Skip to content
2000
Volume 21, Issue 8
  • ISSN: 1573-4064
  • E-ISSN: 1875-6638

Abstract

Indazole, a heterocyclic molecule, has emerged as a useful scaffold in synthetic and medicinal chemistry due to its broad biological activity and ease of synthesis. This article thoroughly analyzes unique synthetic methods used to diversify indazole derivatives, such as metal-catalyzed reactions, ecologically friendly approaches, and novel multicomponent reactions. These advances have increased the efficiency and selectivity of indazole synthesis and its structural variety, paving the path for new biological applications. Furthermore, indazole-based compounds have demonstrated promising biological activities, particularly as anticancer, antibacterial, and anti-inflammatory medicines. This review summarizes the present state of indazole research, focusing on synthetic techniques and biological features that make indazole an attractive target for future drug discovery.

Loading

Article metrics loading...

/content/journals/mc/10.2174/0115734064360528241209074117
2024-12-24
2025-12-08
Loading full text...

Full text loading...

References

  1. AgrawalN. BansalD. GautamV. Synthetic and pharmacological expedition of Pyrazolo[1,5-a]pyridine: A comprehensive review.Lett. Drug Des. Discov.2024211718710.2174/1570180820666230803101948
    [Google Scholar]
  2. AgrawalN. BhardwajA. An appraisal on synthetic and pharmaceutical perspectives of quinoxaline 1, 4‐di‐ N‐oxide scaffold.Chem. Biol. Drug Des.2022100334636310.1111/cbdd.1409435610776
    [Google Scholar]
  3. PanditN. ShahK. AgrawalN. UpmanyuN. ShrivastavaS.K. MishraP. Synthesis, characterization and biological evaluation of some novel fluoroquinolones.Med. Chem. Res.201625584385110.1007/s00044‑016‑1526‑x
    [Google Scholar]
  4. AgrawalN. GoswamiR. PathakS. Synthetic methods for various chromeno-fused heterocycles and their potential as antimicrobial agents.Med. Chem.202420211512910.2174/011573406427474823100507410037855281
    [Google Scholar]
  5. AgrawalN. MishraR. PathakS. GoyalA. ShahK. Hydrazides and hydrazones: Robust scaffolds in neurological and neurodegenerative disorders.Lett. Org. Chem.202320212313610.2174/1570178619666220831122614
    [Google Scholar]
  6. ShangC. HouY. MengT. ShiM. CuiG. The anticancer activity of indazole compounds: A mini review.Curr. Top. Med. Chem.202121536337610.2174/156802662099920112415423133238856
    [Google Scholar]
  7. MalS. MalikU. MahapatraM. MishraA. PalD. PaidesettyS.K. A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective.Drug Dev. Res.20228371469150410.1002/ddr.2197935971890
    [Google Scholar]
  8. SureshbabuP. BhajammanavarV. ChoutipalliV.S.K. SubramanianV. BaidyaM. Unorthodox cascade reaction of arynes and N -nitrosamides leading to indazole scaffolds.Chem. Commun. (Camb.)20225881187119010.1039/D1CC05655G34981799
    [Google Scholar]
  9. SureshbabuP. ChaudharyP. Synthesis of indazole scaffolds from arynes and suitable coupling partners - A brief review.Mini Rev. Org. Chem.2024212110.2174/0118756298321262240719103850
    [Google Scholar]
