Citation: Wang Shuqin, Huang Wanyun, Zhang Xiaorong, Zhang Xiaoting, Pan Chengxue. Synthesis and Bioactive Evaluation of Pyridazino-[6, 1-b]quinazolinones Derivatives[J]. Chinese Journal of Organic Chemistry, ;2020, 40(4): 959-968. doi: 10.6023/cjoc201909017 shu

Synthesis and Bioactive Evaluation of Pyridazino-[6, 1-b]quinazolinones Derivatives

a.
College of Pharmacy, Guilin Medical University, Guilin 541004
b.
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, Guangxi 541004

Corresponding author: Huang Wanyun, hwygxnu@163.com
Received Date: 10 September 2019
Revised Date: 27 November 2019
Available Online: 11 December 2019
Fund Project: the National Natural Science Foundation of China 21362007Project supported by the National Natural Science Foundation of China (No. 21362007)

Figures(6)

Novel nitrogen-containing heterocyclic scaffold pyridazino[6, 1-b]quinazolinones were designed by the combination of two privileged structure units. Then a scheme for the synthesis of pyridazino[6, 1-b]quinazolinone derivatives in 4 steps starting from methyl 2-aminobenzoate was developed in which the intramolecular condensation of acylhydrazone with ester was a key step transformation. 14 pyridazino[6, 1-b]quinazolinone derivatives were synthesized and their structures were characterized and comfirmed by ¹H NMR, ¹³C NMR and HRMS. Their in vitro cytotoxic activities against a panel of human tumor cell lines (SK-OV-3, CNE-2, MGC-803, NCI-H460) and nomal liver cell LO2 were evaluated via methyl thiazolyl tetrazolium (MTT) assay. The result indicated that 2-(4-bromophenyl)-4-hydroxy-10H-pyridazino[6, 1-b]quinazolin-10-one (4b) and 2-(3-chlorophenyl)-4-hydroxy-10H-pyridazino[6, 1-b]quinazolin-10-one (4d) exhibted very potent cytotoxic activity. The IC₅₀value of 4b against CNE-2 and 4d against NCI-H460 cell line lowed to 0.85 and 2.31 μmol/L, respectively, far potent than the positive control cisplatin and almost equivalent to the natrual anticancer medicine camptothecin. Ultraviolet spectrometry and fluorescence titration assay were carried out to evaluate the ability of the compound to interact with DNA. The result indicated that they were able to intercalate in to DNA. Compound 4d, which demonstrated potent antitumor activity while less cytotoxicity against the normal liver cell LO2, could arrest cell cycle at G1 phase and significantly induce apoptosis on NCI-H460 cell in a dose-dependent manner, while 4b which exhibit potent cytotoxicity against LO2, could result in significant DNA double strand break when treated with the cell.
- quinazolinones,
- pyridazine,
- antitumor,
- interaction with DNA
1. [1]
  Hu, Y.; Zhao, T.; Zhang, N.; Zhang, Y.; Cheng, L. Curr. Drug Metab. 2019, 20, 209. doi: 10.2174/1389200219666180925091851
2. [2]
  Regalado, E. L.; Haidar Ahmad, I. A.; Bennett, R.; D'Atri, V.; Makarov, A. A.; Humphrey, G. R.; Mangion, I.; Guillarme, D. Acc. Chem. Res. 2019, 52, 1990. doi: 10.1021/acs.accounts.9b00068
3. [3]
  Surabhi; Singh, B. K. J. Drug Delivery Ther. 2018, 8, 504. doi: 10.22270/jddt.v8i5.1894
4. [4]
  Flick, A. C.; Leverett, C. A.; Ding, H. X.; McInturff, E.; Fink, S. J.; Helal, C. J.; O'Donnell, C. J. J. Med. Chem. 2019, 62(16), 7340. doi: 10.1021/acs.jmedchem.9b00196
5. [5]
