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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

Design, Synthesis, and Anticancer Potential of the Enzyme (PARP-1) Inhibitor with Computational Studies of New Triazole, Thiazolidinone, - Thieno [2, 3-d] Pyrimidinones

Author(s): Ameen Ali Abu-Hashem*, Khadiga Mohamed Abu-Zied, Magdi Elsayed AbdelSalam Zaki, Mohamed Fathy El-Shehry , Hanem Mohamed Awad and Mohammed Abdou Khedr

Volume 17, Issue 6, 2020

Page: [799 - 817] Pages: 19

DOI: 10.2174/1570180817666200117114716

Price: $65

Abstract

Background: Thienopyrimidine, triazole and thiazolidinone derivatives have recently gained attention due to their effective pharmacological activities. They show antioxidant, antitumor, antimicrobial, antiviral, anti-inflammatory and analgesic properties.

Objective: Synthesis of new ethyl 2-amino-4-isopropyl-5-methylthiophene-3-carboxylate (2) was used as a starting material to produce 2-mercapto-methylthienopyrimidinone (3), (4) and 2- hydrazinyl-methylthienopyrimidinone (5), through high yields and evaluating anticancer activities.

Methods: A series of novel Schiff's bases (6-9) were produced after treatment of (5) with aldehydes. Triazolopyrimidinones (6a, 7a, 8a, 9a) were produced from cyclization of benzylidene (6-9) using Br2 / AcOH or dry pyridine /Ac2O. Thiazolidinones (6b, 7b, 8b, 9b) were synthesized from benzylidene (6-9) with mercaptoacetic acid.

Results: All the compounds were synthesized in good yields (55-85%) in a regularly actual system under mild condition. The new compounds have been established by means of diverse spectroscopic ways as IR, NMR and MS. The newly synthesized compounds were evaluated for their antiproliferative activity against the breast MCF-7 carcinoma cell line. Compound (7) showed promising anticancer activity with IC50 of 6.9 μM, and 40.8% of antioxidant effect as DPPH inhibition. Molecular docking of (7) showed ΔG values of-20.54 kcal/ mol and -25.60 kcal/ mol. Molecular dynamics simulation of (7) in complex with PARP-1 revealed RMSD of 3.00 Ǻ.

Conclusion: The QSAR study confirmed the presence of a relationship between anticancer activity and subdivided surface area descriptors with coefficient r2 = 0.98 with high predictive power.

Keywords: Pyrimidines, thienopyrimidines, triazolopyrimidinones, thiazolidinones, anticancer, antioxidant, molecular docking, molecular dynamics, QSAR.

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[1]
Abu-Hashem AA, El-Shehry MF, Badria FA. Design and synthesis of novel thiophenecarbohydrazide, thienopyrazole and thienopyrimidine derivatives as antioxidant and antitumor agents. Acta Pharm 2010; 60(3): 311-23.
[http://dx.doi.org/10.2478/v10007-010-0027-6] [PMID: 21134865]
[2]
Abu-Hashem AA. Synthesis and biological activity of pyrimidines, quinolines, thiazines and pyrazoles bearing a common thieno moiety. Acta. Pol. Pharm -. Drug Res (Stuttg) 2018; 75(1): 59-70.
[3]
Abu-Hashem AA, Abu-Zied KhM, El-Shehry MF. Synthetic utility of bifunctional thiophene derivatives and antimicrobial evaluation of the newly synthesized agents. Monatsh Chem 2011; 142: 539-45.
[http://dx.doi.org/10.1007/s00706-011-0456-z]
[4]
Hassan NA, Shawali AS, Abu-Zied KhM, Osman DA. Synthesis and antiviral evaluation of some new thieno [2, 3-d] pyrimidine S-glycosides. J Appl Sci Res 2013; 9(1): 833-42.
[5]
El-Tombary AA, El-Hawash SAM, Habib NS, Soliman R, El-Ashmawy IM, Shaaban OG. Synthesis and biological evaluation of some novel thieno[2,3-d] pyrimidine derivatives as potential anti-inflammatory and analgesic agents. Med Chem 2013; 9(8): 1099-112.
[http://dx.doi.org/10.2174/1573406411309080012] [PMID: 23628080]
[6]
Noravyan AS, Dzhagatspanyan IA, Nazaryan IM, Akopyan AG. Derivatives of condensed thienopyrimidines: Synthesis and anticonvulsant and tranquilizer activity of hydrochlorides of pyrano[4′,3′:4,5]thieno[3,2-e]imidazo[1,2-a]pyrimidines. Pharm Chem J 2007; 41(11): 588-90.
[http://dx.doi.org/10.1007/s11094-008-0028-7]
[7]
Abu-Hashem AA, Youssef MM, Hussein HAR. Synthesis, antioxidant, antitumor activities of some new thiazolopyrimidines, pyrrolothiazolopyrimidines and triazolo- pyrrolothiazolopyrimidines derivatives. J Chin Chem Soc (Taipei) 2011; 58: 41-8.
[http://dx.doi.org/10.1002/jccs.201190056]
[8]
Abu-Hashem AA, Hussein HAR, Abu-Zied KhM. Synthesis of novel 1, 2, 4-triazolo- pyrimidines and their evaluation as antimicrobial agents. Med Chem Res 2016; 26: 120-30.
[http://dx.doi.org/10.1007/s00044-016-1733-5]
[9]
Abu-Hashem AA, Gouda MA. Synthesis and antimicrobial activity of some novel quinoline, chromene, pyrazole derivatives bearing triazolopyrimidine moiety. J Het Chem 2017; 54: 850-8.
[http://dx.doi.org/10.1002/jhet.2645]
[10]
Abu-Hashem AA, El-Shazly M. Synthesis of new isoxazole-, pyridazine-, pyrimido- pyrazines and their anti-inflammatory and analgesic activity. Med Chem 2018; 14(4): 356-71.
[http://dx.doi.org/10.2174/1573406414666180112110947] [PMID: 29332598]
[11]
Abu-Hashem AA, El-Shazly M. Synthesis and antimicrobial evaluation of novel triazole, tetrazole and spiropyrimidine-thiadiazole derivatives. Polycycl Aromat Compd
[http://dx.doi.org/10.1080/10406638.2019.1598448]
[12]
Abu-Hashem AA, Badria FA. Design, synthesis of novel thiourea and pyrimidine derivatives as potential antitumor agents. J Chin Chem Soc (Taipei) 2015; 62: 506-12.
[http://dx.doi.org/10.1002/jccs.201400351]
[13]
Abu-Hashem AA. Synthesis of new furothiazolo pyrimido quinazolinones from visnagenone or khellinone and antimicrobial activity. Molecules 2018; 23(11): 2793.
[http://dx.doi.org/10.3390/molecules23112793] [PMID: 30373270]
[14]
Abu-Hashem AA, Youssef MM. Synthesis of new visnagen and khellin furochromone pyrimidine derivatives and their anti-inflammatory and analgesic activity. Molecules 2011; 16(3): 1956-72.
[http://dx.doi.org/10.3390/molecules16031956] [PMID: 21358587]
[15]
Abu-Hashem AA, El-Shazly M. Synthesis of new quinoxaline, pyrimidine, and pyrazole furochromone derivatives as cytotoxic agents. Monatsh Chem 2017; 148: 1853-63.
[http://dx.doi.org/10.1007/s00706-017-1960-6]
[16]
Abu-Hashem AA, Hussein HAR. Synthesis and antitumor activity of new pyrimidine and caffeine derivatives. Lett Drug Des Discov 2015; 12(6): 471-8.
[http://dx.doi.org/10.2174/1570180812666150429234237]
[17]
El-Sherief HAM, Youssif BGM, Abbas Bukhari SN, Abdelazeem AH, Abdel-Aziz M, Abdel-Rahman HM. Synthesis, anticancer activity and molecular modeling studies of 1,2,4-triazole derivatives as EGFR inhibitors. Eur J Med Chem 2018; 156: 774-89.
[http://dx.doi.org/10.1016/j.ejmech.2018.07.024] [PMID: 30055463]
[18]
El-Mansury S. Synthesis and anti-colon cancer activity of 1,2,4-triazole derivatives with aliphatic S-substituents. Orient J Chem 2019; 35(1): 77-84.
[http://dx.doi.org/10.13005/ojc/350109]
[19]
