V. Synthesis and biological evaluation of trialzole-vanillin molecular hybrids as anticancer agents. Curr. Bioact. Compd., 2017, 13, 223-235.
[http://dx.doi.org/10.2174/1573407213666161128122552]
[22]
Vasu, K.K.; Ingawale, H.D.; Sagar, S.R.; Sharma, J.A.; Pan-dya, D.H.; Agarwal, M. 2-((1H-1,2,3-triazol-1-yl)methyl)-3-phenylquinazolin-4(3H)-ones: Design, synthesis and evaluation as anti-cancer agents. Curr. Bioact. Compd., 2018, 14, 254-263.
[http://dx.doi.org/10.2174/1573407213666170329131557]
[23]
Głowacka, I.E.; Balzarini, J.; Wróblewski, A.E. The synthesis, antiviral, cytostatic and cytotoxic evaluation of a new series of acyclonucleotide analogues with a 1,2,3-triazole linker. Eur. J. Med. Chem., 2013, 70, 703-722.
[http://dx.doi.org/10.1016/j.ejmech.2013.10.057] [PMID: 24219992]
[24]
Alvarez, R.; Velázquez, S.; San-Félix, A.; Aquaro, S.; De Clercq, E.; Perno, C.F.; Karlsson, A.; Balzarini, J.; Camarasa, M.J. 1,2,3-Triazole-[2′,5′-bis-O-(tert-butyldimethylsilyl)-beta-D- ribofuranosyl]-3′-spiro-5”-(4”-amino-1”,2”-oxathiole 2”,2”-dioxide) (TSAO) analogues: synthesis and anti-HIV-1 activity. J. Med. Chem., 1994, 37(24), 4185-4194.
[http://dx.doi.org/10.1021/jm00050a015] [PMID: 7527463]
[25]
Nuhrich, A.; Varache-Lembège, M.; Vercauteren, J.; Dokhan, R.; Renard, P.; Devaux, G. Synthesis and binding affinities of a series of 1,2-benzisoxazole-3-carboxamides to dopamine and serotonin receptors. Eur. J. Med. Chem., 1996, 31, 957-964.
[http://dx.doi.org/10.1016/S0223-5234(97)86174-0]
[26]
Cai, W-X.; Liu, A-L.; Li, Z-M.; Dong, W-L.; Liu, X-H.; Sun, N-B. Synthesis and anticancer activity of novel thiazole-5-carboxamide derivatives. Appl. Sci. (Basel), 2016, 6, 8.
[http://dx.doi.org/10.3390/app6010008]
[27]
Reddy, K.B.; Rao, G.M.; Kumar, B.V.; Choudhury, C.; Rajan, K.S. Design and synthesis of Benzimidazole-4-carboxamides as potent Poly(ADP-Ribose) Polymerase-1(PARP-1) inhibitors. Curr. Bioact. Compd., 2018, 14, 100-111.
[http://dx.doi.org/10.2174/1573407213666170109154209]
[28]
Kalpana, K.; Kumar, K.R.; Babu, A.V.; Vanjivaka, S.; Van-tikommu, J.; Palle, S. Synthesis and biological evaluation of pyrazole fused combretastatin derivatives as anticancer agents. Curr. Bioact. Compd., 2018, 14, 357-363.
[http://dx.doi.org/10.2174/1573407213666170405122545]
[29]
Kumar, V.; Jaggi, M.; Singh, A.T.; Madaan, A.; Sanna, V.; Singh, P.; Sharma, P.K.; Irchhaiya, R.; Burman, A.C. 1,8-Naphthyridine-3-carboxamide derivatives with anticancer and anti-inflammatory activity. Eur. J. Med. Chem., 2009, 44(8), 3356-3362.
[http://dx.doi.org/10.1016/j.ejmech.2009.03.015] [PMID: 19361894]
[30]
Moreau, S.; Coudert, P.; Rubat, C.; Vallee-Goyet, D.; Gardette, D.; Gramain, J.C.; Couquelet, J. Synthesis and anticonvulsant properties of triazolo- and imidazopyridazinyl carboxamides and carboxylic acids. Bioorg. Med. Chem., 1998, 6(7), 983-991.
