Design, Synthesis, and Antiproliferative Activity of Quinazolin-4-One/Chalcone Hybrids via the EGFR Inhibition Pathway


Цитировать

Полный текст

Аннотация

Background: Quinazolinone scaffolds have drawn international attention due to their potent anticancer activity and therapeutic applications. Furthermore, Chalcone and Oxime are special chemical templates with a wide range of biological activities, including anti-cancer activity. As a result, the purpose of this research is to synthesize and develop a new series of 2-thioxo-3-substituted quinazolin-4-one/chalcone analogues and 2-thioxo-3-substituted quinazolin-4-one/oximes analogues in order to obtain a new cytotoxic agent that can target epidermal growth factor (EGFR) and/or V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAFV600E) oncogene.

Objective: All synthesised compounds were tested for anticancer activity against four human cancer cell lines. The new hybrids' potential anti-cancer mechanism was evaluated using EGFR and BRAF enzymatic tests. The most active molecules within the target enzyme's active site were studied using molecular docking. Apoptosis and cell cycle analysis were also investigated.

Method:The target compounds 7a-j (series I) are obtained in high yields by alkylation of 2-mercapto-3-ethyl-(3H)- quinazolin-4-one 3a with acylated chalcones 6a-j. Alkylation of compounds 3b-c with N-(4-acetylphenyl)-2- bromoacetamide 8, the corresponding ketones intermediates 9b-c was produced in high yields. Compounds 7a-j, 9b-c, and 10b-c were tested for their antiproliferative activity against four human cancer cell lines using the MTT assay and doxorubicin as a control drug. The EGFR and BRAF assay tests were used to assess the inhibitory potency against EGFR and BRAF.

Result:Compounds 7c, 7d, 7f and 10c exhibited high proliferative activity and inhibited EGFR, which could serve as a potential target for antiproliferative activity. The most active hybrid, 7c, primarily caused cell cycle arrest in G0/G1 phase and S phase as well as cell apoptosis. Finally, the most active hybrids were docked well to the EGFR active site.

Conclusion: 2-thioxo-3-substituted quinazolin-4-one/chalcone derivatives have significant apoptotic and antiproliferative properties.

