Abstract
Naphthoquinone is a heterocyclic moiety whose natural derivatives are present as bioactive compounds in many plants and have stimulated a resurgence of interest in the past decades due to their wide range of pharmacological activities. Naphthoquinone agents have dynamic pharmacophores and privileged sub-structures in the chemistry of medicine. They have received much interest in drug discovery as trypanocidal because naphthoquinone and their derivatives revealed massive significance potential against the trypanosomes. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer exhibited useful trypanocidal activities. Some naphthoquinones have already been used commercially as an antiparasitic agent. Several naphthoquinones with diverse structural motifs have been synthesized and evaluated mainly against Trypanosoma cruzi and some studies have also been reported against Trypanosoma brucei and Trypanosoma evansi. This review summarized various mechanisms of action of naphthoquinone like reductive activation of quinone by the production of the semiquinone, generation of reactive oxygen species and free radicals such as superoxide anion radical and H2O2, and oxidative stress in the parasite. The information assembled in this review will help to understand the mechanism behind the activity and may also be useful to find the bio-efficacy of naphthoquinone compounds upon substitution against trypanosomatids.
Keywords: Trypanosomatids, Naphthoquinone, Quinone reduction, Oxidative stress, Reactive oxygen species, Mechanism of action.
[http://dx.doi.org/10.1007/s12649-021-01443-9]
[http://dx.doi.org/10.1016/S0083-6729(07)00005-2] [PMID: 18374191]
[http://dx.doi.org/10.1136/bmj.326.7390.628] [PMID: 12649236]
[http://dx.doi.org/10.1056/NEJM200011163432004] [PMID: 11078770]
[http://dx.doi.org/10.1093/jac/dkf251] [PMID: 12461021]
[http://dx.doi.org/10.1016/j.vetpar.2012.01.016] [PMID: 22305656]
[http://dx.doi.org/10.1292/jvms.65.1171] [PMID: 14665744]
[http://dx.doi.org/10.3390/molecules14114570] [PMID: 19924086]
[http://dx.doi.org/10.1093/jac/30.6.827] [PMID: 1289357]
[http://dx.doi.org/10.1016/j.exppara.2012.01.010] [PMID: 22281156]
[http://dx.doi.org/10.1016/j.exppara.2015.04.017] [PMID: 5911243]
[http://dx.doi.org/10.1128/AAC.02297-16] [PMID: 28167544]
[http://dx.doi.org/10.1111/j.1550-7408.2012.00644.x] [PMID: 23020233]
[http://dx.doi.org/10.1172/JCI33945] [PMID: 18382742]
[http://dx.doi.org/10.1016/S0140-6736(09)60829-1] [PMID: 19833383]
[http://dx.doi.org/10.1016/j.idc.2012.03.002] [PMID: 22632639]
[http://dx.doi.org/10.1172/JCI200421052] [PMID: 14966556]
[http://dx.doi.org/10.1016/S1474-4422(12)70296-X] [PMID: 23260189]
[http://dx.doi.org/10.1371/journal.pntd.0005585] [PMID: 28531222]
[http://dx.doi.org/10.3389/fimmu.2018.02253] [PMID: 30333827]
[http://dx.doi.org/10.1016/j.pt.2015.06.006] [PMID: 26458782]
[http://dx.doi.org/10.1016/S0140-6736(10)60061-X] [PMID: 20399979]
[http://dx.doi.org/10.1371/journal.pntd.0000613] [PMID: 20209152]
[http://dx.doi.org/10.1016/j.pt.2011.06.006] [PMID: 21840261]
[http://dx.doi.org/10.1016/j.idc.2018.10.015] [PMID: 30712757]
[http://dx.doi.org/10.1021/cr500197d] [PMID: 26443079]
[http://dx.doi.org/10.1155/2013/321237] [PMID: 24151595]
[http://dx.doi.org/10.1371/journal.pntd.0003404] [PMID: 25568942]
[http://dx.doi.org/10.1016/0166-6851(91)90203-I] [PMID: 1677160]
[http://dx.doi.org/10.1371/journal.pntd.0004556] [PMID: 27035661]
[http://dx.doi.org/10.1155/2013/194176] [PMID: 24024184]
[PMID: 4379528]
[http://dx.doi.org/10.1016/j.vetpar.2013.04.018] [PMID: 23664710]
[http://dx.doi.org/10.1016/j.vprsr.2017.06.008] [PMID: 31014579]
[http://dx.doi.org/10.4269/ajtmh.2005.73.491] [PMID: 16172469]
[http://dx.doi.org/10.1371/journal.pone.0009796] [PMID: 20339546]
[http://dx.doi.org/10.1093/cid/ciw052] [PMID: 26908809]
[http://dx.doi.org/10.2174/1568026616666160413125453] [PMID: 27072714]
[http://dx.doi.org/10.2174/157341209787314936]
[http://dx.doi.org/10.1155/2014/461393] [PMID: 25045679]
[PMID: 8047025];
(b) Pinto, A.V.; Pinto, C.N. Pinto, Mdo.C.; Rita, R.S.; Pezzella, C.A.; De Castro, S.L. Trypanocidal activity of synthetic heterocyclic de-rivatives of active quinones from Tabebuia sp. Arzneimittelforschung, 1997, 47(1), 74-79.