  10. Pérez-VillanuevaJ. Yépez-MuliaL. González-SánchezI. Palacios-EspinosaJ. Soria-ArtecheO. Sainz-EspuñesT. CerbónM. Rodríguez-VillarK. Rodríguez-VicenteA. Cortés-GinesM. Custodio-GalvánZ. Estrada-CastroD. Synthesis and biological evaluation of 2H-indazole derivatives: towards antimicrobial and anti-inflammatory dual agents.Molecules20172211186410.3390/molecules2211186429088121
    [Google Scholar]
  11. WangY. YanM. MaR. MaS. Synthesis and antibacterial activity of novel 4-bromo-1H-indazole derivatives as FtsZ inhibitors.Arch. Pharm. (Weinheim)2015348426627410.1002/ardp.20140041225773717
    [Google Scholar]
  12. Rodríguez-VillarK. Yépez-MuliaL. Cortés-GinesM. Aguilera-PerdomoJ.D. Quintana-SalazarE.A. Olascoaga Del AngelK.S. Cortés-BenítezF. Palacios-EspinosaJ.F. Soria-ArtecheO. Pérez-VillanuevaJ. Synthesis, antiprotozoal activity, and cheminformatic analysis of 2-Phenyl-2H-indazole derivatives.Molecules2021268214510.3390/molecules2608214533917871
    [Google Scholar]
  13. PoloE. TrillerasJ. RamosJ. GaldámezA. QuirogaJ. GutierrezM. Efficient MW-assisted synthesis, spectroscopic characterization, X-ray and antioxidant properties of indazole derivatives.Molecules201621790310.3390/molecules2107090327409599
    [Google Scholar]
  14. Rodríguez-VillarK. Hernández-CamposA. Yépez-MuliaL. Sainz-EspuñesT.R. Soria-ArtecheO. Palacios-EspinosaJ.F. Cortés-BenítezF. Leyte-LugoM. Varela-PetrissansB. Quintana-SalazarE.A. Pérez-VillanuevaJ. Design, synthesis and anticandidal evaluation of indazole and pyrazole derivatives.Pharmaceuticals202114317610.3390/ph1403017633668364
    [Google Scholar]
  15. LiuJ. WenY. GaoL. GaoL. HeF. ZhouJ. WangJ. DaiR. ChenX. KangD. HuL. Design, synthesis and biological evaluation of novel 1 H -1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors via fragment-based virtual screening.J. Enzyme Inhib. Med. Chem.2020351728410.1080/14756366.2019.167374531682465
    [Google Scholar]
  16. García-ValdiviaA.A. JannusF. García-GarcíaA. Choquesillo-LazarteD. FernándezB. Medina-O’donnellM. LupiáñezJ.A. CepedaJ. Reyes-ZuritaF.J. Rodríguez-DiéguezA. Anti-cancer and anti-inflammatory activities of a new family of coordination compounds based on divalent transition metal ions and indazole-3-carboxylic acid.J. Inorg. Biochem.202121511130810.1016/j.jinorgbio.2020.11130833257004
    [Google Scholar]
  17. AlimZ. 1H‐indazole molecules reduced the activity of human erythrocytes carbonic anhydrase I and II isoenzymes.J. Biochem. Mol. Toxicol.2018329e2219410.1002/jbt.2219429984869
    [Google Scholar]
  18. NobleC. CannaertA. LinnetK. StoveC.P. Application of an activity‐based receptor bioassay to investigate the in vitro activity of selected indole‐ and indazole‐3‐carboxamide‐based synthetic cannabinoids at CB1 and CB2 receptors.Drug Test. Anal.201911350151110.1002/dta.251730280499
    [Google Scholar]
  19. BastosI.M. RebeloS. SilvaV.L.M. A review of poly(ADP-ribose)polymerase-1 (PARP1) role and its inhibitors bearing pyrazole or indazole core for cancer therapy.Biochem. Pharmacol.202422111604510.1016/j.bcp.2024.11604538336156
    [Google Scholar]
  20. GaikwadD.D. ChapolikarA.D. DevkateC.G. WaradK.D. TayadeA.P. PawarR.P. DombA.J. Synthesis of indazole motifs and their medicinal importance: An overview.Eur. J. Med. Chem.20159070773110.1016/j.ejmech.2014.11.02925506810
    [Google Scholar]