Ключевые слова

Об авторах

Mohamed Hisham

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Minia University

Email: info@benthamscience.net

Heba Hassan

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University

Email: info@benthamscience.net

Hesham Gomaa

Department of Pharmacology, College of Pharmacy, Jouf University

Email: info@benthamscience.net

Bahaa Youssif

Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University

Автор, ответственный за переписку.
Email: info@benthamscience.net

Alaa Hayalah

Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University

Email: info@benthamscience.net

Mohamed Abdel-Aziz

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University

Автор, ответственный за переписку.
Email: info@benthamscience.net

Список литературы

  1. Goffin, J.R.; Zbuk, K. Epidermal growth factor receptor: Pathway, therapies, and pipeline. Clin. Ther., 2013, 35(9), 1282-1303. doi: 10.1016/j.clinthera.2013.08.007 PMID: 24054705
  2. Nadeem, A.M.; Kausar, S.; Wang, F.; Zhao, Y.; Cui, H. Advances in targeting the epidermal growth factor receptor pathway by synthetic products and its regulation by epigenetic modulators as a therapy for glioblastoma. Cells, 2019, 8(4), 350. doi: 10.3390/cells8040350 PMID: 31013819
  3. Tebbutt, N.; Pedersen, M.W.; Johns, T.G. Targeting the ERBB family in cancer: Couples therapy. Nat. Rev. Cancer, 2013, 13(9), 663-673. doi: 10.1038/nrc3559 PMID: 23949426
  4. Bhatia, P.; Sharma, V.; Alam, O.; Manaithiya, A.; Alam, P. Kahksha; Alam, M.T.; Imran, M. Novel quinazoline-based EGFR kinase inhibitors: A review focussing on SAR and molecular docking studies (2015-2019). Eur. J. Med. Chem., 2020, 204, 112640. doi: 10.1016/j.ejmech.2020.112640 PMID: 32739648
  5. Mok, T.S.; Wu, Y.L.; Thongprasert, S.; Yang, C.H.; Chu, D.T.; Saijo, N.; Sunpaweravong, P.; Han, B.; Margono, B.; Ichinose, Y.; Nishiwaki, Y.; Ohe, Y.; Yang, J.J.; Chewaskulyong, B.; Jiang, H.; Duffield, E.L.; Watkins, C.L.; Armour, A.A.; Fukuoka, M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med., 2009, 361(10), 947-957. doi: 10.1056/NEJMoa0810699 PMID: 19692680
  6. Bonola, G.; Da Re, P.; Magistretti, M.J.; Massarani, E.; Setnikar, I. 1-Aminoacyl-2,3-dihydro-4(1H)-quinazolinone derivatives with choleretic and antifibrillatory activity. J. Med. Chem., 1968, 11(6), 1136-1139. doi: 10.1021/jm00312a007 PMID: 5680025
  7. Okumura, K.; Oine, T.; Yamada, Y.; Hayashi, G.; Nakama, M. 4-Oxo-1,2,3,4-tetrahydroquinazolines. I. Syntheses and pharmacological properties of 2-methyl-3-aryl-4-oxo-1,2,3,4-tetrahydroquinazolines and their 1-acyl derivatives. J. Med. Chem., 1968, 11(2), 348-352. doi: 10.1021/jm00308a036 PMID: 4385706
  8. Osarumwense, O.P. Synthesis and antibacterial activity of 3-amino- 6-iodo-2-methyl quinazolin 4-(3H)-one and 6-iodo-2-methyl-4Hbenzo D 1, 3 oxazin-4-one. WJARR, 2019, 2(3), 014-020. doi: 10.30574/wjarr.2019.2.3.0041
  9. Dempcy, R.O.; Skibo, E.B. Rational design of quinazoline-based irreversible inhibitors of human erythrocyte purine nucleoside phosphorylase. Biochemistry, 1991, 30(34), 8480-8487. doi: 10.1021/bi00098a028 PMID: 1909177
  10. Grover, G.; Kini, S.G. Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents. Eur. J. Med. Chem., 2006, 41(2), 256-262. doi: 10.1016/j.ejmech.2005.09.002 PMID: 16260068
  11. Pandey, V.; Misra, D.; Shukla, A. Synthesis and antiviral activity of 2-aryl-5-3′-(2′-methyl-6: 8 substituted-quinazolyl)-phenyl-pyrazoles. Indian Drugs-Bombay, 1994, 31, 532.
