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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Synthesis, Cytotoxicity, ADMET and Molecular Docking Studies of Some Quinoline-Pyrimidine Hybrid Compounds: 3-(2-Amino-6-arylpyrimidin-4- yl)-4-hydroxy-1-methylquinolin-2(1H)-ones

Author(s): Duong Ngoc Toan*, Nguyen Dinh Thanh*, Mai Xuan Truong and Dinh Thuy Van

Volume 18 , Issue 1 , 2022

Published on: 29 December, 2020

Page: [36 - 50] Pages: 15

DOI: 10.2174/1573406417666201230092615

Abstract

Aims: This study aims are the synthesis of 3-(2-amino-6-arylpyrimidin-4-yl)-4-hydroxy-1- methylquinolin-2(1H)-ones and estimation their anticancer activities on HepG2 and KB cancer lines.

Background: Many derivatives of quinoline-2-on have been interested to synthesize and evaluate their biological properties by organic chemists due to their various biological effects, including antibacterial, antioxidant, anti-inflammatory, anticancer activities. Quinoline-pyrimidine hybrid compounds exhibited various biological activities, such as antituberculosis, antibacterial, anticancer, antifungal, etc. The connection of 4-hydroxyquinoline-2-one with 2-amino-pyrimidine could initiate the new activities.

Objective: α,β-Unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one were prepared. Novel 2-amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines have been synthesized by reaction of these corresponding α,β-unsaturated ketones with guanidine hydrochloride. Human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines were used for screening their cytotoxicity.

Methods: 3-Acetyl-4-hydroxy-N-methylquinolin-2-one was prepared from N-methylaniline and diethyl malonate. Reaction of (un)substituted benzaldehydes with this 4-hydroxyquinoline-2-one produced corresponding substituted α,β-unsaturated ketones in the presence of piperidine as catalyst. 2- Amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines have been synthesized from these α,β-unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one by reaction of corresponding α,β-unsaturated ketones with guanidine hydrochloride. All obtained pyrimidines were screened for anticancer activity using MTT bio-assay method.

Results: Seven substituted (E)-4-hydroxy-3-(3-(aryl)acryloyl)-1-methylquinolin-2(1H)-ones were prepared and converted to corresponding substituted 2-amino-6-aryl-4-(4′-hydroxy-N-methylquinolin- 2′-on-3′-yl)pyrimidines with yields of 58−74%. All the synthesized pyrimidines were screened for their in vitro anticancer activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines. Compounds 6b and 6e had the best activity in the series, with IC50 values equal to 1.32 and 1.33 μM, respectively. ADMET properties showed that compounds 6b, 6e, and 6f possessed the drug-likeness behavior. Cross-docking results indicated that residues GLN778(A), DT8(C), DT9(D), DA12(F), and DG13(F) in the binding pocket as potential ligand binding hot-spot residues for compounds 6b, 6e, and 6f.

Conclusion: New substituted 2-amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines were obtained and displayed significant inhibition against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines.

Keywords: 3-Acetyl-4-hydroxyquinolin-2(1H)-one, cytotoxicity, KB cell line, HepG2 cell line, 2-aminopyrimidine, α, β- unsaturated ketones.