  21. YuK.H. HungH.Y. Synthetic strategy and structure-activity relationship (SAR) studies of 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1, Lificiguat): A review.RSC Advances202112125126410.1039/D1RA08120A35424505
    [Google Scholar]
  22. KumarK.P. VedavathiP. SubbaiahK.V. ReddyD.V.R. RajuC.N. Design, synthesis, spectral characterization and bioactivity evaluation of new sulfonamide and carbamate derivatives of 5-Nitro-1H-indazole.Organic Communications201710323924910.25135/acg.oc.24.17.05.023
    [Google Scholar]
  23. DenyaI. MalanS.F. JoubertJ. Indazole derivatives and their therapeutic applications: A patent review (2013-2017).Expert Opin. Ther. Pat.201828644145310.1080/13543776.2018.147224029718740
    [Google Scholar]
  24. HoytS.B. TaylorJ. LondonC. AliA. UjjainwallaF. TataJ. StruthersM. CullyD. WisniewskiT. RenN. BoppC. SokA. VerrasA. McMastersD. ChenQ. TungE. TangW. SalituroG. ClemasJ. ZhouG. MacNeilD. DuffyR. XiongY. Discovery of indazole aldosterone synthase (CYP11B2) inhibitors as potential treatments for hypertension.Bioorg. Med. Chem. Lett.201727112384238810.1016/j.bmcl.2017.04.02128416132
    [Google Scholar]
  25. CaoY. LuoC. YangP. LiP. WuC. Indazole scaffold: A generalist for marketed and clinical drugs.Med. Chem. Res.202130350151810.1007/s00044‑020‑02665‑7
    [Google Scholar]
  26. Gross-goupilM. FrançoisL. QuivyA. RavaudA. Axitinib: A review of its safety and efficacy in the treatment of adults with advanced renal cell carcinoma.Clin. Med. Insights Oncol.20137269277
    [Google Scholar]
  27. MonkB.J. PothuriB. VergoteI. GraybillW. MirzaM.R. MccormickC.C. LorussoD. MooreR.G. FreyerG. CearbhaillR.E.O. HeitzF. MalleyD.M.O. RedondoA. ShahinM.S. VulstekeC. BradleyW.H. HaslundC.A. ChaseD.M. PisanoC. HolmanL.L. PérezM.J.R. DisilvestroP. GabaL. HerzogT.J. BruchimI. ComptonN. ShtesselL. MalinowskaI.A. Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial.Ann. Oncol.20243598199210.1016/j.annonc.2024.08.224139284381
    [Google Scholar]
  28. MousaA.B. Sorafenib in the treatment of advanced hepatocellular carcinoma.Saudi J. Gastroenterol.2008141404210.4103/1319‑3767.3780819568496
    [Google Scholar]
  29. MotzerR.J. EscudierB. GannonA. FiglinR.A. Sunitinib: Ten years of successful clinical use and study in advanced renal cell carcinoma.Oncologist2017221415210.1634/theoncologist.2016‑019727807302
    [Google Scholar]
  30. MarotoP. PortaC. CapdevilaJ. ApoloA.B. ViteriS. Rodriguez-AntonaC. MartinL. CastellanoD. Cabozantinib for the treatment of solid tumors: A systematic review.Ther. Adv. Med. Oncol.2022141758835922110711210.1177/1758835922110711235847482
    [Google Scholar]
  31. SuyamaK. IwaseH. Lenvatinib.Cancer Contr.2018251107327481878936110.1177/107327481878936130032643
    [Google Scholar]
  32. ZhangX.H. CaoM.Q. LiX.X. ZhangT. Apatinib as an alternative therapy for advanced hepatocellular carcinoma.World J. Hepatol.2020121076677410.4254/wjh.v12.i10.76633200015
    [Google Scholar]
  33. FramptonJ.E. Entrectinib: A review in NTRK+ solid tumours and ROS1+ NSCLC.Drugs202181669770810.1007/s40265‑021‑01503‑333871816
    [Google Scholar]
  34. ChenJ. GuoJ. ChenZ. WangJ. LiuM. PangX. Linifanib (ABT-869) potentiates the efficacy of chemotherapeutic agents through the suppression of receptor tyrosine kinase-mediated AKT/mTOR signaling pathways in gastric cancer.Sci. Rep.2016612938210.1038/srep2938227387652
