Generic placeholder image

Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Discovery of 1H-indazole-6-amine Derivatives as Anticancer Agents: Simple But Effective

Author(s): Ngo Xuan Hoang, Van-Hai Hoang, Thien Ngo, Thien Y.Vu and Phuong-Thao Tran*

Volume 20, Issue 5, 2023

Published on: 05 August, 2022

Page: [581 - 588] Pages: 8

DOI: 10.2174/1570180819666220512144819

Price: $65


Background: Indazole is a promising structure present in various biological activity compounds; in particular, many 6-aminoindazole-containing compounds demonstrated anticancer activity. In our previous research, we discovered some of the 6-aminoindazole derivatives with excellent cytotoxicity in the human colorectal cancer cell line (HCT116).

Objective: In this study, a series of 6-substituted amino-1H-indazole derivatives were designed and synthesized through simple and well-known chemical reactions, which were evaluated for anti-proliferative activity in four human cancer cell lines.

Methods: The title compounds were designed based on the structures of potential anticancer candidates in our previous report. The synthesis of 6-aminoindazole derivatives through acetylation and reductive amination with 6-amininoindazole as the starting material. Sulforhodamin B (SRB) assay was used for in vitro biological evaluation of synthesized compounds. Various physicochemical properties of them were predicted by online site Molinspiration.

Results: Seven out of eight synthesized compounds showed growth inhibitory activity with IC50 values from 2.9 to 59.0 μM range in all four tested cancer cell lines. Of them, the compound N-(4-fluorobenzyl)- 1H-indazol-6-amine (9f) exhibited a potent anti-proliferative activity, with an IC50 value of 14.3±4.4 μM in the human colorectal cancer cell (HCT116) and non-cytotoxicity in the normal cell (lung fibroblast cells, MRC5, IC50 >100 μM).

Conclusion: The bioactivity result and conformance of the physicochemical properties of the synthesized compounds to the "rule of three" for hit-like compounds suggested that 9f was effective and could be used as a hit for the development of novel anticancer agents.

Keywords: 1H-indazol-6-amine, anti-proliferative, anticancer, cytotoxicity, IC50, HCT116.

