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Current Medicinal Chemistry

Author(s): Stephen Patterson and Alan H. Fairlamb*

DOI: 10.2174/0929867325666180426164352

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Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis

Page: [4454 - 4475] Pages: 22

  • * (Excluding Mailing and Handling)

Abstract

Interest in nitroheterocyclic drugs for the treatment of infectious diseases has undergone a resurgence in recent years. Here we review the current status of monocyclic and bicyclic nitroheterocyclic compounds as existing or potential new treatments for visceral leishmaniasis, Chagas’ disease and human African trypanosomiasis. Both monocyclic (nifurtimox, benznidazole and fexinidazole) and bicyclic (pretomanid (PA-824) and delamanid (OPC-67683)) nitro-compounds are prodrugs, requiring enzymatic activation to exert their parasite toxicity. Current understanding of the nitroreductases involved in activation and possible mechanisms by which parasites develop resistance is discussed along with a description of the pharmacokinetic / pharmacodynamic behaviour and chemical structure-activity relationships of drugs and experimental compounds.

Keywords: Human African trypanosomiasis, Chagas' disease, visceral leishmaniasis, nifurtimox, benznidazole, fexinidazole, pretomanid, delamanid, nitro-drugs.

[1]
Stuart, K.; Brun, R.; Croft, S.; Fairlamb, A.; Gürtler, R.E.; McKerrow, J.; Reed, S.; Tarleton, R. Kinetoplastids: related protozoan pathogens, different diseases. J. Clin. Invest., 2008, 118(4), 1301-1310.
[http://dx.doi.org/10.1172/JCI33945] [PMID: 18382742]
[2]
Dodd, M.C.; Stillman, W.B.; Roys, M.; Crosby, C. The in vitro bacteriostatic action of some simple furan derivatives. J. Pharmacol. Exp. Ther., 1944, 82(1), 11-18.
[3]
Miura, K.; Reckendorf, H.K. The nitrofurans. Prog. Med. Chem., 1967, 5, 320-381.
[http://dx.doi.org/10.1016/S0079-6468(08)70446-6] [PMID: 4863165]
[4]
Ang, C.W.; Jarrad, A.M.; Cooper, M.A.; Blaskovich, M.A.T. Nitroimidazoles: molecular fireworks that combat a broad spectrum of infectious diseases. J. Med. Chem., 2017, 60(18), 7636-7657.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00143] [PMID: 28463485]
[5]
Brener, Z. Present status of chemotherapy and chemoprophylaxis of human trypanosomiasis in the western hemisphere. Pharmacol. Ther., 1979, 7(1), 71-90.
[http://dx.doi.org/10.1016/0163-7258(79)90025-1] [PMID: 118471]
[6]
Urbina, J.A. Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Trop., 2010, 115(1-2), 55-68.
[http://dx.doi.org/10.1016/j.actatropica.2009.10.023] [PMID: 19900395]
[7]
Rodriques Coura, J.; de Castro, S.L. A critical review on Chagas disease chemotherapy. Mem. Inst. Oswaldo Cruz, 2002, 97(1), 3-24.
[http://dx.doi.org/10.1590/S0074-02762002000100001] [PMID: 11992141]
[8]
Ferreira, R.C.; Ferreira, L.C. Mutagenicity of nifurtimox and benznidazole in the Salmonella/microsome assay. Braz. J. Med. Biol. Res., 1986, 19(1), 19-25.
[PMID: 3542090]
[9]
Marin-Neto, J.A.; Cunha-Neto, E.; Maciel, B.C.; Simões, M.V. Pathogenesis of chronic Chagas heart disease. Circulation, 2007, 115(9), 1109-1123.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.624296] [PMID: 17339569]
[10]
Morillo, C.A.; Marin-Neto, J.A.; Avezum, A.; Sosa-Estani, S.; Rassi, A., Jr; Rosas, F.; Villena, E.; Quiroz, R.; Bonilla, R.; Britto, C.; Guhl, F.; Velazquez, E.; Bonilla, L.; Meeks, B.; Rao-Melacini, P.; Pogue, J.; Mattos, A.; Lazdins, J.; Rassi, A.; Connolly, S.J.; Yusuf, S. Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. N. Engl. J. Med., 2015, 373(14), 1295-1306.
[http://dx.doi.org/10.1056/NEJMoa1507574] [PMID: 26323937]
[11]
Marin-Neto, J.A.; Rassi, A., Jr; Avezum, A., Jr; Mattos, A.C.; Rassi, A.; Morillo, C.A.; Sosa-Estani, S.; Yusuf, S. The BENEFIT trial: testing the hypothesis that trypanocidal therapy is beneficial for patients with chronic Chagas heart disease. Mem. Inst. Oswaldo Cruz, 2009, 104(Suppl. 1), 319-324.
[http://dx.doi.org/10.1590/S0074-02762009000900042] [PMID: 19753491]
[12]
Fabbro, D.L.; Danesi, E.; Olivera, V.; Codebó, M.O.; Denner, S.; Heredia, C.; Streiger, M.; Sosa-Estani, S. Trypanocide treatment of women infected with Trypanosoma cruzi and its effect on preventing congenital Chagas. PLoS Negl. Trop. Dis., 2014, 8(11)e3312
[http://dx.doi.org/10.1371/journal.pntd.0003312] [PMID: 25411847]
[13]
de Andrade, A.L.; Zicker, F.; de Oliveira, R.M.; Almeida Silva, S.; Luquetti, A.; Travassos, L.R.; Almeida, I.C.; de Andrade, S.S.; de Andrade, J.G.; Martelli, C.M. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet, 1996, 348(9039), 1407-1413.