    [Google Scholar]
  35. PloskerG.L. GoaK.L. Granisetron.Drugs199142580582410.2165/00003495‑199142050‑000071723376
    [Google Scholar]
  36. ŐszB.E. JîtcăG. SălcudeanA. RuszC.M. VariC.E. Benzydamine—an affordable over-the-counter drug with psychoactive properties—from chemical structure to possible pharmacological properties.Pharmaceuticals (Basel)202316456610.3390/ph1604056637111323
    [Google Scholar]
  37. GuglielmottiA. Capezzone de JoannonA. CazzollaN. MarchettiM. SoldoL. CavalloG. PinzaM. Radical scavenger activity of bendazac, an anticataract non-steroidal anti-inflammatory agent.Pharmacol. Res.199532636937310.1016/S1043‑6618(05)80042‑88736488
    [Google Scholar]
  38. ElsayedN.M.Y. SeryaR.A.T. TolbaM.F. AhmedM. BarakatK. Abou El EllaD.A. AbouzidK.A.M. Design, synthesis, biological evaluation and dynamics simulation of indazole derivatives with antiangiogenic and antiproliferative anticancer activity.Bioorg. Chem.20198234035910.1016/j.bioorg.2018.10.07130428414
    [Google Scholar]
  39. AbdelsalamE.A. ZagharyW.A. AminK.M. Abou TalebN.A. MekaweyA.A.I. EldehnaW.M. Abdel-AzizH.A. HammadS.F. Synthesis and in vitro anticancer evaluation of some fused indazoles, quinazolines and quinolines as potential EGFR inhibitors.Bioorg. Chem.20198910298510.1016/j.bioorg.2019.10298531121559
    [Google Scholar]
  40. WangC. ZhuM. LongX. WangQ. WangZ. OuyangG. Design, synthesis and antitumor activity of 1H-indazole-3-amine derivatives.Int. J. Mol. Sci.202324108686
    [Google Scholar]
  41. El-DamasyA.K. JinH. SeoS.H. BangE.K. KeumG. Design, synthesis, and biological evaluations of novel 3-amino-4-ethynyl indazole derivatives as Bcr-Abl kinase inhibitors with potent cellular antileukemic activity.Eur. J. Med. Chem.202020711271010.1016/j.ejmech.2020.11271032961435
    [Google Scholar]
  42. SongF. XuG. GaulM.D. ZhaoB. LuT. ZhangR. DesJarlaisR.L. DiLoretoK. HuebertN. ShookB. RentzeperisD. SantulliR. EckardtA. DemarestK. Design, synthesis and structure activity relationships of indazole and indole derivatives as potent glucagon receptor antagonists.Bioorg. Med. Chem. Lett.201929151974198010.1016/j.bmcl.2019.05.03631138472
    [Google Scholar]
  43. CuiY.J. MaC.C. ZhangC.M. TangL.Q. LiuZ.P. The discovery of novel indazole derivatives as tubulin colchicine site binding agents that displayed potent antitumor activity both in vitro and in vivo.Eur. J. Med. Chem.202018711196810.1016/j.ejmech.2019.11196831865012
    [Google Scholar]
  44. Pérez-VillanuevaJ. Matadamas-MartínezF. Yépez-MuliaL. Pérez-KoldenkovaV. Leyte-LugoM. Rodríguez-VillarK. Cortés-BenítezF. Macías-JiménezA.P. González-SánchezI. Romero-VelásquezA. Palacios-EspinosaJ.F. Soria-ArtecheO. Synthesis and cytotoxic activity of combretastatin A-4 and 2,3-Diphenyl-2H-indazole hybrids.Pharmaceuticals202114881510.3390/ph1408081534451912
    [Google Scholar]
  45. LaghchiouaF.E. KouakouA. EddahmiM. VialeM. MonticoneM. GangemiR. MaricI. El AmmariL. SaadiM. BaltasM. Kandri RodiY. RakibE.M. Antiproliferative and apoptotic activity of new indazole derivatives as potential anticancer agents.Arch. Pharm. (Weinheim)202035312200017310.1002/ardp.20200017332812268
    [Google Scholar]
