Abstract
Background: Heterocyclic compounds, also called heterocycles, are a major class of organic chemical compound that plays a vital role in the metabolism of all living cells. The heterocyclic compound, indazole, has attracted more attention in recent years and is widely present in numerous commercially available drugs. Indazole-containing derivatives, representing one of the most important heterocycles in drug molecules, are endowed with a broad range of biological properties.
Methods: A literature search was conducted in PubMed, Google Scholar and Web of Science regarding articles related to indazole and its therapeutic application.
Results: The mechanism and structure-activity relationship of indazole and its derivatives were described. Based on their versatile biological activities, the compounds were divided into six groups: anti-inflammatory, antibacterial, anti-HIV, antiarrhythmic, antifungal and antitumour. At least 43 indazole-based therapeutic agents were found to be used in clinical application or clinical trials.
Conclusion: This review is a guide for pharmacologists who are in search of valid preclinical/clinical drug compounds where the progress of approved marketed drugs containing indazole scaffold is examined from 1966 to the present day. Future direction involves more diverse bioactive moieties with indazole scaffold and greater insights into its mechanism.
Keywords: Heterocyclic compound, indazole, therapeutic application, structure-activity relationship, pharmacology, activity.
Graphical Abstract
[http://dx.doi.org/10.3390/biom10040544] [PMID: 32260120]
[http://dx.doi.org/10.2174/1568026619666191011162955] [PMID: 31644408]
[http://dx.doi.org/10.4155/fmc-2019-0159] [PMID: 31702389]
[http://dx.doi.org/10.2174/156802662005200304123442] [PMID: 32242512]
[http://dx.doi.org/10.4155/fmc-2020-0047] [PMID: 32212924]
[http://dx.doi.org/10.2174/1568026619666190618130008] [PMID: 31210108]
[http://dx.doi.org/10.4155/fmc-2019-0258] [PMID: 31983223]
[http://dx.doi.org/10.2174/1568026619666190603094439] [PMID: 31161992]
[http://dx.doi.org/10.2174/156802661917190828111130] [PMID: 31592750]
[http://dx.doi.org/10.1016/j.ejmech.2019.03.008] [PMID: 30877972]
[http://dx.doi.org/10.1021/acs.orglett.0c01232] [PMID: 32463244]
[http://dx.doi.org/10.2174/1389557511313120009] [PMID: 22625410]
[http://dx.doi.org/10.1021/ic501710k] [PMID: 25290960]
[http://dx.doi.org/10.1177/1087057111414902] [PMID: 21821786]
[http://dx.doi.org/10.7860/JCDR/2016/19338.8465] [PMID: 27790461]
[http://dx.doi.org/10.1021/jm500729a] [PMID: 24955776]
[http://dx.doi.org/10.1002/cmdc.201800253] [PMID: 29863292]
[http://dx.doi.org/10.1080/13543776.2018.1472240] [PMID: 29718740]
[http://dx.doi.org/10.1093/jjco/hyz040] [PMID: 30924496]
[http://dx.doi.org/10.2147/DDDT.S109640] [PMID: 29033542]
[PMID: 30369225]
[http://dx.doi.org/10.1007/s40265-015-0483-x] [PMID: 26487541]
[http://dx.doi.org/10.1007/978-3-642-01222-8_3] [PMID: 20072829]
[http://dx.doi.org/10.1007/s12032-018-1113-8] [PMID: 29524031]
[http://dx.doi.org/10.1007/s10637-010-9477-4] [PMID: 20596748]
[http://dx.doi.org/10.18632/oncotarget.13753] [PMID: 27924057]
[http://dx.doi.org/10.1345/aph.1M251] [PMID: 20407031]