[PMID: 9037448]
[PMID: 11190779];
(b) Moura, K.C.G.; Emery, F.S.; Neves, P.C.; Dantas, A.P.; Salomão, K. Synthesis and trypanocidal activity of naphthoquinones isolated from Tabebuia and heterocyclic derivatives: A review from an interdisciplnary study. J. Braz. Chem. Soc., 12(3), 325-338.;
(c) De Moura, K.C.G.; Salomão, K.; Menna, B.R.F.S.; Emery, F.S.; Pinto, M.C.F.R.; Pinto, A.V.; De Castro, S.L. Studies on the trypano-cidal activity of semi-synthetic pyran[b-4,3]naphtho[1,2-d]imidazoles from β-lapachone. Eur. J. Med. Chem., 2004, 39(7), 639-645.
[http://dx.doi.org/10.1016/j.ejmech.2004.02.015] [PMID: 15236845];
(d) Menna-Barreto, R.F.S.; Henriques-Pons, A.; Pinto, A.V.; Morgado-Diaz, J.A.; Soares, M.J.; De Castro, S.L. Effect of a β-lapachone-derived naphthoimidazole on Trypanosoma cruzi: Identification of target organelles. J. Antimicrob. Chemother., 2005, 56(6), 1034-1041.
[http://dx.doi.org/10.1093/jac/dki403] [PMID: 16269551];
(e) Menna, B.R.F.S.; Corrêa, J.R.; Pinto, A.V.; Soares, M.J.; De Castro, S.L. Mitochondrial disruption and DNA fragmentation in Trypa-nosoma cruzi induced by naphthoimidazoles synthesized from β-lapachone. Parasitol. Res., 2007, 101(4), 895-905.
[http://dx.doi.org/10.1007/s00436-007-0556-1] [PMID: 17546464];
(f) Salas, C.; Tapia, R.A.; Ciudad, K.; Armstrong, V.; Orellana, M.; Kemmerling, U.; Ferreira, J.; Maya, J.D.; Morello, A Trypanosoma cruzi: Activities of lapachol and α- and β-lapachone derivatives against epimastigote and trypomastigote forms. Bioorg. Med. Chem., 2008, 16(2), 668-674.
[http://dx.doi.org/10.1016/j.bmc.2007.10.038] [PMID: 18029184];
(g) Da Silva, E.N. Jr; Menna, B.R.F.S.; Pinto, M.C.F.R.; Silva, R.S.F.; Teixeira, D.V.; De Souza, M.C.B.V.; De Simone, C.A.; De Castro, S.L.; Ferreira, V.F.; Pinto, A.V. Naphthoquinoidal [1,2,3]- triazole, a new structural moiety active against Trypanosoma cruzi Eur. J. Med. Chem., 2008, 43(8), 1774-1780.
[http://dx.doi.org/10.1016/j.ejmech.2007.10.015] [PMID: 18045742];
(h) Silva Júnior, E.N.; Moura, M.A.B.F.; Pinto, A.V.; Pinto, M.C.F.R.; Souza, M.C.B.V.; Araújo, A.J.; Pessoa, C.; CostaLotufo, L.V.; Montenegro, R.C.; Moraes, M.O.; Ferreira, V.F.; Goulart, M.O.F. Cytotoxic, trypanocidal activities and physicochemical parameters of nor-²-lapachone-based 1,2,3-triazoles. J. Braz. Chem. Soc, 2009, 20(4), 635-643.