  12. Shah, B.R.; Bhatt, J.J.; Patel, H.H.; Undavia, N.K.; Trivedi, P.B.; Desai, N.C. ChemInform abstract: Synthesis of 2,3-disubstituted-3,1-quinazolin-4(4H)-ones as potential anticancer and anti-HIV agents. ChemInform, 2010, 26(25) doi: 10.1002/chin.199525163
  13. Patel, N.; Lilakar, J. Synthesis of new substituted-4 (3H)-quinazolinones and their antibacterial activity. Indian J. Heterocycl. Chem., 2001, 11(1), 85-86.
  14. Hisham, M.; Hassan, H.A.; Gomaa, H.A.M.; Youssif, B.G.M.; Hayallah, A.M.; Abdel-Aziz, M. Structure-based design, synthesis and antiproliferative action of new quinazoline-4-one/chalcone hybrids as EGFR inhibitors. J. Mol. Struct., 2022, 1254, 132422. doi: 10.1016/j.molstruc.2022.132422
  15. Wang, G.; Liu, W.; Gong, Z.; Huang, Y.; Li, Y.; Peng, Z. Synthesis, biological evaluation, and molecular modelling of new naphthalene-chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells by targeting tubulin colchicine binding site. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 139-144. doi: 10.1080/14756366.2019.1690479 PMID: 31724435
  16. Madhavi, S.; Sreenivasulu, R.; Yazala, J.P.; Raju, R.R. Synthesis of chalcone incorporated quinazoline derivatives as anticancer agents. Saudi Pharm. J., 2017, 25(2), 275-279. doi: 10.1016/j.jsps.2016.06.005 PMID: 28344479
  17. Rashid ur, H.; Xu, Y.; Ahmad, N.; Muhammad, Y.; Wang, L. Promising anti-inflammatory effects of chalcones via inhibition of cyclooxygenase, prostaglandin E2, inducible NO synthase and nuclear factor κb activities. Bioorg. Chem., 2019, 87, 335-365. doi: 10.1016/j.bioorg.2019.03.033 PMID: 30921740
  18. Abdellatif, K.R.A.; Elshemy, H.A.H.; Salama, S.A.; Omar, H.A. Synthesis, characterization and biological evaluation of novel 4′-fluoro-2′-hydroxy-chalcone derivatives as antioxidant, anti-inflammatory and analgesic agents. J. Enzyme Inhib. Med. Chem., 2015, 30(3), 484-491. doi: 10.3109/14756366.2014.949255 PMID: 25198887
  19. Wang, J.; Huang, L.; Cheng, C.; Li, G.; Xie, J.; Shen, M.; Chen, Q.; Li, W.; He, W.; Qiu, P.; Wu, J. Design, synthesis and biological evaluation of chalcone analogues with novel dual antioxidant mechanisms as potential anti-ischemic stroke agents. Acta Pharm. Sin. B, 2019, 9(2), 335-350. doi: 10.1016/j.apsb.2019.01.003 PMID: 30972281
  20. Dan, W.; Dai, J. Recent developments of chalcones as potential antibacterial agents in medicinal chemistry. Eur. J. Med. Chem., 2020, 187111980. doi: 10.1016/j.ejmech.2019.111980 PMID: 31877539
  21. Burmaoglu, S.; Algul, O.; Gobek, A.; Aktas, A.D.; Ulger, M.; Erturk, B.G.; Kaplan, E.; Dogen, A.; Aslan, G. Design of potent fluoro-substituted chalcones as antimicrobial agents. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 490-495. doi: 10.1080/14756366.2016.1265517 PMID: 28118738
  22. Anandam, R.; Jadav, S.S.; Ala, V.B.; Ahsan, M.J.; Bollikolla, H.B. Synthesis of new C-dimethylated chalcones as potent antitubercular agents. Med. Chem. Res., 2018, 27(6), 1690-1704. doi: 10.1007/s00044-018-2183-z
  23. Al-Hazam, H.A.; Al-Shamkani, Z.A.; Al-Masoudi, N.A.; Saeed, B.A.; Pannecouque, C. New chalcones and thiopyrimidine analogues derived from mefenamic acid: microwave-assisted synthesis, anti-HIV activity and cytotoxicity as antileukemic agents. Z. Naturforsch. B. J. Chem. Sci., 2017, 72(4), 249-256. doi: 10.1515/znb-2016-0223
  24. Cole, A.L.; Hossain, S.; Cole, A.M.; Phanstiel, O.I.V. Synthesis and bioevaluation of substituted chalcones, coumaranones and other fla-vonoids as anti-HIV agents. Bioorg. Med. Chem., 2016, 24(12), 2768-2776. doi: 10.1016/j.bmc.2016.04.045 PMID: 27161874