  Kim, J.; Kim, H.; Park, S. B. J. Am. Chem. Soc. 2014, 136, 14629. doi: 10.1021/ja508343a
6. [6]
  Kalaria, P. N.; Karad, S. C.; Raval, D. K. Eur. J. Med. Chem. 2018, 158, 917. doi: 10.1016/j.ejmech.2018.08.040
7. [7]
  Meyers, J.; Chessum, N. E. A.; Ali, S.; Mok, N. Y.; Wilding, B.; Pasqua, A. E.; Rowlands, M.; Tucker, M. J.; Evans, L. E.; Rye, C. S.; O'Fee, L.; Le Bihan, Y.-V.; Burke, R.; Carter, M.; Workman, P.; Blagg, J.; Brown, N.; van Montfort, R. L. M.; Jones, K.; Cheeseman, M. D. ACS Med. Chem. Lett. 2018, 9, 1199. doi: 10.1021/acsmedchemlett.8b00364
8. [8]
  Duarte, C. D.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med. Chem. 2007, 7, 1108. doi: 10.2174/138955707782331722
9. [9]
  Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfieldt, J. J. Med. Chem. 1988, 31, 2235. doi: 10.1021/jm00120a002
10. [10]
  Patchett, A. A.; Nargund, R. P. Annu. Rep. Med. Chem. 2000, 35, 289.
11. [11]
  Alagarsamy, V.; Chitra, K.; Saravanan, G.; Solomon, V. R.; Sulthana, M. T.; Narendhar, B. Eur. J. Med. Chem. 2018, 151, 628. doi: 10.1016/j.ejmech.2018.03.076
12. [12]
  Hameed, A.; Ali, S. A.; Arshia; Ishtiaq, M.; Khan, K. M.; Al-Rashida, M.; Uroos, M. Expert Opin. Ther. Pat. 2018, 28, 281. doi: 10.1080/13543776.2018.1432596
13. [13]
  He, D.; Wang, M.; Zhao, S.; Shu, Y.; Zeng, H.; Xiao, C.; Lu, C.; Liu, Y. Fitoterapia 2017, 119, 136. doi: 10.1016/j.fitote.2017.05.001
14. [14]
  Cao, Q. C.; Wang, H.; Reddy, T. V. K.; Lavanya, G.; Cai, G. X.; Zhou, C. H. Sci. Sin. Chim. 2017, 47, 844(in Chinese).
15. [15]
  Du, H.; Fan, Z. J.; Yang, L.; Bao, X. P. Chin. J. Org. Chem. 2018, 38, 531(in Chinese).
16. [16]
  Luo, X.; Zhou, X.; Lin, X.; Qin, X.; Zhang, T.; Wang, J.; Tu, Z.; Yang, B.; Liao, S.; Tian, Y.; Pang, X.; Kaliyaperumal, K.; Li, J. L.; Tao, H.; Liu, Y. Nat. Prod. Res. 2017, 31, 1958. doi: 10.1080/14786419.2016.1266353
17. [17]
  Zhang, H.; Liu, R.; Yang, J.; Li, H.; Zhou, F. Chem. Nat. Compd. 2017, 53, 802. doi: 10.1007/s10600-017-2128-7
18. [18]
  Motegi, M.; Nugroho, A. E.; Hirasawa, Y.; Arai, T.; Hadi, A. H. A.; Morita, H. Tetrahedron Lett. 2012, 53, 1227. doi: 10.1016/j.tetlet.2011.12.116
19. [19]
  Jaballah, M.; Serya, R.; Abouzid, K. Drug Res. 2017, 67, 138. doi: 10.1055/s-0042-119992
20. [20]
  Asif, M. Curr. Med. Chem. 2012, 19, 2984. doi: 10.2174/092986712800672139
21. [21]
  Lamberth, C. J. Heterocycl. Chem. 2017, 54, 2974. doi: 10.1002/jhet.2945
22. [22]
  Shemchuk, L. A.; Chernykh, V. P.; Arzumanov, P. S. Russ. J. Org. Chem. 2007, 43, 719. doi: 10.1134/S1070428007050120
23. [23]
  Tian, T.; Xiao, H.; Weng, X. C.; Wang, S. R.; Zhou, X. Sci. Sin. Chim. 2012, 42, 1700(in Chinese).
24. [24]
  Liu, J.; Luo, G. A.; Wang, Y. M.; Sun, H. W. Acta Pharm. Sin. 2001, 36, 74(in Chinese).
25. [25]
  Wang, Z. B.; Liu, Q. Q.; Zhang, W.; Pan, C. X.; Su, G. F. Chin. J. Org. Chem. 2019, 39, 1962(in Chinese).
26. [26]
  Yu, Y. K.; Zhu, X. Q.; Yang, J. J. Toxicol. 2006, 20, 408(in Chinese). doi: 10.3969/j.issn.1002-3127.2006.06.023
27. [27]
  Zhang, L.; Liu, L.; Zheng, C. Y.; Wang, Y.; Wang, J.; Yao, Q. Z. Chin. J. Org. Chem. 2017, 37, 1523(in Chinese).
28. [28]
  Li, Y. K.; Liu, P.; Zhang, L. J.; Zhu, J. H.; Wan, C. P.; Mao, Z. W. Chin. J. Org. Chem. 2018, 38, 949(in Chinese).
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1.
沈阳化工大学材料科学与工程学院沈阳 110142