Graphical Abstract
[1]
Abdou, M.M.; Seferoğlu, Z.; Fathy, M.; Akitsu, T.; Koketsu, M.; Kellow, R.; Amigues, E. Synthesis and chemical transformations of 3-acetyl-4-hydroxyquinolin-2(1H)-one and N-substituted derivatives: bird’s eye view. Res. Chem. Intermed., 2019, 45(3), 919-934.
[2]
Karel, P.; Stanislav, K.; Janez, K. Chemistry and Applications of 4-Hydroxyquinolin-2-one and Quinoline-2,4-dione-based Compounds. Curr. Org. Chem., 2017, 21(19), 1949-1975.
[3]
Romero, A.H. Role of Trifluoromethyl Substitution in Design of Antimalarial Quinolones: a Comprehensive Review. Top. Curr. Chem., 2019, 377(2), 9.
[4]
Sharma, K.; Khandelwal, S.; Samarth, R.M.; Kumar, M. Natural Product-Mimetic Scaffolds with Privileged Heterocyclic Systems: Design, Synthesis, and Evaluation of Antioxidant Activity of Quinazoquinobenzothiazinones. J. Heterocycl. Chem., 2016, 53(1), 220-228.
[5]
El-Neketi, M.; Ebrahim, W.; Lin, W.; Gedara, S.; Badria, F.; Saad, H-E.A.; Lai, D.; Proksch, P. Alkaloids and Polyketides from Penicillium citrinum, an Endophyte Isolated from the Moroccan Plant Ceratonia siliqua. Journal of Natural Products, 2013, 76(6), 1099-1104.
[6]
Bessonova, I.A. Components ofHaplophyllum bucharicum. Chem. Nat. Compd., 2000, 36(3), 323-324.
[7]
Ferretti, M.D.; Neto, A.T.; Morel, A.F.; Kaufman, T.S.; Larghi, E.L. Synthesis of symmetrically substituted 3,3-dibenzyl-4-hydroxy-3,4-dihydro-1H-quinolin-2-ones, as novel quinoline derivatives with antibacterial activity. Eur. J. Med. Chem., 2014, 81, 253-266.
[8]
Zwergel, C.; Czepukojc, B.; Evain-Bana, E.; Xu, Z.; Stazi, G.; Mori, M.; Patsilinakos, A.; Mai, A.; Botta, B.; Ragno, R.; Bagrel, D.; Kirsch, G.; Meiser, P.; Jacob, C.; Montenarh, M.; Valente, S. Novel coumarin- and quinolinone-based polycycles as cell division cycle 25-A and -C phosphatases inhibitors induce proliferation arrest and apoptosis in cancer cells. Eur. J. Med. Chem., 2017, 134, 316-333.
[9]
Greeff, J.; Joubert, J.; Malan, S.F.; van Dyk, S. Antioxidant properties of 4-quinolones and structurally related flavones. Bioorg. Med. Chem., 2012, 20(2), 809-818.
[10]
Mukherjee, S.; Pal, M. Quinolines: a new hope against inflammation. Drug Discov. Today, 2013, 18(7), 389-398.
[11]
Hsu, S-C.; Yang, J-S.; Kuo, C-L.; Lo, C.; Lin, J-P.; Hsia, T-C.; Lin, J-J.; Lai, K-C.; Kuo, H-M.; Huang, L-J.; Kuo, S-C.; Wood, W.G.; Chung, J-G. Novel quinolone CHM-1 induces apoptosis and inhibits metastasis in a human osterogenic sarcoma cell line. J. Orthop. Res., 2009, 27(12), 1637-1644.
[12]
Cocco, M.T.; Congiu, C.; Onnis, V.; Piras, R. Synthesis and antitumor evaluation of 6-thioxo-, 6-oxo- and 2,4-dioxopyrimidine derivatives. Farmaco, 2001, 56(10), 741-748.
[13]
Meneghesso, S.; Vanderlinden, E.; Stevaert, A.; McGuigan, C.; Balzarini, J.; Naesens, L. Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus. Antiviral Res., 2012, 94(1), 35-43.
[14]
Mallikarjunaswamy, C.; Mallesha, L.; Bhadregowda, D.G.; Pinto, O. Studies on synthesis of pyrimidine derivatives and their antimicrobial activity. Arab. J. Chem., 2017, 10, S484-S490.
[15]
Bhalgat, C.M.; Irfan Ali, M.; Ramesh, B.; Ramu, G. Novel pyrimidine and its triazole fused derivatives: Synthesis and investigation of antioxidant and anti-inflammatory activity. Arab. J. Chem., 2014, 7(6), 986-993.
[16]
Varothai, S.; Bergfeld, W.F. Androgenetic Alopecia: An Evidence-Based Treatment Update. Am. J. Clin. Dermatol., 2014, 15(3), 217-230.
[17]
Stellbrink, H-J. Antiviral drugs in the treatment of AIDS: what is in the pipeline? Eur. J. Med. Res., 2007, 12(9), 483-495.
[18]