[http://dx.doi.org/10.1016/S0140-6736(96)04128-1] [PMID: 8937280]
[14]
Altcheh, J.; Moscatelli, G.; Mastrantonio, G.; Moroni, S.; Giglio, N.; Marson, M.E.; Ballering, G.; Bisio, M.; Koren, G.; García-Bournissen, F. Population pharmacokinetic study of benznidazole in pediatric Chagas disease suggests efficacy despite lower plasma concentrations than in adults. PLoS Negl. Trop. Dis., 2014, 8(5)e2907
[http://dx.doi.org/10.1371/journal.pntd.0002907] [PMID: 24853169]
[15]
Fernández, M.L.; Marson, M.E.; Ramirez, J.C.; Mastrantonio, G.; Schijman, A.G.; Altcheh, J.; Riarte, A.R.; Bournissen, F.G. Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole. Mem. Inst. Oswaldo Cruz, 2016, 111(3), 218-221.
[http://dx.doi.org/10.1590/0074-02760150401] [PMID: 26982179]
[16]
Bustamante, J.M.; Craft, J.M.; Crowe, B.D.; Ketchie, S.A.; Tarleton, R.L. New, combined, and reduced dosing treatment protocols cure Trypanosoma cruzi infection in mice. J. Infect. Dis., 2014, 209(1), 150-162.
[http://dx.doi.org/10.1093/infdis/jit420] [PMID: 23945371]
[17]
Janssens, P.G.; De Muynck, A. Clinical trials with “nifurtimox” in African trypanosomiasis. Ann. Soc. Belg. Med. Trop., 1977, 57(4-5), 475-480.
[PMID: 345982]
[18]
Aubé, J. Drug repurposing and the medicinal chemist. ACS Med. Chem. Lett., 2012, 3(6), 442-444.
[http://dx.doi.org/10.1021/ml300114c] [PMID: 24900492]
[19]
Andrews, K.T.; Fisher, G.; Skinner-Adams, T.S. Drug repurposing and human parasitic protozoan diseases. Int. J. Parasitol. Drugs Drug Resist., 2014, 4(2), 95-111.
[http://dx.doi.org/10.1016/j.ijpddr.2014.02.002] [PMID: 25057459]
[20]
Moens, F.; De Wilde, M.; Ngato, K. Essai de traitement au nifurtimox de la trypanosomiase humaine africaine. Ann. Soc. Belg. Med. Trop., 1984, 64(1), 37-43.
[PMID: 6732304]
[21]
Pépin, J.; Milord, F.; Mpia, B.; Meurice, F.; Ethier, L.; DeGroof, D.; Bruneel, H. An open clinical trial of nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness in central Zaire. Trans. R. Soc. Trop. Med. Hyg., 1989, 83(4), 514-517.
[http://dx.doi.org/10.1016/0035-9203(89)90270-8] [PMID: 2694491]
[22]
Pépin, J.; Milord, F.; Meurice, F.; Ethier, L.; Loko, L.; Mpia, B. High-dose nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness: an open trial in central Zaire. Trans. R. Soc. Trop. Med. Hyg., 1992, 86(3), 254-256.
[http://dx.doi.org/10.1016/0035-9203(92)90298-Q] [PMID: 1412646]
[23]
Fairlamb, A.H. Chemotherapy of human African trypanosomiasis: current and future prospects. Trends Parasitol., 2003, 19(11), 488-494.
[http://dx.doi.org/10.1016/j.pt.2003.09.002] [PMID: 14580959]
[24]
Priotto, G.; Fogg, C.; Balasegaram, M.; Erphas, O.; Louga, A.; Checchi, F.; Ghabri, S.; Piola, P. Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda. PLoS Clin. Trials, 2006, 1(8)e39
[http://dx.doi.org/10.1371/journal.pctr.0010039] [PMID: 17160135]
[25]
Bisser, S.; N’Siesi, F.X.; Lejon, V.; Preux, P.M.; Van Nieuwenhove, S.; Miaka Mia Bilenge, C.; Būscher, P. Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. J. Infect. Dis., 2007, 195(3), 322-329.
[http://dx.doi.org/10.1086/510534] [PMID: 17205469]
[26]
Priotto, G.; Kasparian, S.; Mutombo, W.; Ngouama, D.; Ghorashian, S.; Arnold, U.; Ghabri, S.; Baudin, E.; Buard, V.; Kazadi-Kyanza, S.; Ilunga, M.; Mutangala, W.; Pohlig, G.; Schmid, C.; Karunakara, U.; Torreele, E.; Kande, V. Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet, 2009, 374(9683), 56-64.
[http://dx.doi.org/10.1016/S0140-6736(09)61117-X] [PMID: 19559476]
[27]
Eperon, G.; Balasegaram, M.; Potet, J.; Mowbray, C.; Valverde, O.; Chappuis, F. Treatment options for second-stage gambiense human African trypanosomiasis. Expert Rev. Anti Infect. Ther., 2014, 12(11), 1407-1417.
[http://dx.doi.org/10.1586/14787210.2014.959496] [PMID: 25204360]
[28]
Enanga, B.; Keita, M.; Chauvière, G.; Dumas, M.; Bouteille, B. Megazol combined with suramin: a chemotherapy regimen which reversed the CNS pathology in a model of human African trypanosomiasis in mice. Trop. Med. Int. Health, 1998, 3(9), 736-741.
[http://dx.doi.org/10.1046/j.1365-3156.1998.00291.x] [PMID: 9754669]
[29]
Darsaud, A.; Chevrier, C.; Bourdon, L.; Dumas, M.; Buguet, A.; Bouteille, B. Megazol combined with suramin improves a new diagnosis index of the early meningo-encephalitic phase of experimental African trypanosomiasis. Trop. Med. Int. Health, 2004, 9(1), 83-91.
[http://dx.doi.org/10.1046/j.1365-3156.2003.01154.x] [PMID: 14728611]
[30]
Nesslany, F.; Brugier, S.; Mouriès, M.A.; Le Curieux, F.; Marzin, D. In vitro and in vivo chromosomal aberrations induced by megazol. Mutat. Res., 2004, 560(2), 147-158.
