Citation: Hui-Li ZHANG, Hong-Yan CUI, Wen-Long HUANG, Guo-Qiang HU. Synthesis and Antitumor Activity of Rhodanine Methylene-Substituted Levofloxacin Derivatives[J]. Chinese Journal of Applied Chemistry, ;2021, 38(2): 188-194. doi: 10.19894/j.issn.1000-0518.200199 shu

Synthesis and Antitumor Activity of Rhodanine Methylene-Substituted Levofloxacin Derivatives

1.
Henan Engineering Technology Research Center of Water Environment and Health, Zhengzhou University of Industrial Technology, Zhengzhou 451150, China
2.
School of Clinical Medicine, Henan University, Kaifeng 475001, China
3.
Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China

Corresponding author: Hong-Yan CUI, lee7758521_1@163.com Guo-Qiang HU, hgqxy@sina.com.cn
Received Date: 28 June 2020
Accepted Date: 4 September 2020

Fund Project: the National Natural Science Foundation of China 20872028the National Natural Science Foundation of China 21072045

Figures(2)

To explore an efficient structural modification strategy to enhance the antitumor activity of fluoroquinolones, a methane-rhodanine fragment was used as the bioisosteric replacement of the C-3 carboxylic acid group and consequently twelve new C-3 α, β-unsaturated thiazolone derivatives (6a-6l) were designed and synthesized by Claisen-Schmid condensation reaction with oxazinoquinolin-7-one-6-carbaldehyde (5) derived from levofloxacin (1) and N-substituted rhodanines (2a-2l), respectively. The in vitro antitumor activity of the synthesized compounds is more potent than that of levofloxacin along with lower cytotoxicity against Vero cells. Meanwhile, the structure-activity relationship (SAR) reveals that halophenyl, N-unsubstituted or cyclopropyl rhodaninec ompounds display a better activity than those of the control compounds, especially the IC₅₀ values of cyclopropyl rhodanine compound (6j) against A549 cell growth is comparable to doxorubicin. Thus, an unsaturated ketone annulated rhodanine scaffold as a bioisostere of the C-3 carboxylic acid group is found to be an alternative proposal for improving the antitumor activity of fluoroquinolones. Furthermore, whether an α, β-unsaturated ketone fragment is a promising bioisostere of the C-3 carboxylic acid group is worth further developing.
- Fluoroquinolone,
- Rhodanine,
- Unsaturated ketone,
- Bioisostere,
- Antitumor activity
1. [1]
  ABDOLMALEKI A, GHASEMI J B. Dual-acting of hybrid compounds-a new dawn in the discovery of multi-target drugs: lead generation approaches[J]. Curr Top Med Chem, 2017,17(9):1096-1114. doi: 10.2174/1568026616666160927151144
2. [2]
  BATTINI L, BOLLINI M. challenges and approaches in the discovery of human immunodeficiency virus type-1 non-nucleoside reverse transcriptase inhibitors[J]. Med Res Rev, 2019,39(4):1235-1273. doi: 10.1002/med.21544
3. [3]
  CHO S, KIM S H, SHIN D. Recent applications of hydantoin and thiohydantoin in medicinal chemistry[J]. Eur J Med Chem, 2019,164:517-545. doi: 10.1016/j.ejmech.2018.12.066
4. [4]
  KAMINSKYY D, KRYSHCHYSHYN A, LESYK R. Recent developments with rhodanine as a scaffold for drug discovery[J]. Expert Opin Drug Discov, 2017,12(12):1233-1252. doi: 10.1080/17460441.2017.1388370
5. [5]