World Health, O. World Health Organization model list of essential medicines: 21st list 2019; World Health Organization: Geneva, 2019.
[19]
Parkes, A.L.; Yule, I.A. Hybrid antibiotics – clinical progress and novel designs. Expert Opin. Drug Discov., 2016, 11(7), 665-680.
[20]
Yang, Y.; Hahne, H.; Kuster, B.; Verhelst, S.H.L. A simple and effective cleavable linker for chemical proteomics applications. Mol. Cell. Proteomics, 2013, 12(1), 237-244.
[21]
Bargh, J.D.; Isidro-Llobet, A.; Parker, J.S.; Spring, D.R. Cleavable linkers in antibody–drug conjugates. Chem. Soc. Rev., 2019, 48(16), 4361-4374.
[22]
Pedrosa, M.; da Cruz, R.; Viana, J.; de Moura, R.; Ishiki, H.; Filho, J.M.B. MFFM Diniz, MT Scotti, L. Scotti, FJBM Junior, Hybrid compounds as direct multitarget ligands: a review. Curr. Top. Med. Chem., 2017, 17, 1044-1079.
[23]
Bérubé, G. An overview of molecular hybrids in drug discovery. Expert Opin. Drug Discov., 2016, 11(3), 281-305.
[24]
Hu, Y-Q.; Zhang, S.; Xu, Z.; Lv, Z-S.; Liu, M-L.; Feng, L-S. 4-Quinolone hybrids and their antibacterial activities. Eur. J. Med. Chem., 2017, 141, 335-345.
[25]
Mao, T-Q.; He, Q-Q.; Wan, Z-Y.; Chen, W-X.; Chen, F-E.; Tang, G-F.; De Clercq, E.; Daelemans, D.; Pannecouque, C. Anti-HIV diarylpyrimidine–quinolone hybrids and their mode of action. Bioorg. Med. Chem., 2015, 23(13), 3860-3868.
[26]
Maurya, S.S.; Bahuguna, A.; Khan, S.I.; Kumar, D.; Kholiya, R.; Rawat, D.S. N-Substituted aminoquinoline-pyrimidine hybrids: Synthesis, in vitro antimalarial activity evaluation and docking studies. Eur. J. Med. Chem., 2019, 162, 277-289.
[27]
Chopra, R.; Chibale, K.; Singh, K. Pyrimidine-chloroquinoline hybrids: Synthesis and antiplasmodial activity. Eur. J. Med. Chem., 2018, 148, 39-53.
[28]
Heba, A.E.M.; Hossa, F.A-S. Design, Synthesis, Anti-Proliferative Evaluation and Cell Cycle Analysis of Hybrid 2-Quinolones. Anticancer. Agents Med. Chem., 2019, 19(9), 1132-1140.
[29]
Vettorazzi, M.; Insuasty, D.; Lima, S.; Gutiérrez, L.; Nogueras, M.; Marchal, A.; Abonia, R.; Andújar, S.; Spiegel, S.; Cobo, J.; Enriz, R.D. Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors. Bioorg. Chem., 2020, 94103414
[30]
Butler, M.M.; Lamarr, W.A.; Foster, K.A.; Barnes, M.H.; Skow, D.J.; Lyden, P.T.; Kustigian, L.M.; Zhi, C.; Brown, N.C.; Wright, G.E.; Bowlin, T.L. Antibacterial activity and mechanism of action of a novel anilinouracil-fluoroquinolone hybrid compound. Antimicrob. Agents Chemother., 2007, 51(1), 119-127.
[31]
Labischinski, H.; Cherian, J.; Calanasan, C.; Boyce, R., Hybrid antimicrobial compounds and their use. WO2010025906 . 2010.
[32]
Champoux, J.J.; Topoisomerases, D.N.A. Structure, Function, and Mechanism. Annu. Rev. Biochem., 2001, 70(1), 369-413.
[33]
Aldred, K.J.; Kerns, R.J.; Osheroff, N. Mechanism of Quinolone Action and Resistance. Biochemistry, 2014, 53(10), 1565-1574.
[34]
Liang, X.; Wu, Q.; Luan, S.; Yin, Z.; He, C.; Yin, L.; Zou, Y.; Yuan, Z.; Li, L.; Song, X.; He, M.; Lv, C.; Zhang, W. A comprehensive review of topoisomerase inhibitors as anticancer agents in the past decade. Eur. J. Med. Chem., 2019, 171, 129-168.
[35]
Gao, F.; Zhang, X.; Wang, T.; Xiao, J. Quinolone hybrids and their anti-cancer activities: An overview. Eur. J. Med. Chem., 2019, 165, 59-79.
[36]
Roschger, P.; Stadlbauer, W. Organic azides in heterocyclic synthesis, 11. Ring closure of 3-acetyl-4-azido-2-quinolones to isoxazolo[4,3-c]quinolones. Liebigs Ann. Chem., 1990, 1990(8), 821-823.
[37]
Faber, K.; Kappe, T. Non-steroidal antiinflammatory agents. 2. Synthesis of 4-hydroxy-1-methyl-2-oxo-dihydroquinolin-3-yl acetic acid and related tetrazolyl derivatives. J. Heterocycl. Chem., 1984, 21(6), 1881-1883.