[http://dx.doi.org/10.1590/S0103-50532009000400007]
[http://dx.doi.org/10.1016/j.ejmech.2012.03.039] [PMID: 22483633];
(b) Diogo, E.B.T.; Dias, G.G.; Rodrigues, B.L.; Guimarães, T.T.; Valença, W.O.; Camara, C.A.; De Oliveira, R.N.; da Silva, M.G.; Fer-reira, V.F.; De Paiva, Y.G.; Goulart, M.O.F.; Menna, B.R.F.S.; De Castro, S.L.; Da Silva Júnior, E.N. Synthesis and anti-Trypanosoma cruzi activity of naphthoquinone-containing triazoles: Electrochemical studies on the effects of the quinoidal moiety. Bioorg. Med. Chem., 2013, 21(21), 6337-6348.
[http://dx.doi.org/10.1016/j.bmc.2013.08.055] [PMID: 24074878];
(c) Jardim, G.A.M.; Reis, W.J.; Ribeiro, M.F.; Ottoni, F.M.; Alves, R.J.; Silva, T.L.; Goulart, M.O.F.; Braga, A.L.; Menna, B.R.F.S.; Sa-lomão, K.; De Castro, S.L.; Da Silva Júnior, E.N. On the investigation of hybrid quinones: Synthesis, electrochemical studies and evalua-tion of trypanocidal activity. RSC Advances, 2015, 5(95), 78047-78060.
[http://dx.doi.org/10.1039/C5RA16213K];
(d) Bahia, S.B.B.B.; Reis, W.J.; Jardim, G.A.M.; Souto, F.T.; de Simone, C.A.; Gatto, C.C.; Menna, B.R.F.S.; De Castro, S.L.; Cavalcanti, B.C.; Pessoa, C.; Araujo, M.H.; Da Silva, Jr E.N. Molecular hybridization as a powerful tool towards multitarget quinoidal systems: Syn-thesis, trypanocidal and antitumor activities of naphthoquinone-based 5-iodo-1,4-disubstituted-, 1,4- and 1,5-disubstituted-1,2,3-triazoles. MedChemComm, 2016, 7(8), 1555-1563.
[http://dx.doi.org/10.1039/C6MD00216A];
(e) Jardim, G.A.M.; Silva, T.L.; Goulart, M.O.F.; de Simone, C.A.; Barbosa, J.M.C.; Salomão, K.; De Castro, S.L.; Bower, J.F.; Da Silva Júnior, E.N. Rhodium-catalyzed C-H bond activation for the synthesis of quinonoid compounds: Significant anti-Trypanosoma cruzi ac-tivities and electrochemical studies of functionalized quinones. Eur. J. Med. Chem., 2017, 136, 406-419.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.011] [PMID: 28521262];
(f) Jardim, G.A.M.; Oliveira, W.X.C.; De Freitas, R.P.; Menna, B.R.F.S.; Silva, T.L.; Goulart, M.O.F.; Da Silva Júnior, E.N. Direct se-quential C-H iodination/organoyl-thiolation for the benzenoid A-ring modification of quinonoid deactivated systems: A new protocol for potent trypanocidal quinones. Org. Biomol. Chem., 2018, 16(10), 1686-1691.
[http://dx.doi.org/10.1039/C8OB00196K] [PMID: 29450434];
(g) Jardim, G.A.M.; Bozzi, Í.A.O.; Oliveira, W.X.C.; Mesquita, R.C.; Menna, B.R.F.S.; Kumar, R.A.; Gravel, E.; Doris, E.; Braga, A.L.; Da Silva Júnior, E.N. Copper complexes and carbon nanotube-copper ferrite-catalyzed benzenoid A-ring selenation of quinones: An effi-cient method for the synthesis of trypanocidal agents. New J. Chem., 2019, 43(35), 13751-13763.
[http://dx.doi.org/10.1039/C9NJ02026H];
(h) Almeida, R.G.; Valença, W.O.; Rosa, L.G.; de Simone, C.A.; de Castro, S.L.; Barbosa, J.M.C.; Pinheiro, D.P.; Paier, C.R.K.; de Car-valho, G.G.C.; Pessoa, C.; Goulart, M.O.F.; Kharma, A.; da Silva Júnior, E.N. Synthesis of quinone imine and sulphur-containing com-pounds with antitumor and trypanocidal activities: Redox and biological implications. RSC Medicinal Chemistry, 2020, 11(10), 1145-1160.