[PMID: 22166325]
[http://dx.doi.org/10.2165/11209950-000000000-00000] [PMID: 23072642]
[http://dx.doi.org/10.1016/j.critrevonc.2013.08.012] [PMID: 24041629]
[http://dx.doi.org/10.1080/13543784.2019.1607291] [PMID: 31010343]
[http://dx.doi.org/10.2165/11205480-000000000-00000] [PMID: 20649181]
[http://dx.doi.org/10.2165/11588960-000000000-00000] [PMID: 21395357]
[http://dx.doi.org/10.1111/cbdd.12243] [PMID: 24119291]
[http://dx.doi.org/10.1186/1756-8722-2-33] [PMID: 19642998]
[http://dx.doi.org/10.1200/JCO.2013.54.3298] [PMID: 25488963]
[http://dx.doi.org/10.1016/j.cell.2018.09.038] [PMID: 30343896]
[http://dx.doi.org/10.1038/s41591-018-0007-9] [PMID: 29686424]
[http://dx.doi.org/10.1007/s10637-012-9912-9] [PMID: 23275061]
[http://dx.doi.org/10.1021/acs.oprd.8b00016]
[http://dx.doi.org/10.1158/1078-0432.CCR-13-1758] [PMID: 23989980]
[http://dx.doi.org/10.1002/mc.22449] [PMID: 26757360]
[http://dx.doi.org/10.1634/theoncologist.2018-0411] [PMID: 30833489]
[http://dx.doi.org/10.1177/0269216307083383] [PMID: 18073263]
[PMID: 2169778]
[http://dx.doi.org/10.1200/JCO.1990.8.2.337] [PMID: 2153767]
[http://dx.doi.org/10.1016/S0959-8049(05)80256-4] [PMID: 8381293]
[http://dx.doi.org/10.2165/00003495-199448050-00008] [PMID: 7530631]
[http://dx.doi.org/10.1007/BF00199881] [PMID: 8039536]
[http://dx.doi.org/10.2165/11202780-000000000-00000] [PMID: 19943709]
[http://dx.doi.org/10.1188/09.CJON.711-714] [PMID: 19948469]
[http://dx.doi.org/10.2147/CMAR.S4953] [PMID: 21188092]
[http://dx.doi.org/10.1007/s00520-010-0990-y] [PMID: 20835873]
[PMID: 18633256]
[PMID: 19755818]
[PMID: 15853230]
[http://dx.doi.org/10.1517/13543784.2015.1096344] [PMID: 26457764]
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0419] [PMID: 29237803]
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0758] [PMID: 26939704]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00064] [PMID: 27003761]
[http://dx.doi.org/10.2147/TCRM.S147381] [PMID: 30050303]
[http://dx.doi.org/10.1158/2159-8290.CD-16-1237] [PMID: 28183697]
[http://dx.doi.org/10.1177/2040620716636542] [PMID: 27247756]
[http://dx.doi.org/10.1182/blood-2014-08-595934] [PMID: 25696919]
[http://dx.doi.org/10.1080/10428194.2018.1562180] [PMID: 30633573]
[http://dx.doi.org/10.18632/oncotarget.1484] [PMID: 24659719]
[http://dx.doi.org/10.1016/j.clml.2018.05.022] [PMID: 29934062]
[http://dx.doi.org/10.1186/s13045-017-0512-1] [PMID: 28754125]
[http://dx.doi.org/10.1111/bjh.15552] [PMID: 30183069]
[http://dx.doi.org/10.1021/jm500228a] [PMID: 24779514]
[http://dx.doi.org/10.1007/s40261-016-0476-x] [PMID: 27785737]
[http://dx.doi.org/10.1093/jnci/86.16.1239] [PMID: 8040892]
[http://dx.doi.org/10.1006/jmbi.1994.1075] [PMID: 8308885]
[http://dx.doi.org/10.1124/dmd.30.4.464] [PMID: 11901102]
[http://dx.doi.org/10.1200/JCO.1991.9.12.2141] [PMID: 1960556]
[http://dx.doi.org/10.1021/ci060056y] [PMID: 16859314]
[http://dx.doi.org/10.1002/1097-0142(19940915)74:6<1733::AIDCNCR2820740615>3.0.CO;2-D] [PMID: 8082075]
[http://dx.doi.org/10.1007/BF00873050] [PMID: 7775136]
[http://dx.doi.org/10.1007/BF02614226] [PMID: 7499114]
[http://dx.doi.org/10.1097/00001813-199607000-00006] [PMID: 8862719]