[38]
Ruano, J.G.; Pedregal, C.; Rodríguez, J.H. Synthesis and tautomerism of 2,4-dihydroxyquinolines. Heterocycles, 1991, 32(11), 2151-2159.
[39]
Abdou, M.M. Chemistry of 4-Hydroxy-2(1H)-quinolone. Part 1: Synthesis and reactions. Arab. J. Chem., 2017, 10, S3324-S3337.
[40]
Giridhar, R.; Tamboli, R.S.; Ramajayam, R.; Prajapati, D.G.; Yadav, M.R. Assessment of antiplatelet activity of 2-aminopyrimidines. Eur. J. Med. Chem., 2012, 50, 428-432.
[41]
Robinson, S.J.; Petzer, J.P. Terre’Blanche, G.; Petzer, A.; van der Walt, M. M.; Bergh, J. J.; Lourens, A. C. U., 2-Aminopyrimidines as dual adenosine A1/A2A antagonists. Eur. J. Med. Chem., 2015, 104, 177-188.
[42]
Ingarsal, N.; Saravanan, G.; Amutha, P.; Nagarajan, S. Synthesis, in vitro antibacterial and antifungal evaluations of 2-amino-4-(1-naphthyl)-6-arylpyrimidines. Eur. J. Med. Chem., 2007, 42(4), 517-520.
[43]
Thanh, N.D.; Mai, N.T.T. Synthesis of N-tetra-O-acetyl-β-D-glucopyranosyl-N′-(4′,6′-diarylpyrimidin-2′-yl)thioureas. Carbohydr. Res., 2009, 344(17), 2399-2405.
[44]
Lagorce, D.; Reynes, C.; Camproux, A.C.; Miteva, M.A.; Sperandio, O.; Villoutreix, B.O. In silico adme/tox predictions. ADMET for Medicinal Chemists; John Wiley & Sons, Inc, 2011, pp. 29-124.
[45]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[46]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 1997, 23(1-3), 3-25.
[47]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[48]
Egan, W.J.; Merz, K.M.; Baldwin, J.J. Prediction of Drug Absorption Using Multivariate Statistics. J. Med. Chem., 2000, 43(21), 3867-3877.
[49]
Zhao, Y.H.; Abraham, M.H.; Le, J.; Hersey, A.; Luscombe, C.N.; Beck, G.; Sherborne, B.; Cooper, I. Rate-limited steps of human oral absorption and QSAR studies. Pharm. Res., 2002, 19(10), 1446-1457.
[50]
Wu, C.C.; Li, T.K.; Farh, L.; Lin, L.Y.; Lin, T.S.; Yu, Y.J.; Yen, T.J.; Chiang, C.W.; Chan, N.L. Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science, 2011, 333(6041), 459-462.
[51]
Goodwin, S.; Smith, A.F.; Horning, E.C. Alkaloids of Ochrosia elliptica Labill.1. J. Am. Chem. Soc., 1959, 81(8), 1903-1908.
[52]
Auclair, C. Multimodal action of antitumor agents on DNA: The ellipticine series. Arch. Biochem. Biophys., 1987, 259(1), 1-14.
[53]
Stiborová, M.; Poljaková, J.; Martínková, E.; Bořek-Dohalská, L.; Eckschlager, T.; Kizek, R.; Frei, E. Ellipticine cytotoxicity to cancer cell lines - a comparative study. Interdiscip. Toxicol., 2011, 4(2), 98-105.
[54]
Salerno, S.; La Pietra, V.; Hyeraci, M.; Taliani, S.; Robello, M.; Barresi, E.; Milite, C.; Simorini, F.; García-Argáez, A.N.; Marinelli, L.; Novellino, E.; Da Settimo, F.; Marini, A.M.; Dalla Via, L. Benzothiopyranoindole- and pyridothiopyranoindole-based antiproliferative agents targeting topoisomerases. Eur. J. Med. Chem., 2019, 165, 46-58.
[55]
Wu, C-C.; Li, Y-C.; Wang, Y-R.; Li, T-K.; Chan, N-L. On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs. Nucleic Acids Res., 2013, 41(22), 10630-10640.
[56]
Scudiero, D.A.; Shoemaker, R.H.; Paull, K.D.; Monks, A.; Tierney, S.; Nofziger, T.H.; Currens, M.J.; Seniff, D.; Boyd, M.R. Evaluation of a Soluble Tetrazolium/Formazan Assay for Cell Growth and Drug Sensitivity in Culture Using Human and Other Tumor Cell Lines. Cancer Res., 1988, 48(17), 4827-4833.
[57]
Schrödinger, suite 2018-4; Schrödinger, LLC: New York, NY, 2018.
[58]
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening. J. Med. Chem., 2004, 47(7), 1750-1759.

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