[http://dx.doi.org/10.1039/D0MD00072H] [PMID: 33479619]
[http://dx.doi.org/10.3390/molecules200610082] [PMID: 26035104];
(b) Pacheco, P.A.F.; De Menezes, R.T.; Dos Santos, G.R.M.; Dos Santos, E.G.; Faria, A.F.M.; Von Ranke, N.L.; Bello, M.L.; Rodrigues, C.R.; Ferreira, V.F.; Souza, A.L.A.; De Jesús, H.D.; Da Silva, C.K.; Faria, R.X.; Da Rocha, D.R. Synthesis of new N,S-acetal analogs de-rived from juglone with cytotoxic activity against Trypanossoma cruzi. J. Bioenerg. Biomembr., 2020, 52(3), 199-213.
[http://dx.doi.org/10.1007/s10863-020-09834-8] [PMID: 32418003];
(c) Moideen, S.V.K.; Houghton, P.J.; Rock, P.; Croft, S.L.; Aboagye, N.F. Activity of extracts and naphthoquinones from Kigelia pinnata against Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense. Planta Med., 1999, 65(6), 536-540.
[http://dx.doi.org/10.1055/s-1999-14011] [PMID: 10483374]
[http://dx.doi.org/10.1016/j.vetpar.2021.109367] [PMID: 33516118]
[http://dx.doi.org/10.1016/j.ejps.2022.106118] [PMID: 35007713]
[http://dx.doi.org/10.1039/C4RA13547D]
[http://dx.doi.org/10.1007/s12192-011-0293-3] [PMID: 21956695]
[http://dx.doi.org/10.1155/2016/4350965] [PMID: 26998193]
[http://dx.doi.org/10.1155/2012/217037]
[http://dx.doi.org/10.3727/096504010X12671222663593] [PMID: 20524400]
[http://dx.doi.org/10.3390/biom9110735] [PMID: 31766246]
[http://dx.doi.org/10.1007/s00018-020-03536-5] [PMID: 32358622]
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.09.021] [PMID: 20937380]
[http://dx.doi.org/10.3390/molecules23010084] [PMID: 29301225]
[http://dx.doi.org/10.1016/j.exppara.2020.108018] [PMID: 33049224]
[http://dx.doi.org/10.1007/s00436-020-06861-7] [PMID: 32869169]
[http://dx.doi.org/10.1155/2019/5381692] [PMID: 31929855]
[http://dx.doi.org/10.1016/j.biopha.2019.109004] [PMID: 31128404]
[http://dx.doi.org/10.1126/science.162.3859.1277] [PMID: 4387010]
[http://dx.doi.org/10.1084/jem.149.5.1056] [PMID: 376774]
[PMID: 6288939]
[http://dx.doi.org/10.1089/ars.2013.5447] [PMID: 23992156]
[http://dx.doi.org/10.1179/135100001101536328] [PMID: 11642718]
[http://dx.doi.org/10.1016/0003-9861(82)90383-6] [PMID: 6297399]
[http://dx.doi.org/10.1073/pnas.0711014105] [PMID: 18367671]
[http://dx.doi.org/10.1371/journal.pntd.0002844] [PMID: 24853684]
[http://dx.doi.org/10.1128/AAC.05135-11] [PMID: 22037852]
[http://dx.doi.org/10.1016/j.taap.2016.05.007] [PMID: 27180241]
[http://dx.doi.org/10.1016/j.bbrc.2006.12.238] [PMID: 17292866]
[http://dx.doi.org/10.1371/journal.pntd.0006661] [PMID: 30036366]
[http://dx.doi.org/10.1016/j.molbiopara.2003.08.011] [PMID: 14668010]
[http://dx.doi.org/10.1016/j.ibmb.2006.01.009] [PMID: 16551546]
[http://dx.doi.org/10.1073/pnas.0602224103] [PMID: 16698925]
[PMID: 339293]
[http://dx.doi.org/10.1016/0306-4492(78)90063-1] [PMID: 33002]
[http://dx.doi.org/10.1007/BF00928032] [PMID: 216177]
[http://dx.doi.org/10.1016/0014-4894(77)90071-6] [PMID: 324785]
[http://dx.doi.org/10.1016/0003-9861(85)90033-5] [PMID: 2409922]
[PMID: 6086046]
[http://dx.doi.org/10.1007/BF01954247] [PMID: 2189749]
[PMID: 7641181]
[PMID: 11474885]
[http://dx.doi.org/10.1006/excr.2001.5234] [PMID: 11412042]
[PMID: 9620443]
[http://dx.doi.org/10.1007/s002800000221] [PMID: 11320661]