  25. Al-Anazi, M.; Al-Najjar, B.; Khairuddean, M. Structure-based drug design studies toward the discovery of novel chalcone derivatives as potential epidermal growth factor receptor (EGFR) inhibitors. Molecules, 2018, 23(12), 3203. doi: 10.3390/molecules23123203 PMID: 30563058
  26. Rizvi, S.U.F.; Siddiqui, H.L.; Nisar, M.; Khan, N.; Khan, I. Discovery and molecular docking of quinolyl-thienyl chalcones as anti-angiogenic agents targeting VEGFR-2 tyrosine kinase. Bioorg. Med. Chem. Lett., 2012, 22(2), 942-944. doi: 10.1016/j.bmcl.2011.12.017 PMID: 22200597
  27. Li, Q.S.; Li, C.Y.; Lu, X.; Zhang, H.; Zhu, H.L. Design, synthesis and biological evaluation of novel (E)-α-benzylsulfonyl chalcone derivatives as potential BRAF inhibitors. Eur. J. Med. Chem., 2012, 50, 288-295. doi: 10.1016/j.ejmech.2012.02.007 PMID: 22361686
  28. Dantas, B.; Ribeiro, T.; Assis, V.; Furtado, F.; Assis, K.; Alves, J.; Silva, T.; Camara, C.; França-Silva, M.; Veras, R.; Medeiros, I.; Alencar, J.; Braga, V. Vasorelaxation induced by a new naphthoquinone-oxime is mediated by NO-sGC-cGMP pathway. Molecules, 2014, 19(7), 9773-9785. doi: 10.3390/molecules19079773 PMID: 25006785
  29. Abdel-Aziz, M.; Abuo-Rahma, G.E.D.A.A.; Beshr, E.A.M.; Ali, T.F.S. New nitric oxide donating 1,2,4-triazole/oxime hybrids: Synthesis, investigation of anti-inflammatory, ulceroginic liability and antiproliferative activities. Bioorg. Med. Chem., 2013, 21(13), 3839-3849. doi: 10.1016/j.bmc.2013.04.022 PMID: 23665142
  30. Hisham, M.; Youssif, B.G.M.; Osman, E.E.A.; Hayallah, A.M.; Abdel-Aziz, M. Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents. Eur. J. Med. Chem., 2019, 176, 117-128. doi: 10.1016/j.ejmech.2019.05.015 PMID: 31108261
  31. Moriya, R.; Uehara, T.; Nomura, Y. Mechanism of nitric oxide-induced apoptosis in human neuroblastoma SH-SY5Y cells. FEBS Lett., 2000, 484(3), 253-260. doi: 10.1016/S0014-5793(00)02167-0 PMID: 11078888
  32. Brown, G.C.; Borutaite, V. Nitric oxide, mitochondria, and cell death. IUBMB Life, 2001, 52(3-5), 189-195. doi: 10.1080/15216540152845993 PMID: 11798032
  33. Shin, H. Synthesis and evaluation of ornithine decarboxylase inhibitors with oxime moiety and MCF-7 breast cancer cells. Biochem. Pharmacol., 2013, 2(01), 2167-0501. doi: 10.4172/2167-0501.1000111
  34. Al-Rashood, S.T.; Aboldahab, I.A.; Nagi, M.N.; Abouzeid, L.A.; Abdel-Aziz, A.A.M.; Abdel-hamide, S.G.; Youssef, K.M.; Al-Obaid, A.M.; El-Subbagh, H.I. Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs. Bioorg. Med. Chem., 2006, 14(24), 8608-8621. doi: 10.1016/j.bmc.2006.08.030 PMID: 16971132
  35. Monirah, A.; Danah, A.; Fatima, E. Synthesis of some-2-thioxo-3-substituted-2, 3-dihydro-1H-quinazolin-4-one derivatives as potential antibacterial and antifungal agents. Res. J. Chem. Environ., 2013, 17, 48-52.
  36. Abou-Zied, H.A.; Youssif, B.G.M.; Mohamed, M.F.A.; Hayallah, A.M.; Abdel-Aziz, M. EGFR inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid molecules. Bioorg. Chem., 2019, 89102997. doi: 10.1016/j.bioorg.2019.102997 PMID: 31136902
  37. Abuo-Rahma, G.E.D.A.A.; Abdel-Aziz, M.; Beshr, E.A.M.; Ali, T.F.S. 1,2,4-Triazole/oxime hybrids as new strategy for nitric oxide donors: Synthesis, anti-inflammatory, ulceroginicity and antiproliferative activities. Eur. J. Med. Chem., 2014, 71, 185-198. doi: 10.1016/j.ejmech.2013.11.006 PMID: 24308998
