Login Register Cart 0
Generic placeholder image

Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Moxifloxacin-isatin Hybrids Tethered by 1,2,3-triazole and their Anticancer Activities

Author(s): Mingli Yang, Hailin Liu*, Yazhou Zhang*, Xiujun Wang* and Zhi Xu

Volume 20, Issue 16, 2020

Page: [1461 - 1467] Pages: 7

DOI: 10.2174/1568026620666200128144825

Price: $65

Abstract

Aims: To explore more active fluoroquinolone anticancer candidates.

Background: Cancer which can affect almost any part of the body, is most striking and deadliest disease. It is estimated that around one in five people globally develop cancer during their lifetime, and approximately 10% people eventually die from this disease, and 18.1 million new cancer cases with 9.6 million deaths occurred in 2018. The anticancer agents play an intriguingly role in fighting against cancer, and above 100 drugs have already been marketed for this purpose. However, the major drawback of current accessible anticancer agents is the low specificity which results in many side effects. Moreover, cancer cells have already generated resistance to almost all available drugs, creating an urgent need to novel anticancer agents with high specificity and great efficiency especially towards drug-resistant cancers. Quinolone and isatin derivatives were reported to possess promising anticancer activity, high specificity, and relatively few side effects. Currently, several quinolone and isatin derivatives such as Voreloxin, Quarfloxin, AT-3639, Semaxanib, Sunitinib and Nintedanib have already been introduced in clinical practice or under evaluations for the treatment of cancer including drug-resistant cancers, revealing their potential as novel anticancer agents. Hybrid molecules have the potential to increase the specificity, improve the efficiency, and overcome the drug resistance, so hybridization is a promising strategy in the drug discovery. Some of the moxifloxacin-isatin hybrids exhibited considerable activity against various cancer cells even drug-resistant cells, so it is conceivable that hybridization of quinolone and isatin moieties may provide novel anticancer candidates. The structure-activity relationships (SARs) demonstrated that the linkers between quinolone and isatin skeletons were critical for the biological activity, and 1,2,3-triazole could exert various noncovalent interactions with biological targets, so introduction of 1,2,3-triazole as the linker between the two moieties may provide more efficient anticancer candidates.

Objective: To explore more active fluoroquinolone anticancer candidates and enrich the structureactivity relationships of fluoroquinolone-isatin hybrids.

Methods: The synthesized moxifloxacin-isatin hybrids 5a-c, 6a-g and 13a-d were assessed for their anticancer activities against liver cancer cells HepG2, breast cancer cells MCF-7, MCF-7/DOX, prostate cancer cells DU-145 and MDR DU-145 by MTT assay. Hybrid 5b was selected for further evaluation of its tubulin polymerization inhibitory activity with combretastatin A-4 as comparison.

Result: Most of the synthesized hybrids were active against the tested cancer cell lines, and the most active hybrid 5b (IC50: 31.3-76.8 μM) was more potent than vorinostat (IC50: 96.7->100 μM), demonstrating moxifloxacin-isatin hybrids are potential anticancer candidates.

Conclusion: The mechanism study revealed that inhibition of tubulin polymerization is at least one of the mechanisms of action for this kind of hybrids.

Other: The structure-activity relationship was summarized for further rational design of more efficient anticancer candidates.

Keywords: Moxifloxacin, Isatin, Hybrid molecules, Anticancer, Structure-activity relationship, Tubulin polymerization.