[http://dx.doi.org/10.1074/jbc.275.8.5416] [PMID: 10681517]
[http://dx.doi.org/10.1006/excr.1999.4790] [PMID: 10694431]
[http://dx.doi.org/10.1590/S0100-879X2006005000159] [PMID: 17713652]
[http://dx.doi.org/10.1007/s10637-009-9231-y] [PMID: 19255723]
[http://dx.doi.org/10.32604/biocell.2003.27.213] [PMID: 14510240]
[http://dx.doi.org/10.1017/S0031182009005745] [PMID: 19281638]
[http://dx.doi.org/10.1186/1471-2180-13-196] [PMID: 24004461]
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.11.012] [PMID: 30445126]
[http://dx.doi.org/10.1016/j.ijpddr.2016.10.003] [PMID: 27770751]
[http://dx.doi.org/10.1155/2011/174614] [PMID: 22007287]
[http://dx.doi.org/10.1016/j.bbagen.2013.01.013] [PMID: 23396001]
[http://dx.doi.org/10.1074/jbc.M204403200] [PMID: 12121990]
[http://dx.doi.org/10.3389/fcimb.2019.00435] [PMID: 31921709]
[http://dx.doi.org/10.1016/j.freeradbiomed.2008.05.028] [PMID: 18588970]
[http://dx.doi.org/10.1007/s10863-011-9365-4] [PMID: 21732175]
[http://dx.doi.org/10.1046/j.1432-1327.2000.01701.x] [PMID: 11012661]
[http://dx.doi.org/10.1016/S0166-6851(01)00285-7] [PMID: 11420105]
[http://dx.doi.org/10.1007/s00436-002-0771-8] [PMID: 12709793]
[http://dx.doi.org/10.1016/j.freeradbiomed.2004.02.008] [PMID: 15110394]
[http://dx.doi.org/10.1177/117739280700200007] [PMID: 21901070]
[http://dx.doi.org/10.1371/journal.pntd.0004617] [PMID: 27070550]
[http://dx.doi.org/10.1155/2018/8676578] [PMID: 30473742]
[http://dx.doi.org/10.3390/molecules25081924] [PMID: 32326257]
[http://dx.doi.org/10.1073/pnas.85.15.5374] [PMID: 3135548]
[http://dx.doi.org/10.1021/bi00175a021] [PMID: 8117712]
[http://dx.doi.org/10.1021/jm001079l] [PMID: 11170645]
[http://dx.doi.org/10.1590/S0074-02762003000400026] [PMID: 12937775]
[http://dx.doi.org/10.1016/j.ejmech.2017.12.052] [PMID: 29289882]
[http://dx.doi.org/10.1093/jac/dks498] [PMID: 23288404]
[http://dx.doi.org/10.1007/s10495-016-1259-9] [PMID: 27315817]
[http://dx.doi.org/10.1016/j.abb.2016.03.004] [PMID: 26946942]
[http://dx.doi.org/10.1016/j.biopha.2020.111186] [PMID: 33395606]
[http://dx.doi.org/10.3390/molecules22050798] [PMID: 28505088]
[http://dx.doi.org/10.1016/0003-9861(78)90438-1] [PMID: 205176]
[http://dx.doi.org/10.1016/S0006-2952(96)00601-6] [PMID: 8951346]
[http://dx.doi.org/10.1016/j.ejmech.2020.112962] [PMID: 33158575]
[http://dx.doi.org/10.1016/0006-2952(92)90007-6] [PMID: 1642640]
[http://dx.doi.org/10.1016/j.ejmech.2013.10.011] [PMID: 24211630]
[http://dx.doi.org/10.1146/annurev-pharmtox-010611-134517] [PMID: 21942631]
[http://dx.doi.org/10.1021/es203032v] [PMID: 22288565]
[http://dx.doi.org/10.1016/j.ijheh.2013.04.001] [PMID: 23735462]
[http://dx.doi.org/10.1021/acs.chemrestox.6b00256] [PMID: 27617882]
[http://dx.doi.org/10.3857/roj.2013.31.2.57] [PMID: 23865001]
[http://dx.doi.org/10.1038/cddis.2014.202] [PMID: 24832602]
[http://dx.doi.org/10.1016/0006-2952(90)90256-K] [PMID: 2157443]
[http://dx.doi.org/10.1016/j.abb.2004.09.020] [PMID: 15542051]
[http://dx.doi.org/10.1016/0006-2952(95)02168-X] [PMID: 8573194]
[http://dx.doi.org/10.1016/j.ejmech.2007.12.023] [PMID: 18276039]
[http://dx.doi.org/10.1017/S0031182018000045] [PMID: 29400267]