[http://dx.doi.org/10.1016/S0968-0896(98)00057-1] [PMID: 9730234]
[31]
Lu, X.; Tang, J.; Cui, S.; Wan, B.; Franzblauc, S.G.; Zhang, T.; Zhang, X.; Ding, K. Pyrazolo[1,5-a]pyridine-3-carboxamide hybrids: Design, synthesis and evaluation of anti-tubercular activity. Eur. J. Med. Chem., 2017, 125, 41-48.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.030] [PMID: 27654393]
[32]
Kim, S.H.; Lee, Y.H.; Jung, S.Y.; Kim, H.J.; Jin, C.; Lee, Y.S. Synthesis of chromone carboxamide derivatives with antioxidative and calpain inhibitory properties. Eur. J. Med. Chem., 2011, 46(5), 1721-1728.
[http://dx.doi.org/10.1016/j.ejmech.2011.02.025] [PMID: 21397369]
[33]
Bylov, I.E.; Vasylyev, M.V.; Bilokin, Y.V. Synthesis and anti-inflammatory activity of N-substituted 2-oxo-2H-1-benzopyran-3-carboxamides and their 2-iminoanalogues. Eur. J. Med. Chem., 1999, 34(11), 997-1001.
[http://dx.doi.org/10.1016/S0223-5234(99)00119-1] [PMID: 10889323]
[34]
Krishnamurthy, B.; Vinaya, K.; Prasanna, S.D.; Raghava, B.; Rangappa, K.S. Synthesis of 2-methyl-3-(2-(piperzin-1-yl)ethyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one derivatives as antimicrobial agents. Lett. Drug Des. Discov., 2011, 8, 988-995.
[http://dx.doi.org/10.2174/157018011797655304]
[35]
Husain, A.; Ahmad, A.; Khan, S.A.; Asif, M.; Bhutani, R.; Al-Abbasi, F.A. Synthesis, molecular properties, toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents. Saudi Pharm. J., 2016, 24(1), 104-114.
[http://dx.doi.org/10.1016/j.jsps.2015.02.008] [PMID: 26903774]
[36]
Chandra Mohan, A.; Geetha, S.; Gajalakshmi, R.; Divya, S.R.; Dhanarajan, M.S. Determination of molecular property, bioactivity score and binding energy of the phytochemical compounds present in cassia auriculata by molinspiration and DFT method. Texila. Int. J. Basic Med. Sci., 2017, 2(2), 1-15.
[37]
Hassan, G.S. EI-Messery, S.M.; Abbas, A. Synthesis anti-cancer activity of new thiazolo[3,2-a]pyrimidines: DNA binding and molecular modeling study. Bioorg. Med. Chem. Lett., 2017, 74, 41-52.
[http://dx.doi.org/10.1016/j.bioorg.2017.07.008] [PMID: 28750204]
[38]
Pasternack, R.F.; Gibbs, E.J.; Villafranca, J.J. Interactions of porphyrins with nucleic acids. Biochemistry, 1983, 22(23), 5409-5417.
[http://dx.doi.org/10.1021/bi00292a024] [PMID: 6652071]
[39]
Cindrić, M.; Perić, M.; Kralj, M.; Martin-Kleiner, I.; David-Cordonnier, M-H.; Paljetak, H.Č.; Matijašić, M.; Verbanac, D.; Karminski-Zamola, G.; Hranjec, M. Antibacterial and antiproliferative activity of novel 2-benzimidazolyl- and 2-benzothiazolyl-substituted benzo[b]thieno-2-carboxamides. Mol. Divers., 2018, 22(3), 637-646.
[http://dx.doi.org/10.1007/s11030-018-9822-7] [PMID: 29557543]


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VOLUME: 16
ISSUE: 6
Year: 2020
Published on: 01 October, 2020
Page: [911 - 923]
Pages: 13
DOI: 10.2174/1573407215666190328222350
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