[http://dx.doi.org/10.1016/j.mrgentox.2004.02.013] [PMID: 15157652]
[31]
Walsh, J.S.; Miwa, G.T. Bioactivation of drugs: risk and drug design. Annu. Rev. Pharmacol. Toxicol., 2011, 51, 145-167.
[http://dx.doi.org/10.1146/annurev-pharmtox-010510-100514] [PMID: 21210745]
[32]
Torreele, E.; Bourdin Trunz, B.; Tweats, D.; Kaiser, M.; Brun, R.; Mazué, G.; Bray, M.A.; Pécoul, B. Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl. Trop. Dis., 2010, 4(12)e923
[http://dx.doi.org/10.1371/journal.pntd.0000923] [PMID: 21200426]
[33]
Winkelmann, E.; Raether, W. Chemotherapeutically acitve nitro compounds. 4. 5-Nitroimidazoles (Part III). Arzneimittelforschung, 1978, 28(5), 739-749.
[PMID: 107955]
[34]
Jennings, F.W.; Urquhart, G.M. The use of the 2 substituted 5-nitroimidazole, Fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice. Z. Parasitenkd., 1983, 69(5), 577-581.
[http://dx.doi.org/10.1007/BF00926669] [PMID: 6636983]
[35]
Tweats, D.; Bourdin Trunz, B.; Torreele, E. Genotoxicity profile of fexinidazole--a drug candidate in clinical development for human African trypanomiasis (sleeping sickness). Mutagenesis, 2012, 27(5), 523-532.
[http://dx.doi.org/10.1093/mutage/ges015] [PMID: 22539226]
[36]
Tarral, A.; Blesson, S.; Mordt, O.V.; Torreele, E.; Sassella, D.; Bray, M.A.; Hovsepian, L.; Evène, E.; Gualano, V.; Felices, M.; Strub-Wourgaft, N. Determination of an optimal dosing regimen for fexinidazole, a novel oral drug for the treatment of human African trypanosomiasis: first-in-human studies. Clin. Pharmacokinet., 2014, 53(6), 565-580.
[http://dx.doi.org/10.1007/s40262-014-0136-3] [PMID: 24535888]
[37]
Kaiser, M.; Bray, M.A.; Cal, M.; Bourdin Trunz, B.; Torreele, E.; Brun, R. Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrob. Agents Chemother., 2011, 55(12), 5602-5608.
[http://dx.doi.org/10.1128/AAC.00246-11] [PMID: 21911566]
[38]
Sokolova, A.Y.; Wyllie, S.; Patterson, S.; Oza, S.L.; Read, K.D.; Fairlamb, A.H. Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis. Antimicrob. Agents Chemother., 2010, 54(7), 2893-2900.
[http://dx.doi.org/10.1128/AAC.00332-10] [PMID: 20439607]
[39]
Mesu, V.K.B.K.; Kalonji, W.M.; Bardonneau, C.; Mordt, O.V.; Blesson, S.; Simon, F.; Delhomme, S.; Bernhard, S.; Kuziena, W.; Lubaki, J.F.; Vuvu, S.L.; Ngima, P.N.; Mbembo, H.M.; Ilunga, M.; Bonama, A.K.; Heradi, J.A.; Solomo, J.L.L.; Mandula, G.; Badibabi, L.K.; Dama, F.R.; Lukula, P.K.; Tete, D.N.; Lumbala, C.; Scherrer, B.; Strub-Wourgaft, N.; Tarral, A. Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. Lancet, 2018, 391(10116), 144-154.
[http://dx.doi.org/10.1016/S0140-6736(17)32758-7] [PMID: 29113731]
[40]
Wyllie, S.; Patterson, S.; Fairlamb, A.H. Assessing the essentiality of Leishmania donovani nitroreductase and its role in nitro drug activation. Antimicrob. Agents Chemother., 2013, 57(2), 901-906.
[http://dx.doi.org/10.1128/AAC.01788-12] [PMID: 23208716]
[41]
Wyllie, S.; Patterson, S.; Stojanovski, L.; Simeons, F.R.; Norval, S.; Kime, R.; Read, K.D.; Fairlamb, A.H. The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis. Sci. Transl. Med., 2012, 4(119)119re1
[http://dx.doi.org/10.1126/scitranslmed.3003326] [PMID: 22301556]
[42]
DNDi. Fexinidazole / miltefosine combination (VL).. https://www.dndi.org/diseases-projects/portfolio/completed-projects/fexinidazole-vl/ (Accessed Mar. 13 2018).
[43]
DNDi . Progress through partnership; DNDi Annual Report 2016; pp 24-30, DNDi: Geneva,, 2017.
[44]
Raether, W.; Seidenath, H. The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica. Ann. Trop. Med. Parasitol., 1983, 77(1), 13-26.
[http://dx.doi.org/10.1080/00034983.1983.11811668] [PMID: 6411009]
[45]
Bahia, M.T.; de Andrade, I.M.; Martins, T.A.; do Nascimento, A.F. Diniz, Lde.F.; Caldas, I.S.; Talvani, A.; Trunz, B.B.; Torreele, E.; Ribeiro, I. Fexinidazole: a potential new drug candidate for Chagas disease. PLoS Negl. Trop. Dis., 2012, 6(11)e1870
[http://dx.doi.org/10.1371/journal.pntd.0001870] [PMID: 23133682]
[46]
Bahia, M.T.; Nascimento, A.F.; Mazzeti, A.L.; Marques, L.F.; Gonçalves, K.R.; Mota, L.W. Diniz, Lde.F.; Caldas, I.S.; Talvani, A.; Shackleford, D.M.; Koltun, M.; Saunders, J.; White, K.L.; Scandale, I.; Charman, S.A.; Chatelain, E. Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease. Antimicrob. Agents Chemother., 2014, 58(8), 4362-4370.