[http://dx.doi.org/10.1007/BF00874449] [PMID: 7860236]
[http://dx.doi.org/10.1007/BF00873970] [PMID: 7896547]
[http://dx.doi.org/10.1093/oxfordjournals.annonc.a058627] [PMID: 8241002]
[http://dx.doi.org/10.1007/BF00874163] [PMID: 8262739]
[http://dx.doi.org/10.1093/oxfordjournals.annonc.a058628] [PMID: 8241003]
[http://dx.doi.org/10.1097/00001813-200401000-00003] [PMID: 15090738]
[http://dx.doi.org/10.1007/s10637-005-1445-z] [PMID: 16012796]
[http://dx.doi.org/10.1159/000055380] [PMID: 11574780]
[http://dx.doi.org/10.1021/jm9804432] [PMID: 9876113]
[http://dx.doi.org/10.1007/s002800050650] [PMID: 9219505]
[http://dx.doi.org/10.1006/gyno.2001.6491] [PMID: 11812081]
[http://dx.doi.org/10.1007/s00280-002-0470-2] [PMID: 12172981]
[http://dx.doi.org/10.1023/A:1016293527755] [PMID: 12201497]
[http://dx.doi.org/10.1111/j.1743-7563.2010.01328.x] [PMID: 21114779]
[http://dx.doi.org/10.1007/s002800050878] [PMID: 9923823]
[http://dx.doi.org/10.1097/00000421-200012000-00015] [PMID: 11202806]
[http://dx.doi.org/10.1007/s002800051126] [PMID: 10550573]
[http://dx.doi.org/10.1023/B:DRUG.0000011795.82694.80] [PMID: 14739667]
[PMID: 28994564]
[http://dx.doi.org/10.1016/j.ctrv.2018.12.002] [PMID: 30543930]
[http://dx.doi.org/10.1007/s40265-017-0752-y] [PMID: 28474297]
[PMID: 31117037]
[http://dx.doi.org/10.1080/14737140.2018.1490180] [PMID: 29911447]
[http://dx.doi.org/10.2217/fon-2018-0101] [PMID: 29856239]
[http://dx.doi.org/10.1080/14656566.2017.1297423] [PMID: 28299955]
[http://dx.doi.org/10.1056/NEJMoa1611310] [PMID: 27717299]
[http://dx.doi.org/10.1007/s11523-018-0582-1] [PMID: 30073633]
[http://dx.doi.org/10.1016/S1470-2045(18)30333-4] [PMID: 30026000]
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0306] [PMID: 21900693]
[http://dx.doi.org/10.1016/j.critrevonc.2017.02.018] [PMID: 28427515]
[http://dx.doi.org/10.1007/s11523-017-0502-9] [PMID: 28589492]
[http://dx.doi.org/10.2174/1871520618666180510113822] [PMID: 29745343]
[http://dx.doi.org/10.1021/acsmedchemlett.7b00349] [PMID: 29259745]
[http://dx.doi.org/10.7554/eLife.44851] [PMID: 30614786]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00054] [PMID: 25879485]
[http://dx.doi.org/10.1007/s00280-018-3716-3] [PMID: 30386887]
[http://dx.doi.org/10.1016/j.jpba.2019.04.045] [PMID: 31055184]
[http://dx.doi.org/10.1021/jm800295d] [PMID: 18754654]
[http://dx.doi.org/10.1158/1078-0432.CCR-09-2828] [PMID: 20453058]
[http://dx.doi.org/10.1158/1078-0432.CCR-14-0947] [PMID: 25370471]
[http://dx.doi.org/10.1200/JCO.2015.63.9179] [PMID: 26976426]
[http://dx.doi.org/10.1016/S1470-2045(16)00106-6] [PMID: 27155741]
[http://dx.doi.org/10.1021/ci200434f] [PMID: 22142286]
[http://dx.doi.org/10.1182/blood-2009-01-199307] [PMID: 19541823]
[http://dx.doi.org/10.1182/blood-2008-09-177030] [PMID: 19029442]
[http://dx.doi.org/10.1681/ASN.2006060604] [PMID: 17202416]
[http://dx.doi.org/10.1038/sj.ki.5002404] [PMID: 17597698]
[http://dx.doi.org/10.1158/0008-5472.CAN-15-3062] [PMID: 27287719]
[http://dx.doi.org/10.1158/1078-0432.CCR-14-1765] [PMID: 25480830]
[http://dx.doi.org/10.1158/1078-0432.CCR-06-0642] [PMID: 17062696]
[http://dx.doi.org/10.1093/annonc/mdr137] [PMID: 21576284]