  38. Mahdy, H.A.; Ibrahim, M.K.; Metwaly, A.M.; Belal, A.; Mehany, A.B.M.; El-Gamal, K.M.A.; El-Sharkawy, A.; Elhendawy, M.A.; Radwan, M.M.; Elsohly, M.A.; Eissa, I.H. Design, synthesis, molecular modeling, in vivo studies and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers. Bioorg. Chem., 2020, 94, 103422. doi: 10.1016/j.bioorg.2019.103422 PMID: 31812261
  39. Abdelrahman, M.H.; Aboraia, A.S.; Youssif, B.G.M.; Elsadek, B.E.M. Design, synthesis and pharmacophoric model building of new 3-alkoxymethyl/3-phenyl indole-2-carboxamides with potential antiproliferative activity. Chem. Biol. Drug Des., 2017, 90(1), 64-82. doi: 10.1111/cbdd.12928 PMID: 28019082
  40. Mohamed, F.A.M.; Gomaa, H.A.M.; Hendawy, O.M.; Ali, A.T.; Farghaly, H.S.; Gouda, A.M.; Abdelazeem, A.H.; Abdelrahman, M.H.; Trembleau, L.; Youssif, B.G.M. Design, synthesis, and biological evaluation of novel EGFR inhibitors containing 5-chloro-3-hydroxymethyl-indole-2-carboxamide scaffold with apoptotic antiproliferative activity. Bioorg. Chem., 2021, 112, 104960. doi: 10.1016/j.bioorg.2021.104960 PMID: 34020242
  41. Cohen, G.M. Caspases: The executioners of apoptosis. Biochem. J., 1997, 326(Pt 1), 1-16. doi: 10.1042/bj3260001
  42. Youssif, B.G.M.; Abdelrahman, M.H.; Abdelazeem, A.H.; Abdelgawad, M.A.; Ibrahim, H.M.; Salem, O.I.A.; Mohamed, M.F.A.; Tream-bleau, L.; Bukhari, S.N.A. Design, synthesis, mechanistic and histopathological studies of small-molecules of novel indole-2-carboxamides and pyrazino1,2-aindol-1(2H)-ones as potential anticancer agents effecting the reactive oxygen species production. Eur. J. Med. Chem., 2018, 146, 260-273. doi: 10.1016/j.ejmech.2018.01.042 PMID: 29407956
  43. Abdelazeem, A.H.; El-Saadi, M.T.; Said, E.G.; Youssif, B.G.M.; Omar, H.A.; El-Moghazy, S.M. Novel diphenylthiazole derivatives with multi-target mechanism: Synthesis, docking study, anticancer and anti-inflammatory activities. Bioorg. Chem., 2017, 75, 127-138. doi: 10.1016/j.bioorg.2017.09.009 PMID: 28938224
  44. Sun, M.; Behrens, C.; Feng, L.; Ozburn, N.; Tang, X.; Yin, G.; Komaki, R.; Varella-Garcia, M.; Hong, W.K.; Aldape, K.D.; Wistuba, I.I. HER family receptor abnormalities in lung cancer brain metastases and corresponding primary tumors. Clin. Cancer Res., 2009, 15(15), 4829-4837. doi: 10.1158/1078-0432.CCR-08-2921 PMID: 19622585
  45. Urich, R.; Wishart, G.; Kiczun, M.; Richters, A.; Tidten-Luksch, N.; Rauh, D.; Sherborne, B.; Wyatt, P.G.; Brenk, R. De novo design of protein kinase inhibitors by in silico identification of hinge region-binding fragments. ACS Chem. Biol., 2013, 8(5), 1044-1052. doi: 10.1021/cb300729y PMID: 23534475
  46. 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. doi: 10.1038/srep42717 PMID: 28256516
  47. Lipinski, C.A. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods, 2000, 44(1), 235-249. doi: 10.1016/S1056-8719(00)00107-6 PMID: 11274893
  48. Veber, D.F.; Johnson, S.R.; Cheng, H-Y.; Smith, B.R.; Ward, K.W. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
  49. Tsaioun, K.; Bottlaender, M.; Mabondzo, A. ADDME-avoiding drug development mistakes early: Central nervous system drug discovery perspective. BMC Neurol., 2009, 9(S1), S1. doi: 10.1186/1471-2377-9-S1-S1
  50. Mustafa, M.; Mostafa, Y.A. A facile synthesis, drug-likeness, and in silico molecular docking of certain new azidosulfonamide–chalcones and their in vitro antimicrobial activity. Chemical Monthly, 2020, 151(3), 417-427. doi: 10.1007/s00706-020-02568-8

Дополнительные файлы

Доп. файлы
Действие
1. JATS XML
Скачать

© Bentham Science Publishers, 2023