[http://dx.doi.org/10.1128/AAC.02754-13] [PMID: 24841257]
[47]
DNDi. Fexinidazole (Chagas).. https://www.dndi.org/diseases-projects/portfolio/fexinidazole-chagas/ (Accessed March 13 2018).
[48]
DNDi Drug trial for leading parasitic killer of the americas shows mixed results but provides new evidence for improved therapy.. https://www.dndi.org/2013/media-centre/press-releases/e1224/ (Accessed March 13 2018).
[49]
Molina, I.; Gómez i Prat, J.; Salvador, F.; Treviño, B.; Sulleiro, E.; Serre, N.; Pou, D.; Roure, S.; Cabezos, J.; Valerio, L.; Blanco-Grau, A.; Sánchez-Montalvá, A.; Vidal, X.; Pahissa, A. Randomized trial of posaconazole and benznidazole for chronic Chagas’ disease. N. Engl. J. Med., 2014, 370(20), 1899-1908.
[http://dx.doi.org/10.1056/NEJMoa1313122] [PMID: 24827034]
[50]
Morillo, C.A.; Waskin, H.; Sosa-Estani, S.; Del Carmen Bangher, M.; Cuneo, C.; Milesi, R.; Mallagray, M.; Apt, W.; Beloscar, J.; Gascon, J.; Molina, I.; Echeverria, L.E.; Colombo, H.; Perez-Molina, J.A.; Wyss, F.; Meeks, B.; Bonilla, L.R.; Gao, P.; Wei, B.; McCarthy, M.; Yusuf, S. Benznidazole and posaconazole in eliminating parasites in asymptomatic T. cruzi carriers: The STOP-CHAGAS Trial. J. Am. Coll. Cardiol., 2017, 69(8), 939-947.
[http://dx.doi.org/10.1016/j.jacc.2016.12.023] [PMID: 28231946]
[51]
Mukherjee, T.; Boshoff, H. Nitroimidazoles for the treatment of TB: past, present and future. Future Med. Chem., 2011, 3(11), 1427-1454.
[http://dx.doi.org/10.4155/fmc.11.90] [PMID: 21879846]
[52]
Makarov, V.; Manina, G.; Mikusova, K.; Möllmann, U.; Ryabova, O.; Saint-Joanis, B.; Dhar, N.; Pasca, M.R.; Buroni, S.; Lucarelli, A.P.; Milano, A.; De Rossi, E.; Belanova, M.; Bobovska, A.; Dianiskova, P.; Kordulakova, J.; Sala, C.; Fullam, E.; Schneider, P.; McKinney, J.D.; Brodin, P.; Christophe, T.; Waddell, S.; Butcher, P.; Albrethsen, J.; Rosenkrands, I.; Brosch, R.; Nandi, V.; Bharath, S.; Gaonkar, S.; Shandil, R.K.; Balasubramanian, V.; Balganesh, T.; Tyagi, S.; Grosset, J.; Riccardi, G.; Cole, S.T. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science, 2009, 324(5928), 801-804.
[http://dx.doi.org/10.1126/science.1171583] [PMID: 19299584]
[53]
Stover, C.K.; Warrener, P.; VanDevanter, D.R.; Sherman, D.R.; Arain, T.M.; Langhorne, M.H.; Anderson, S.W.; Towell, J.A.; Yuan, Y.; McMurray, D.N.; Kreiswirth, B.N.; Barry, C.E.; Baker, W.R. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature, 2000, 405(6789), 962-966.
[http://dx.doi.org/10.1038/35016103] [PMID: 10879539]
[54]
Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med., 2006, 3(11)e466
[http://dx.doi.org/10.1371/journal.pmed.0030466] [PMID: 17132069]
[55]
DNDi. New potential TB drugs to be investigated against multiple neglected diseases., https://www.dndi.org/2010/media-centre/press-releases/tbi-dndi-collaboration/ (Accessed Mar. 13 2018).
[56]
Alliance, T.B. Pretomanid. https://www.tballiance.org/portfolio/compound/pretomanid (Accessed Mar. 13 2018).
[57]
Patterson, S.; Wyllie, S.; Stojanovski, L.; Perry, M.R.; Simeons, F.R.; Norval, S.; Osuna-Cabello, M.; De Rycker, M.; Read, K.D.; Fairlamb, A.H. The R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral Leishmaniasis. Antimicrob. Agents Chemother., 2013, 57(10), 4699-4706.
[http://dx.doi.org/10.1128/AAC.00722-13] [PMID: 23856774]
[58]
Gurumurthy, M.; Mukherjee, T.; Dowd, C.S.; Singh, R.; Niyomrattanakit, P.; Tay, J.A.; Nayyar, A.; Lee, Y.S.; Cherian, J.; Boshoff, H.I.; Dick, T.; Barry, C.E., III; Manjunatha, U.H. Substrate specificity of the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles. FEBS J., 2012, 279(1), 113-125.
[http://dx.doi.org/10.1111/j.1742-4658.2011.08404.x] [PMID: 22023140]
[59]
Thompson, A.M.; Marshall, A.J.; Maes, L.; Yarlett, N.; Bacchi, C.J.; Gaukel, E.; Wring, S.A.; Launay, D.; Braillard, S.; Chatelain, E.; Mowbray, C.E.; Denny, W.A. Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides. Bioorg. Med. Chem. Lett., 2018, 28(2), 207-213.