« Previous Next »
Graphical Abstract

[1]
Shewach, D.S.; Kuchta, R.D. Introduction to cancer chemotherapeutics. Chem. Rev., 2009, 109(7), 2859-2861.
[http://dx.doi.org/10.1021/cr900208x] [PMID: 19583428]
[2]
Fan, W.; Yung, B.; Huang, P.; Chen, X. Nanotechnology for multimodal dynergistic cancer therapy. Chem. Rev., 2017, 117(22), 13566-13638.
[http://dx.doi.org/10.1021/acs.chemrev.7b00258] [PMID: 29048884]
[3]
WHO. Cancer control: knowledge into action. Available from:, http://www.who.int/cancer/modules/en/
[4]
International Agency for Research on Cancer. Latest global cancer data: Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018., 2018.Available from:. https://www.iarc.fr/featured-news/latest-global-cancer-data-cancer-burden-rises-to-18-1-million-new-cases-and-9-6-million-cancer-deaths-in-2018/
[5]
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.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.017] [PMID: 30660827]
[6]
Chu, X.M.; Wang, C.; Wang, W.L.; Liang, L.L.; Liu, W.; Gong, K.K.; Sun, K.L. Triazole derivatives and their antiplasmodial and antimalarial activities. Eur. J. Med. Chem., 2019, 166, 206-223.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.047] [PMID: 30711831]
[7]
Zhang, J.; Wang, S.; Ba, Y.; Xu, Z. Tetrazole hybrids with potential anticancer activity. Eur. J. Med. Chem., 2019, 178, 341-351.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.071] [PMID: 31200236]
[8]
Gottesman, M.M. Mechanisms of cancer drug resistance. Annu. Rev. Med., 2002, 53, 615-627.
[http://dx.doi.org/10.1146/annurev.med.53.082901.103929] [PMID: 11818492]
[9]
Jia, X.D.; Wang, S.; Wang, M.H.; Liu, M.L.; Xia, G.M.; Liu, X.J.; Chai, Y.; He, H.W. Synthesis and in vitro antitumor activity of novel naphthyridinone derivatives. Chin. Chem. Lett., 2017, 28, 235-239.
[http://dx.doi.org/10.1016/j.cclet.2016.07.024]
[10]
Xu, Z.; Zhang, S.; Gao, C.; Fan, J.; Zhao, F.; Lv, Z.S.; Feng, L.S. Isatin hybrids and their anti-tuberculosis activity. Chin. Chem. Lett., 2017, 28, 159-167.
[http://dx.doi.org/10.1016/j.cclet.2016.07.032]
[11]
Musiol, R. An overview of quinoline as a privileged scaffold in cancer drug discovery. Expert Opin. Drug Discov., 2017, 12(6), 583-597.
[http://dx.doi.org/10.1080/17460441.2017.1319357] [PMID: 28399679]
[12]
Makhanya, T.R.; Gengan, R.M.; Pandian, P.; Chuturgoon, A.A.; Tiloke, C.; Atar, A. Phosphotungstic acid catalyzed one pot synthesis of 4,8,8-trimethyl-5-phenyl-5,5a,8,9-tetrahydrobenzo[b] [1,8]naphthyridin-6(7H)-one derivatives and their biological evaluation against A549 lung cancer cells. J. Heterocycl. Chem., 2018, 55, 1193-1204.
[http://dx.doi.org/10.1002/jhet.3153]
[13]
Xie, X.B.; Guo, X.L.; Xu, Y.; Xu, Z.; Guan, J.G.; Gao, C. Hybrids as antifungal, antitubercular and anticancer agents. World Notes on Antibiotics, 2018, 39, 28-42.
[14]
Shaveta, ; Mishra, S.; Singh, P. Hybrid molecules: The privileged scaffolds for various pharmaceuticals. Eur. J. Med. Chem., 2016, 124, 500-536.
[http://dx.doi.org/10.1016/j.ejmech.2016.08.039] [PMID: 27598238]
[15]
Meunier, B. Hybrid molecules with a dual mode of action: dream or reality? Acc. Chem. Res., 2008, 41(1), 69-77.
[http://dx.doi.org/10.1021/ar7000843] [PMID: 17665872]
[16]
Dan, J.; Zhang, G.F. Moxifloxacin/Gatifloxacin-1,2,3-triazole-isatin hybrids with hydrogen-bond donor and their in vitro anticancer activity. J. Heterocycl. Chem., 2019, 56, 2691-2694.
[http://dx.doi.org/10.1002/jhet.3670]
[17]
Xu, Z.; Zhao, S.J.; Lv, Z.S.; Gao, F.; Wang, Y.; Zhang, F.; Bai, L.; Deng, J.L. Fluoroquinolone-isatin hybrids and their biological activities. Eur. J. Med. Chem., 2019, 162, 396-406.
[http://dx.doi.org/10.1016/j.ejmech.2018.11.032] [PMID: 30453247]
[18]
Xu, Z.; Zhao, S.J.; Deng, J.L.; Wang, Q.; Lv, Z.S. Ciprofloxacin-isatin hybrids and their antimycobacterial activities. J. Heterocycl. Chem., 2019, 56, 319-324.
[http://dx.doi.org/10.1002/jhet.3382]
[19]
Xu, Z.; Zhao, S.J.; Deng, J.L.; Wang, Q.; Lv, Z.S. Design, synthesis, and antimycobacterial activities of diethylene glycol tethered moxifloxacin-isatin hybrids. J. Heterocycl. Chem., 2019, 56, 331-337.
[http://dx.doi.org/10.1002/jhet.3386]
[20]
Zhang, S.; Xu, Z.; Gao, C.; Ren, Q.C.; Chang, L.; Lv, Z.S.; Feng, L.S. Triazole derivatives and their anti-tubercular activity. Eur. J. Med. Chem., 2017, 138, 501-513.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.051] [PMID: 28692915]
[21]
Zhang, B. Comprehensive review on the anti-bacterial activity of 1,2,3-triazole hybrids. Eur. J. Med. Chem., 2019, 168, 357-372.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.055] [PMID: 30826511]
[22]
Gao, F.; Ye, L.; Kong, F.; Huang, G.; Xiao, J. Design, synthesis and antibacterial activity evaluation of moxifloxacin-amide-1,2,3-triazole-isatin hybrids. Bioorg. Chem., 2019, 91, 103162
[http://dx.doi.org/10.1016/j.bioorg.2019.103162] [PMID: 31382058]

Rights & Permissions Print Cite
Article Metrics
37
World Chagas Disease
© 2024 Bentham Science Publishers | Privacy Policy