  46. WangS. ShiJ.T. WangX.R. MuH.X. WangX.T. XuK.Y. WangQ.S. ChenS.W. 1H-Indazoles derivatives targeting PI3K/AKT/mTOR pathway: Synthesis, anti-tumor effect and molecular mechanism.Bioorg. Chem.202313310641210.1016/j.bioorg.2023.10641236773456
    [Google Scholar]
  47. Al-tuwaijriH.M. Al-abdullahE.S. El-rashedyA.A. AnsariS.A. AlmomenA. AlshiblH.M. HaibaM.E. AlkahtaniH.M. New indazol-pyrimidine-based derivatives as selective anticancer agents: design, synthesis, and in silico studies.Molecules20232893664
    [Google Scholar]
  48. Mohamed AbdelahiM.M. El BakriY. LaiC.H. SubramaniK. AnouarE.H. AhmadS. BenchidmiM. MagueJ.T. Popović-DjordjevićJ. Goumri-SaidS. Novel 3-chloro-6-nitro-1 H -indazole derivatives as promising antileishmanial candidates: Synthesis, biological activity, and molecular modelling studies.J. Enzyme Inhib. Med. Chem.202237115116710.1080/14756366.2021.199538034894940
    [Google Scholar]
  49. BurkeA. Di FilippoM. SpiccioS. SchitoA.M. CavigliaD. BrulloC. BaumannM. Antimicrobial evaluation of new pyrazoles, indazoles and pyrazolines prepared in continuous flow mode.Int. J. Mol. Sci.2023246531910.3390/ijms2406531936982392
    [Google Scholar]
  50. LuoG. ChenL. EastonA. NewtonA. BourinC. ShieldsE. MosureK. SoarsM.G. KnoxR.J. MatchettM. PieschlR.L. Post-MunsonD.J. WangS. HerringtonJ. GraefJ. NewberryK. SivaraoD.V. SenapatiA. BristowL.J. MeanwellN.A. ThompsonL.A. DzierbaC. Discovery of indole- and indazole-acylsulfonamides as potent and selective Na V 1.7 inhibitors for the treatment of pain.J. Med. Chem.201962283185610.1021/acs.jmedchem.8b0155030576602
    [Google Scholar]
  51. HouS. YangX. YangY. TongY. ChenQ. WanB. WeiR. LuT. ChenY. HuQ. Design, synthesis and biological evaluation of 1H-indazole derivatives as novel ASK1 inhibitors.Eur. J. Med. Chem.202122011348210.1016/j.ejmech.2021.11348233906048
    [Google Scholar]
  52. ImD. JunJ. BaekJ. KimH. KangD. BaeH. ChoH. HahJ.M. Rational design and synthesis of 2-(1 H -indazol-6-yl)-1 H -benzo[d]imidazole derivatives as inhibitors targeting FMS-like tyrosine kinase 3 (FLT3) and its mutants.J. Enzyme Inhib. Med. Chem.202237147248610.1080/14756366.2021.202077235067150
    [Google Scholar]
  53. FukudaT. UedaK. IshiyamaT. GotoR. MuramatsuS. HashimotoM. WatanabeK. TanakaN. Synthesis and SAR studies of 3,6-disubstituted indazole derivatives as potent hepcidin production inhibitors.Bioorg. Med. Chem. Lett.201727102148215210.1016/j.bmcl.2017.03.05628377056
    [Google Scholar]
  54. LiL. LiuF. JinN. TangS. ChenZ. YangX. DingJ. GengM. JiangL. HuangM. CaoJ. Discovery and structure activity relationship study of novel indazole amide inhibitors for extracellular signal-regulated kinase1/2 (ERK1/2).Bioorg. Med. Chem. Lett.201626112600260410.1016/j.bmcl.2016.04.02927106711
    [Google Scholar]
  55. LiuJ. ZhouJ. HeF. GaoL. WenY. GaoL. WangP. KangD. HuL. Design, synthesis and biological evaluation of novel indazole-based derivatives as potent HDAC inhibitors via fragment-based virtual screening.Eur. J. Med. Chem.202019211218910.1016/j.ejmech.2020.11218932151834
    [Google Scholar]
/content/journals/mc/10.2174/0115734064360528241209074117
Loading
/content/journals/mc/10.2174/0115734064360528241209074117
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test