[http://dx.doi.org/10.1016/j.bmcl.2017.10.067] [PMID: 29191556]
[60]
Jacobs, R.T.; Nare, B.; Wring, S.A.; Orr, M.D.; Chen, D.; Sligar, J.M.; Jenks, M.X.; Noe, R.A.; Bowling, T.S.; Mercer, L.T.; Rewerts, C.; Gaukel, E.; Owens, J.; Parham, R.; Randolph, R.; Beaudet, B.; Bacchi, C.J.; Yarlett, N.; Plattner, J.J.; Freund, Y.; Ding, C.; Akama, T.; Zhang, Y.K.; Brun, R.; Kaiser, M.; Scandale, I.; Don, R. SCYX-7158, an orally-active benzoxaborole for the treatment of stage 2 human African trypanosomiasis. PLoS Negl. Trop. Dis., 2011, 5(6)e1151
[http://dx.doi.org/10.1371/journal.pntd.0001151] [PMID: 21738803]
[61]
DNDi. SCYX-2035811.. https://www.dndi.org/diseases-projects/portfolio/completed-projects/nitroimidazole-backup/ (Accessed Feb. 2 2018).
[62]
Gupta, S.; Yardley, V.; Vishwakarma, P.; Shivahare, R.; Sharma, B.; Launay, D.; Martin, D.; Puri, S.K. Nitroimidazo-oxazole compound DNDI-VL-2098: an orally effective preclinical drug candidate for the treatment of visceral leishmaniasis. J. Antimicrob. Chemother., 2015, 70(2), 518-527.
[http://dx.doi.org/10.1093/jac/dku422] [PMID: 25389223]
[63]
Thompson, A.M.; O’Connor, P.D.; Blaser, A.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Martin, D.; Franzblau, S.G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W.A. Repositioning antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for neglected tropical diseases: structure-activity studies on a preclinical candidate for visceral leishmaniasis. J. Med. Chem., 2016, 59(6), 2530-2550.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01699] [PMID: 26901446]
[64]
Mukkavilli, R.; Pinjari, J.; Patel, B.; Sengottuvelan, S.; Mondal, S.; Gadekar, A.; Verma, M.; Patel, J.; Pothuri, L.; Chandrashekar, G.; Koiram, P.; Harisudhan, T.; Moinuddin, A.; Launay, D.; Vachharajani, N.; Ramanathan, V.; Martin, D. In vitro metabolism, disposition, preclinical pharmacokinetics and prediction of human pharmacokinetics of DNDI-VL-2098, a potential oral treatment for Visceral Leishmaniasis. Eur. J. Pharm. Sci., 2014, 65, 147-155.
[http://dx.doi.org/10.1016/j.ejps.2014.09.006] [PMID: 25261338]
[65]
DNDi. VL-2098.. https://www.dndi.org/diseases-projects/portfolio/completed-projects/vl-2098/ (Accessed Mar. 13 2018).
[66]
Shashiprabha, ; Nayak, S.P.; Rao, K.S.; Nagarajan, K.; Shridhara, K.; Torreele, E.; Trunz, B.B. Shashiprabha; Nayak, S. P.; Rao, K. S.; Nagarajan, K.; Shridhara, K.; Torreele, E.; Trunz, B. B. Nitroimidazooxazoles(#) part xxiv, Search for antileishmanial agents: 2,3-dihydro-6- nitroimidazo[2,1-b]oxazoles as potential antileishmanial agents. Indian J. Pharm. Sci., 2014, 76(1), 92-95.
[PMID: 24799745]
[67]
Ryan, N.J.; Lo, J.H. Delamanid: first global approval. Drugs, 2014, 74(9), 1041-1045.
[http://dx.doi.org/10.1007/s40265-014-0241-5] [PMID: 24923253]
[68]
Patterson, S.; Wyllie, S.; Norval, S.; Stojanovski, L.; Simeons, F.R.C.; Auer, J.L.; Osuna-Cabello, M.; Read, K.D.; Fairlamb, A.H. The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis. eLife, 2016, 5e09744 .
[http://dx.doi.org/10.7554/eLife.09744] [PMID: 27215734]
[69]
Wyllie, S.; Roberts, A.J.; Norval, S.; Patterson, S.; Foth, B.J.; Berriman, M.; Read, K.D.; Fairlamb, A.H. Activation of bicyclic nitro-drugs by a novel nitroreductase (NTR2) in Leishmania. PLoS Pathog., 2016, 12(11)e1005971
[http://dx.doi.org/10.1371/journal.ppat.1005971] [PMID: 27812217]
[70]
Smith, D.A.; Di, L.; Kerns, E.H. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat. Rev. Drug Discov., 2010, 9(12), 929-939.
[http://dx.doi.org/10.1038/nrd3287] [PMID: 21119731]
[71]
Shimokawa, Y.; Sasahara, K.; Koyama, N.; Kitano, K.; Shibata, M.; Yoda, N.; Umehara, K. Metabolic mechanism of delamanid, a new anti-tuberculosis drug, in human plasma. Drug Metab. Dispos., 2015, 43(8), 1277-1283.
[http://dx.doi.org/10.1124/dmd.115.064550] [PMID: 26055621]
[72]
Sasahara, K.; Shimokawa, Y.; Hirao, Y.; Koyama, N.; Kitano, K.; Shibata, M.; Umehara, K. Pharmacokinetics and metabolism of delamanid, a novel anti-tuberculosis drug, in animals and humans: importance of albumin metabolism in vivo. Drug Metab. Dispos., 2015, 43(8), 1267-1276.
[http://dx.doi.org/10.1124/dmd.115.064527] [PMID: 26055620]
[73]
Committee for Medicinal Products for Human Use. Assessment Report: Deltyba - International non-proprietary name: delamanid; EMEA/H/C/002552; European Medicines Agency: London, Dec 5, 2013.
[74]
Lewis, M.D.; Francisco, A.F.; Taylor, M.C.; Kelly, J.M. A new experimental model for assessing drug efficacy against Trypanosoma cruzi infection based on highly sensitive in vivo imaging. J. Biomol. Screen., 2015, 20(1), 36-43.
[http://dx.doi.org/10.1177/1087057114552623] [PMID: 25296657]
[75]
Thompson, A.M.; Blaser, A.; Palmer, B.D.; Anderson, R.F.; Shinde, S.S.; Launay, D.; Chatelain, E.; Maes, L.; Franzblau, S.G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W.A. 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases. Bioorg. Med. Chem. Lett., 2017, 27(11), 2583-2589.