Graphical Abstract
WHO. Available from: (Accessed on October 28, 2021).
Zugazagoitia, J.; Guedes, C.; Ponce, S.; Ferrer, I.; Molina-Pinelo, S.; Paz-Ares, L. Current challenges in cancer treatment. Clin. Ther., 2016, 38(7), 1551-1566.
[] [PMID: 27158009]
Badr, M.H.; Elbayaa, R.Y.; El-Ashmawy, I.M. Design, synthesis and molecular docking study of some substituted 4,5- dihydro-2H-indazole derivatives as potential anti-inflammatory agents. Med. Chem., 2013, 9(5), 718-730.
[] [PMID: 23061568]
Cheekavolu, C.; Muniappan, M. In vivo and in vitro anti-inflammatory activity of indazole and its derivatives. J. Clin. Diagn. Res., 2016, 10(9), FF01-FF06.
[] [PMID: 27790461]
Zhang, J.; Yang, Q.; Romero, J.A.C.; Cross, J.; Wang, B.; Poutsiaka, K.M.; Epie, F.; Bevan, D.; Wu, Y.; Moy, T.; Daniel, A.; Chamberlain, B.; Carter, N.; Shotwell, J.; Arya, A.; Kumar, V.; Silverman, J.; Nguyen, K.; Metcalf, C.A., III; Ryan, D.; Lippa, B.; Dolle, R.E. Discovery of indazole derivatives as a novel class of bacterial gyrase B inhibitors. ACS Med. Chem. Lett., 2015, 6(10), 1080-1085.
[] [PMID: 26487916]
Anuruddha, C.; Bhanudas, K.; Pradeep, L.; Mangesh, T.; Bharat, P.; Vinayak, K.; Swati, J.; Vasant, C. Design, synthesis and evaluation of antibacterial activity of novel indazole derivatives. Curr. Bioact. Compd., 2013, 9(4), 263-269.
Li, X.; Chu, S.; Feher, V.A.; Khalili, M.; Nie, Z.; Margosiak, S.; Nikulin, V.; Levin, J.; Sprankle, K.G.; Tedder, M.E.; Almassy, R.; Appelt, K.; Yager, K.M. Structure-based design, synthesis, and antimicrobial activity of indazole-derived SAH/MTA nucleosidase inhibitors. J. Med. Chem., 2003, 46(26), 5663-5673.
[] [PMID: 14667220]
Khan, R.; Shah, F.; Salman, M.; Khan, Z.; Tavman, A. Synthesis, in vitro and in silico antibacterial evaluation of 4,5-dihydro-1H-indazoles. ChemistrySelect, 2017, 2(29), 9364-9368.
Kim, S-H.; Markovitz, B.; Trovato, R.; Murphy, B.R.; Austin, H.; Willardsen, A.J.; Baichwal, V.; Morham, S.; Bajji, A. Discovery of a new HIV-1 inhibitor scaffold and synthesis of potential prodrugs of indazoles. Bioorg. Med. Chem. Lett., 2013, 23(10), 2888-2892.
[] [PMID: 23566519]
Jones, L.H.; Allan, G.; Barba, O.; Burt, C.; Corbau, R.; Dupont, T.; Knöchel, T.; Irving, S.; Middleton, D.S.; Mowbray, C.E.; Perros, M.; Ringrose, H.; Swain, N.A.; Webster, R.; Westby, M.; Phillips, C. Novel indazole non-nucleoside reverse transcriptase inhibitors using molecular hybridization based on crystallographic overlays. J. Med. Chem., 2009, 52(4), 1219-1223.
[] [PMID: 19175319]
Dong, J.; Zhang, Q.; Wang, Z.; Huang, G.; Li, S. Recent advances in the development of indazole-based anticancer agents. ChemMedChem, 2018, 13(15), 1490-1507.
[] [PMID: 29863292]
Liu, J.; Qian, C.; Zhu, Y.; Cai, J.; He, Y.; Li, J.; Wang, T.; Zhu, H.; Li, Z.; Li, W.; Hu, L. Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold. Bioorg. Med. Chem., 2018, 26(3), 747-757.
[] [PMID: 29317150]
Tomassi, S.; Lategahn, J.; Engel, J.; Keul, M.; Tumbrink, H.L.; Ketzer, J.; Mühlenberg, T.; Baumann, M.; Schultz-Fademrecht, C.; Bauer, S.; Rauh, D. Indazole-based covalent inhibitors to target drug-resistant epidermal growth factor receptor. J. Med. Chem., 2017, 60(6), 2361-2372.
[] [PMID: 28225269]
Liu, Z.; Lei, Q.; Wei, W.; Xiong, L.; Shi, Y.; Yan, G.; Gao, C.; Ye, T.; Wang, N.; Yu, L. Synthesis and biological evaluation of (E)-4-(3-arylvinyl-1H-indazol-6-yl)pyrimidin-2-amine derivatives as PLK4 inhibitors for the treatment of breast cancer. RSC Advances, 2017, 7(44), 27737-27746.
Song, P.; Chen, M.; Ma, X.; Xu, L.; Liu, T.; Zhou, Y.; Hu, Y. Identification of novel inhibitors of Aurora A with a 3-(pyrrolopyridin-2-yl)indazole scaffold. Bioorg. Med. Chem., 2015, 23(8), 1858-1868.
[] [PMID: 25771484]
Chang, C-F.; Lin, W-H.; Ke, Y-Y.; Lin, Y-S.; Wang, W-C.; Chen, C-H.; Kuo, P-C.; Hsu, J.T.A.; Uang, B-J.; Hsieh, H-P. Discovery of novel inhibitors of Aurora kinases with indazole scaffold: In silico fragment-based and knowledge-based drug design. Eur. J. Med. Chem., 2016, 124, 186-199.
[] [PMID: 27573544]
Roskoski, R. Jr Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacol. Res., 2019, 144, 19-50.
[] [PMID: 30877063]
Abbassi, N.; Rakib, M.; Chicha, H.; Bouissane, L.; Hannioui, A.; Aiello, C.; Gangemi, R.; Castagnola, P.; Rosano, C.; Viale, M. Synthesis and antitumor activity of some substituted indazole derivatives. Arch. Pharm. (Weinheim), 2014, 347(6), 423-431.
[] [PMID: 24554280]
Aman, W.; Lee, J.; Kim, M.; Yang, S.; Jung, H.; Hah, J-M. Discovery of highly selective CRAF inhibitors, 3-carboxamido-2H-indazole-6-arylamide: In silico FBLD design, synthesis and evaluation. Bioorg. Med. Chem. Lett., 2016, 26(4), 1188-1192.
[] [PMID: 26810260]
Qi, H.; Chen, L.; Liu, B.; Wang, X.; Long, L.; Liu, D. Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents. Bioorg. Med. Chem. Lett., 2014, 24(4), 1108-1110.
[] [PMID: 24456902]
Jia, Y.; Zhang, J.; Feng, J.; Xu, F.; Pan, H.; Xu, W. Design, synthesis and biological evaluation of pazopanib derivatives as antitumor agents. Chem. Biol. Drug Des., 2014, 83(3), 306-316.
[] [PMID: 24119291]
Hoang, N.X.; Hoang, V-H.; Luu, H.N.; Ngo, T.; Van Hieu, D.; Long, N.H.; Ngo, S.T.; Nguyen, Y.T.K.; Han, B.W.; Nguyen, T.X. Design, synthesis and bioevaluation of novel 6-substituted aminoindazole derivatives as anticancer agents. RSC Advances, 2020, 10(73), 45199-45206.
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82(13), 1107-1112.
[] [PMID: 2359136]
Molinspiration Cheminformatics. 2022. Available from: (Accessed on October 27).
Menichincheri, M.; Ardini, E.; Magnaghi, P.; Avanzi, N.; Banfi, P.; Bossi, R.; Buffa, L.; Canevari, G.; Ceriani, L.; Colombo, M.; Corti, L.; Donati, D.; Fasolini, M.; Felder, E.; Fiorelli, C.; Fiorentini, F.; Galvani, A.; Isacchi, A.; Borgia, A.L.; Marchionni, C.; Nesi, M.; Orrenius, C.; Panzeri, A.; Pesenti, E.; Rusconi, L.; Saccardo, M.B.; Vanotti, E.; Perrone, E.; Orsini, P. Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor. J. Med. Chem., 2016, 59(7), 3392-3408.
[] [PMID: 27003761]
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 1PII of original article: S0169-409X(96)00423-1. Adv. Drug Deliv. Rev., 2001, 46(1), 3-26.
[] [PMID: 11259830]
Congreve, M.; Carr, R.; Murray, C.; Jhoti, H.A. ‘rule of three’ for fragment-based lead discovery? Drug Discov. Today, 2003, 8(19), 876-877.
[] [PMID: 14554012]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy