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

Ameen    Ali   Abu-Hashem; Khadiga    Mohamed   Abu-Zied; Magdi    Elsayed    AbdelSalam Zaki; Mohamed    Fathy   El-Shehry; Hanem    Mohamed   Awad; Mohammed    Abdou   Khedr

doi:10.2174/1570180817666200117114716

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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DOI https://dx.doi.org/10.2174/1570180817666200117114716	Print ISSN 1570-1808
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Design, Synthesis, and Anticancer Potential of the Enzyme (PARP-1) Inhibitor with Computational Studies of New Triazole, Thiazolidinone, - Thieno [2, 3-d] Pyrimidinones

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