[http://dx.doi.org/10.1016/j.bmcl.2017.03.069] [PMID: 28462832]
[76]
Thompson, A.M.; O’Connor, P.D.; Marshall, A.J.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Braillard, S.; Chatelain, E.; Franzblau, S.G.; Wan, B.; Wang, Y.; Ma, Z.; Cooper, C.B.; Denny, W.A. 7-Substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: novel antitubercular agents lead to a new preclinical candidate for visceral leishmaniasis. J. Med. Chem., 2017, 60(10), 4212-4233.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00034] [PMID: 28459575]
[77]
DNDi. DNDI-0690 Nitroimidazole. https://www.dndi.org/diseases-projects/portfolio/nitroimidazole/
[78]
Thompson, A.M.; O’Connor, P.D.; Marshall, A.J.; Blaser, A.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Braillard, S.; Chatelain, E.; Wan, B.; Franzblau, S.G.; Ma, Z.; Cooper, C.B.; Denny, W.A. Development of (6 R)-2-nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A new lead for visceral leishmaniasis. J. Med. Chem., 2018, 61(6), 2329-2352.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01581] [PMID: 29461823]
[79]
Bruhn, D.F.; Wyllie, S.; Rodríguez-Cortés, A.; Carrillo, A.K. Rakesh; Guy, R.K.; Fairlamb, A.H.; Lee, R.E. Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes. J. Antimicrob. Chemother., 2016, 71(4), 956-963.
[http://dx.doi.org/10.1093/jac/dkv417] [PMID: 26682963]
[80]
Romero, A.H.; Rodríguez, J.; García-Marchan, Y.; Leañez, J.; Serrano-Martín, X.; López, S.E. Aryl- or heteroaryl-based hydrazinylphthalazine derivatives as new potential antitrypanosomal agents. Bioorg. Chem., 2017, 72, 51-56.
[http://dx.doi.org/10.1016/j.bioorg.2017.03.008] [PMID: 28359970]
[81]
Papadopoulou, M.V.; Bloomer, W.D.; Rosenzweig, H.S.; Wilkinson, S.R.; Szular, J.; Kaiser, M. Nitrotriazole-based acetamides and propanamides with broad spectrum antitrypanosomal activity. Eur. J. Med. Chem., 2016, 123, 895-904.
[http://dx.doi.org/10.1016/j.ejmech.2016.08.002] [PMID: 27543881]
[82]
Fonseca-Berzal, C.; Ibáñez-Escribano, A.; Reviriego, F.; Cumella, J.; Morales, P.; Jagerovic, N.; Nogal-Ruiz, J.J.; Escario, J.A.; da Silva, P.B. Soeiro, Mde.N.; Gómez-Barrio, A.; Arán, V.J. Antichagasic and trichomonacidal activity of 1-substituted 2-benzyl-5-nitroindazolin-3-ones and 3-alkoxy-2-benzyl-5-nitro-2H-indazoles. Eur. J. Med. Chem., 2016, 115, 295-310.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.036] [PMID: 27017556]
[83]
Dikhit, M.R.; Purkait, B.; Singh, R.; Sahoo, B.R.; Kumar, A.; Kar, R.K.; Ansari, M.Y.; Saini, S.; Abhishek, K.; Sahoo, G.C.; Das, S.; Das, P. Activity of a novel sulfonamide compound 2-nitro-N-(pyridin-2-ylmethyl)benzenesulfona-mide against Leishmania donovani. Drug Des. Devel. Ther., 2016, 10, 1753-1761.
[PMID: 27307706]
[84]
Olmo, F.; Gómez-Contreras, F.; Navarro, P.; Marín, C.; Yunta, M.J.; Cano, C.; Campayo, L.; Martín-Oliva, D.; Rosales, M.J.; Sánchez-Moreno, M. Synthesis and evaluation of in vitro and in vivo trypanocidal properties of a new imidazole-containing nitrophthalazine derivative. Eur. J. Med. Chem., 2015, 106, 106-119.
[http://dx.doi.org/10.1016/j.ejmech.2015.10.034] [PMID: 26523668]
[85]
Papadopoulou, M.V.; Bloomer, W.D.; Lepesheva, G.I.; Rosenzweig, H.S.; Kaiser, M.; Aguilera-Venegas, B.; Wilkinson, S.R.; Chatelain, E.; Ioset, J.R. Novel 3-nitrotriazole-based amides and carbinols as bifunctional antichagasic agents. J. Med. Chem., 2015, 58(3), 1307-1319.
[http://dx.doi.org/10.1021/jm5015742] [PMID: 25580906]
[86]
Zhou, L.; Stewart, G.; Rideau, E.; Westwood, N.J.; Smith, T.K. A class of 5-nitro-2-furancarboxylamides with potent trypanocidal activity against Trypanosoma brucei in vitro. J. Med. Chem., 2013, 56(3), 796-806.
[http://dx.doi.org/10.1021/jm301215e] [PMID: 23281892]
[87]
Trunz, B.B.; Jędrysiak, R.; Tweats, D.; Brun, R.; Kaiser, M.; Suwiński, J.; Torreele, E. 1-Aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis. Eur. J. Med. Chem., 2011, 46(5), 1524-1535.
[http://dx.doi.org/10.1016/j.ejmech.2011.01.071] [PMID: 21353728]
[88]
Papadopoulou, M.V.; Bloomer, W.D.; Rosenzweig, H.S.; Wilkinson, S.R.; Szular, J.; Kaiser, M. Antitrypanosomal activity of 5-nitro-2-aminothiazole-based compounds. Eur. J. Med. Chem., 2016, 117, 179-186.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.010] [PMID: 27092415]
[89]
Docampo, R.; Stoppani, A.O. Generation of superoxide anion and hydrogen peroxide induced by nifurtimox in Trypanosoma cruzi. Arch. Biochem. Biophys., 1979, 197(1), 317-321.