  ZHUANG C, ZHANG W, SHENG C. Chalcone: a privileged structure in medicinal chemistry[J]. Chem Rev, 2017,117(12):7762-7810. doi: 10.1021/acs.chemrev.7b00020
6. [6]
  MIGNANI S, EL BRAHMI N, EL KAZZOULI S. A novel class of ethacrynic acid derivatives as promising drug-like potent generation of anticancer agents with established mechanism of action[J]. Eur J Med Chem, 2016,122:656-673. doi: 10.1016/j.ejmech.2016.05.063
7. [7]
  CORTÉS-BENÍTEZ F, CABEZA M, RAMÍREZ-APAN M T. Synthesis of 17β-N-arylcarbamoylandrost-4-en-3-one derivatives and their anti-proliferative effect on human androgen-sensitive LNCaP cell line[J]. Eur J Med Chem, 2016,121:737-736. doi: 10.1016/j.ejmech.2016.05.059
8. [8]
  SONG M. Progress in discovery of KIF5B-RET kinase inhibitors for the treatment of non-small-cell lung cancer[J]. J Med Chem, 2015,59(9):3672-3681.
9. [9]
  JACKSON P A, WIDEN J C, HARKI D A. Covalent modifiers: a chemical perspective on the reactivity of α, β-unsaturated carbonyls with thiols via hetero-michael addition reactions[J]. J Med Chem, 2017,60(3):839-885. doi: 10.1021/acs.jmedchem.6b00788
10. [10]
  KAMINSKYY D, KRYSHCHYSHYN A, LESYK R. 5-Ene-4-thiazolidinones-an efficient tool in medicinal chemistry[J]. Eur J Med Chem, 2017,140:542-549. doi: 10.1016/j.ejmech.2017.09.031
11. [11]
  SKOK Ž, ZIDAR N, KIKELJ D. Dual inhibitors of human DNA topoisomerase II and other cancer-related targets[J]. J Med Chem, 2020,63(3):884-904. doi: 10.1021/acs.jmedchem.9b00726
12. [12]
  SUAIFAN G A R Y, MOHAMMED A A M. Fluoroquinolones structural and medicinal developments (2013-2018): where are we now?[J]. Bioorg Med Chem, 2019,27(14):3005-3060. doi: 10.1016/j.bmc.2019.05.038
13. [13]
  YOU Q D, LI Z Y, HUANG C H. Discovery of a novel series of quinolone and naphthyridine derivatives as potential topoisomerase I inhibitors by scaffold modification[J]. J Med Chem, 2009,52(18):5649-5661. doi: 10.1021/jm900469e
14. [14]
  HU W, HUANG X S, WU J F. Discovery of novel topoisomerase II inhibitors by medicinal chemistry approaches[J]. J Med Chem, 2018,61(20):8947-8980. doi: 10.1021/acs.jmedchem.7b01202
15. [15]
  LI Y Y, ZHANG C X, HUANG W L. Synthesis and antitumor activities of C-3 thiazolotriazole unsaturated Ketone derivatives of levofloxacoin[J]. Chinese J Appl Chem, 2019,36(6):671-676.
16. [16]
  ZHANG H L, LI K, HUANG W L. Synthesis and antitumor activity of N-arylidene-rhodanine levofloxacin amides[J]. Chinese J Appl Chem, 2019,36(8):897-903.
17. [17]
  HU G Q, WANG G Q, DUAN N N. Design, synthesis and antitumor activity of fluoroquinolone C3 heterocyclic bis-oxadiazole methylsulfide derivatives derived from levofloxacin[J]. Chem Res Chinese Univ, 2012,28(6):980-984.
18. [18]
  BROWN F C, BRADSHER C K, MORGAN E C. Some 3-substituted rhodanines[J]. J Am Chem Soc, 1956,78:384-388. doi: 10.1021/ja01583a037
19. [19]
  CHEN L H, XIE L, XIE J Z. Total synthesis of an analogue of schizandrin[J]. Acta Pharm Sin, 1991,26(1):20-24.
20. [20]
  MA B, BANERJEE B, LITVINOV D N. Total synthesis of the antimitotic bicyclic peptide celogentin C[J]. J Am Chem Soc, 2010,132(3):1159-1171. doi: 10.1021/ja909870g
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沈阳化工大学材料科学与工程学院沈阳 110142