Lakkakulaa R, Roya A, Mukkantib K, Sridharc G. Synthesis and anticancer activity of 1, 2, 3-triazole fused N-arylpyrazole derivatives. Russian J of Chem 2019; 89(4): 831-5.
[http://dx.doi.org/10.1134/S1070363219040315]
[20]
Shyam R, Tiwari RC. Bull Chem Soc Jpn 1972; 49: 171.
[21]
Litvinchuk MD. Farmakol. Toxicol. 1963, 26, 725. Chem Abstr 1964; 60: 13761.
[22]
Brattain MG, Fine WD, Khaled FM, Thompson J, Brattain DE. Heterogeneity of malignant cells from a human colonic carcinoma. Cancer Res 1981; 41(5): 1751-6.
[PMID: 7214343]
[23]
Katherine RTMD. F A, S N; F A, C P In chronic kidney disease, dialysis, and. 3rd ed. Transplantation 2010.
[24]
Bojková B, Garajová M, Kajo K, et al. Péc, M.; Kubatka, P.; Kassayová, M.; Kisková, T.; Orendás, P.; Ahlersová, E.; Ahlers, I. Pioglitazone in chemically induced mammary carcinogenesis in rats. Eur J Cancer Prev 2010; 19(5): 379-384.
[http://dx.doi.org/10.1097/CEJ.0b013e32833ca233] [PMID: 20581687]
[25]
Mughal A, Kumar D, Vikram A. Effects of Thiazolidinediones on metabolism and cancer: Relative influence of PPARγ and IGF-1 signaling. Eur J Pharmacol 2015; 768: 217-25.
[http://dx.doi.org/10.1016/j.ejphar.2015.10.057] [PMID: 26542126]
[26]
Dang YF, Jiang XN, Gong FL, Guo XL. New insights into molecular mechanisms of rosiglitazone in monotherapy or combination therapy against cancers. Chem Biol Interact 2018; 296: 162-70.
[http://dx.doi.org/10.1016/j.cbi.2018.09.019] [PMID: 30278161]
[27]
Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Audeh, M.W.; Friedlander, M.; Balmaña, J.; Mitchell, G.; Fried, G.; Stemmer, S.M.; Hubert, A.; Rosengarten, O.; Steiner, M.; Loman, N.; Bowen, K.; Fielding, A.; Domchek, S.M. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.
[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685]
[28]
Solimando DA Jr, Waddell JA. Drug Monographs: Olaratumab and Rucaparib. Hosp Pharm 2017; 52(4): 258-63.
[http://dx.doi.org/10.1310/hpx5203-258] [PMID: 28515503]
[29]
Kummar S, Chen A, Ji J, et al. Zhang, Y.; Reid, J.M.; Ames, M.; Jia, L.; Weil, M.; Speranza, G.; Murgo, A.J.; Kinders, R.; Wang, L.; Parchment, R.E.; Carter, J.; Stotler, H.; Rubinstein, L.; Hollingshead, M.; Melillo, G.; Pommier, Y.; Bonner, W.; Tomaszewski, J.E.; Doroshow, J.H. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res 2011; 71(17): 5626-34.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-1227] [PMID: 21795476]
[30]
Wang L, Liang C, Li F, et al. Guan, D.; Wu, X.; Fu, X.; Lu, A.; Zhang, G. PARP-1 in carcinoma and PARP-1 inhibitors as antineoplastic drugs. Int. J. Mol. Sci, 2017, 18(10), 2111, 1-16.
[31]
Elmongy EI, Khedr MA, Taleb NA, Awad HM, Abbas SE-S. Design, synthesis and biological evaluation of some cyclohepta[b] and substituted pentahydrocycloheptatheino[2, 3-d] pyrimidine derivatives. J Het Chem 2017; 54(2): 1084-93.
[http://dx.doi.org/10.1002/jhet.2678]
[32]
Soliman HA, Yousif MNM, Said MM, et al. Hassan, N.A.; Ali, M.M.; Awad, H.M.; Abdel-Megeid, F.M.E. Synthesis of novel 1,6-naphthyridines, pyrano[3,2-c]pyridines and pyrido[4,3-d] pyrimidines derived from 2,2,6,6-tetramethyl-piperidin-4-one for in vitro anticancer and antioxidant evaluation. Pharma Chem 2014; 6(3): 394-410.
[33]
Mohamed SF, Kotb ER, Abd El-Meguid EA, Awad HM. Synthesis and anticancer activity of novel 2-substituted pyranopyridine derivatives. Res Chem Intermed 2017; 43(1): 437-56.
[http://dx.doi.org/10.1007/s11164-016-2633-5]
[34]
Flefel EM, El-Sayed WA, Mohamed AM, El-Sofanyand WI, Awad HM. synthesis and anticancer activity of new 1-thia-4-azaspiro [4.5]decane, their derived thiazolo- pyrimidine and 1, 3, 4-thiadiazole thioglycosides. Molecules 2017; 22(701): 1-13.
[35]
Hassan AS, Mady MF, Awad HM, Hafez TS. Synthesis and antitumor activity of some new pyrazolo[1, 5-a]pyrimidines. Chin Chem Lett 2017; 28(2): 388-93.
[http://dx.doi.org/10.1016/j.cclet.2016.10.022]
[36]
Hamdy NA, Anwar MM, Abu-Zied KM, Awad HM. Synthesis, tumor inhibitory and antioxidant activity of new polyfunctionally 2-substituted 5,6,7,8-tetrahydronaphthalene derivatives containing pyridine, thioxopyridine and pyrazolopyridine moieties. Acta Pol Pharm 2013; 70(6): 987-1001.
[PMID: 24383322]
[37]
Gewald K, Schinke E, Böttcher H. Schwefel. 2-amino-thiophene ausmethylenaktiven nitrilen, carbonyl-verbindungen. Ber 1966; 99: 94-100.
[38]
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]

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