[http://dx.doi.org/10.1016/0003-9861(79)90251-0] [PMID: 232403]
[90]
Docampo, R.; Moreno, S.N.J.; Stoppani, A.O.M.; Leon, W.; Cruz, F.S.; Villalta, F.; Muniz, R.F. Mechanism of nifurtimox toxicity in different forms of Trypanosoma cruzi. Biochem. Pharmacol., 1981, 30(14), 1947-1951.
[http://dx.doi.org/10.1016/0006-2952(81)90204-5] [PMID: 7023488]
[91]
Moreno, S.N.J.; Mason, R.P.; Docampo, R. Reduction of nifurtimox and nitrofurantoin to free radical metabolites by rat liver mitochondria. Evidence of an outer membrane-located nitroreductase. J. Biol. Chem., 1984, 259(10), 6298-6305.
[PMID: 6327675]
[92]
Docampo, R.; Moreno, S.N.J. Free radical metabolites in the mode of action of chemotherapeutic agents and phagocytic cells on Trypanosoma cruzi. Rev. Infect. Dis., 1984, 6(2), 223-238.
[http://dx.doi.org/10.1093/clinids/6.2.223] [PMID: 6328615]
[93]
Blumenstiel, K.; Schöneck, R.; Yardley, V.; Croft, S.L.; Krauth-Siegel, R.L. Nitrofuran drugs as common subversive substrates of Trypanosoma cruzi lipoamide dehydrogenase and trypanothione reductase. Biochem. Pharmacol., 1999, 58(11), 1791-1799.
[http://dx.doi.org/10.1016/S0006-2952(99)00264-6] [PMID: 10571254]
[94]
Viodé, C.; Bettache, N.; Cenas, N.; Krauth-Siegel, R.L.; Chauvière, G.; Bakalara, N.; Périé, J. Enzymatic reduction studies of nitroheterocycles. Biochem. Pharmacol., 1999, 57(5), 549-557.
[http://dx.doi.org/10.1016/S0006-2952(98)00324-4] [PMID: 9952319]
[95]
Henderson, G.B.; Ulrich, P.; Fairlamb, A.H.; Rosenberg, I.; Pereira, M.; Sela, M.; Cerami, A. “Subversive” substrates for the enzyme trypanothione disulfide reductase: alternative approach to chemotherapy of Chagas disease. Proc. Natl. Acad. Sci. USA, 1988, 85(15), 5374-5378.
[http://dx.doi.org/10.1073/pnas.85.15.5374] [PMID: 3135548]
[96]
Kubata, B.K.; Kabututu, Z.; Nozaki, T.; Munday, C.J.; Fukuzumi, S.; Ohkubo, K.; Lazarus, M.; Maruyama, T.; Martin, S.K.; Duszenko, M.; Urade, Y. A key role for old yellow enzyme in the metabolism of drugs by Trypanosoma cruzi. J. Exp. Med., 2002, 196(9), 1241-1251.
[http://dx.doi.org/10.1084/jem.20020885] [PMID: 12417633]
[97]
Patterson, S.; Wyllie, S. Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects. Trends Parasitol., 2014, 30(6), 289-298.
[http://dx.doi.org/10.1016/j.pt.2014.04.003] [PMID: 24776300]
[98]
Berriman, M.; Ghedin, E.; Hertz-Fowler, C.; Blandin, G.; Renauld, H.; Bartholomeu, D.C.; Lennard, N.J.; Caler, E.; Hamlin, N.E.; Haas, B.; Böhme, U.; Hannick, L.; Aslett, M.A.; Shallom, J.; Marcello, L.; Hou, L.; Wickstead, B.; Alsmark, U.C.; Arrowsmith, C.; Atkin, R.J.; Barron, A.J.; Bringaud, F.; Brooks, K.; Carrington, M.; Cherevach, I.; Chillingworth, T.J.; Churcher, C.; Clark, L.N.; Corton, C.H.; Cronin, A.; Davies, R.M.; Doggett, J.; Djikeng, A.; Feldblyum, T.; Field, M.C.; Fraser, A.; Goodhead, I.; Hance, Z.; Harper, D.; Harris, B.R.; Hauser, H.; Hostetler, J.; Ivens, A.; Jagels, K.; Johnson, D.; Johnson, J.; Jones, K.; Kerhornou, A.X.; Koo, H.; Larke, N.; Landfear, S.; Larkin, C.; Leech, V.; Line, A.; Lord, A.; Macleod, A.; Mooney, P.J.; Moule, S.; Martin, D.M.; Morgan, G.W.; Mungall, K.; Norbertczak, H.; Ormond, D.; Pai, G.; Peacock, C.S.; Peterson, J.; Quail, M.A.; Rabbinowitsch, E.; Rajandream, M.A.; Reitter, C.; Salzberg, S.L.; Sanders, M.; Schobel, S.; Sharp, S.; Simmonds, M.; Simpson, A.J.; Tallon, L.; Turner, C.M.; Tait, A.; Tivey, A.R.; Van Aken, S.; Walker, D.; Wanless, D.; Wang, S.; White, B.; White, O.; Whitehead, S.; Woodward, J.; Wortman, J.; Adams, M.D.; Embley, T.M.; Gull, K.; Ullu, E.; Barry, J.D.; Fairlamb, A.H.; Opperdoes, F.; Barrell, B.G.; Donelson, J.E.; Hall, N.; Fraser, C.M.; Melville, S.E.; El-Sayed, N.M. The genome of the African trypanosome Trypanosoma brucei. Science, 2005, 309(5733), 416-422.