[http://dx.doi.org/10.1021/jm400380m] [PMID: 23829549]
[http://dx.doi.org/10.1038/s41416-019-0517-3] [PMID: 31303643]
[http://dx.doi.org/10.18632/oncotarget.13619] [PMID: 27902970]
[http://dx.doi.org/10.1038/nrc2602] [PMID: 19238148]
[PMID: 19370178]
[http://dx.doi.org/10.1056/NEJMc2000644] [PMID: 32294361]
[http://dx.doi.org/10.1039/C3SC53243G]
[http://dx.doi.org/10.1136/esmoopen-2016-000154] [PMID: 28848672]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00600] [PMID: 27196130]
[http://dx.doi.org/10.1016/j.ejca.2013.05.018] [PMID: 23790465]
[http://dx.doi.org/10.1021/acsmedchemlett.8b00220] [PMID: 30034615]
[http://dx.doi.org/10.1172/jci.insight.92352] [PMID: 29467321]
[http://dx.doi.org/10.1016/j.phrs.2019.01.039] [PMID: 30794926]
[http://dx.doi.org/10.1016/j.jmb.2018.03.009] [PMID: 29573988]
[http://dx.doi.org/10.1016/j.molonc.2016.03.006] [PMID: 27071719]
[http://dx.doi.org/10.1517/13543784.2015.1078310] [PMID: 26293110]
[http://dx.doi.org/10.1016/j.bmcl.2014.03.070] [PMID: 24755427]
[http://dx.doi.org/10.1021/acs.jmedchem.7b01215] [PMID: 28937774]
[http://dx.doi.org/10.1084/jem.187.1.129] [PMID: 9419219]
[http://dx.doi.org/10.2174/15680266106061335] [PMID: 16918452]
[http://dx.doi.org/10.1016/j.bmcl.2012.02.104] [PMID: 22437117]
[http://dx.doi.org/10.1126/science.296.5573.1655] [PMID: 12040186]
[http://dx.doi.org/10.1038/nrm2882] [PMID: 20379207]
[http://dx.doi.org/10.1042/BST20110665] [PMID: 22260698]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00767] [PMID: 26301626]
[http://dx.doi.org/10.1021/acs.oprd.8b00006]
[http://dx.doi.org/10.1002/acn3.19] [PMID: 24466563]
[http://dx.doi.org/10.1073/pnas.1414189111] [PMID: 25385601]
[http://dx.doi.org/10.1080/21623945.2019.1590929] [PMID: 30860936]
[http://dx.doi.org/10.1080/1120009X.1992.11739190] [PMID: 1287137]
[PMID: 7600413]
[http://dx.doi.org/10.1191/096032799678840264] [PMID: 10454080]
[http://dx.doi.org/10.1155/2014/290365] [PMID: 25343054]
[http://dx.doi.org/10.1016/S1359-6446(96)10048-9]
[http://dx.doi.org/10.1517/13543776.7.2.111]
[http://dx.doi.org/10.1016/S1074-5521(98)90117-X] [PMID: 9818151]
[http://dx.doi.org/10.1021/jm2010173] [PMID: 21985673]
[http://dx.doi.org/10.1128/AAC.00102-12] [PMID: 22391531]
[http://dx.doi.org/10.1152/physrev.00021.2006] [PMID: 17237345]
[http://dx.doi.org/10.1038/nrd2280] [PMID: 17464295]
[http://dx.doi.org/10.1021/jm0492958] [PMID: 15689158]
[http://dx.doi.org/10.1021/jm701007g] [PMID: 18183945]
[http://dx.doi.org/10.1016/S0014-2999(97)01251-X] [PMID: 9384259]
[http://dx.doi.org/10.1016/S0014-2999(99)00133-8] [PMID: 10323259]
[http://dx.doi.org/10.1038/nature05413] [PMID: 17167479]
[http://dx.doi.org/10.1038/srep39662] [PMID: 28045073]
[http://dx.doi.org/10.1021/jm1007825] [PMID: 20932009]
[http://dx.doi.org/10.1016/j.bcp.2011.06.034] [PMID: 21741954]
[http://dx.doi.org/10.1124/jpet.110.171892] [PMID: 20959364]
[http://dx.doi.org/10.1016/j.pnpbp.2008.11.018] [PMID: 19110025]
[http://dx.doi.org/10.1016/j.pharmthera.2012.08.012] [PMID: 22925690]
[http://dx.doi.org/10.1038/s41598-019-51691-y] [PMID: 31641194]
[http://dx.doi.org/10.1007/PL00000301] [PMID: 12056513]
[http://dx.doi.org/10.1177/0091270009335768] [PMID: 19398602]