[http://dx.doi.org/10.1126/science.1112642] [PMID: 16020726]
[99]
El-Sayed, N.M.; Myler, P.J.; Blandin, G.; Berriman, M.; Crabtree, J.; Aggarwal, G.; Caler, E.; Renauld, H.; Worthey, E.A.; Hertz-Fowler, C.; Ghedin, E.; Peacock, C.; Bartholomeu, D.C.; Haas, B.J.; Tran, A.N.; Wortman, J.R.; Alsmark, U.C.M.; Angiuoli, S.; Anupama, A.; Badger, J.; Bringaud, F.; Cadag, E.; Carlton, J.M.; Cerqueira, G.C.; Creasy, T.; Delcher, A.L.; Djikeng, A.; Embley, T.M.; Hauser, C.; Ivens, A.C.; Kummerfeld, S.K.; Pereira-Leal, J.B.; Nilsson, D.; Peterson, J.; Salzberg, S.L.; Shallom, J.; Silva, J.C.; Sundaram, J.; Westenberger, S.; White, O.; Melville, S.E.; Donelson, J.E.; Andersson, B.; Stuart, K.D.; Hall, N. Comparative genomics of trypanosomatid parasitic protozoa. Science, 2005, 309(5733), 404-409.
[http://dx.doi.org/10.1126/science.1112181] [PMID: 16020724]
[100]
Ivens, A.C.; Peacock, C.S.; Worthey, E.A.; Murphy, L.; Aggarwal, G.; Berriman, M.; Sisk, E.; Rajandream, M.A.; Adlem, E.; Aert, R.; Anupama, A.; Apostolou, Z.; Attipoe, P.; Bason, N.; Bauser, C.; Beck, A.; Beverley, S.M.; Bianchettin, G.; Borzym, K.; Bothe, G.; Bruschi, C.V.; Collins, M.; Cadag, E.; Ciarloni, L.; Clayton, C.; Coulson, R.M.; Cronin, A.; Cruz, A.K.; Davies, R.M.; De Gaudenzi, J.; Dobson, D.E.; Duesterhoeft, A.; Fazelina, G.; Fosker, N.; Frasch, A.C.; Fraser, A.; Fuchs, M.; Gabel, C.; Goble, A.; Goffeau, A.; Harris, D.; Hertz-Fowler, C.; Hilbert, H.; Horn, D.; Huang, Y.; Klages, S.; Knights, A.; Kube, M.; Larke, N.; Litvin, L.; Lord, A.; Louie, T.; Marra, M.; Masuy, D.; Matthews, K.; Michaeli, S.; Mottram, J.C.; Müller-Auer, S.; Munden, H.; Nelson, S.; Norbertczak, H.; Oliver, K.; O’neil, S.; Pentony, M.; Pohl, T.M.; Price, C.; Purnelle, B.; Quail, M.A.; Rabbinowitsch, E.; Reinhardt, R.; Rieger, M.; Rinta, J.; Robben, J.; Robertson, L.; Ruiz, J.C.; Rutter, S.; Saunders, D.; Schäfer, M.; Schein, J.; Schwartz, D.C.; Seeger, K.; Seyler, A.; Sharp, S.; Shin, H.; Sivam, D.; Squares, R.; Squares, S.; Tosato, V.; Vogt, C.; Volckaert, G.; Wambutt, R.; Warren, T.; Wedler, H.; Woodward, J.; Zhou, S.; Zimmermann, W.; Smith, D.F.; Blackwell, J.M.; Stuart, K.D.; Barrell, B.; Myler, P.J. The genome of the kinetoplastid parasite, Leishmania major. Science, 2005, 309(5733), 436-442.
[http://dx.doi.org/10.1126/science.1112680] [PMID: 16020728]
[101]
Wilkinson, S.R.; Taylor, M.C.; Horn, D.; Kelly, J.M.; Cheeseman, I. A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes. Proc. Natl. Acad. Sci. USA, 2008, 105(13), 5022-5027.
[http://dx.doi.org/10.1073/pnas.0711014105] [PMID: 18367671]
[102]
Hall, B.S.; Bot, C.; Wilkinson, S.R. Nifurtimox activation by trypanosomal type I nitroreductases generates cytotoxic nitrile metabolites. J. Biol. Chem., 2011, 286(15), 13088-13095.
[http://dx.doi.org/10.1074/jbc.M111.230847] [PMID: 21345801]
[103]
Fairlamb, A.H.; Blackburn, P.; Ulrich, P.; Chait, B.T.; Cerami, A. Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids. Science, 1985, 227(4693), 1485-1487.
[http://dx.doi.org/10.1126/science.3883489] [PMID: 3883489]
[104]
Nogoceke, E.; Gommel, D.U.; Kiess, M.; Kalisz, H.M.; Flohé, L. A unique cascade of oxidoreductases catalyses trypanothione-mediated peroxide metabolism in Crithidia fasciculata. Biol. Chem., 1997, 378(8), 827-836.
[http://dx.doi.org/10.1515/bchm.1997.378.8.827] [PMID: 9377478]
[105]
Henderson, G.B.; Fairlamb, A.H.; Cerami, A. Trypanothione dependent peroxide metabolism in Crithidia fasciculata and Trypanosoma brucei. Mol. Biochem. Parasitol., 1987, 24(1), 39-45.
[http://dx.doi.org/10.1016/0166-6851(87)90113-7] [PMID: 3614271]
[106]
Boiani, M.; Piacenza, L.; Hernández, P.; Boiani, L.; Cerecetto, H.; González, M.; Denicola, A. Mode of action of nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: is oxidative stress involved? Biochem. Pharmacol., 2010, 79(12), 1736-1745.
[http://dx.doi.org/10.1016/j.bcp.2010.02.009] [PMID: 20178775]
[107]
Repetto, Y.; Opazo, E.; Maya, J.D.; Agosin, M.; Morello, A. Glutathione and trypanothione in several strains of Trypanosoma cruzi: effect of drugs. Comp. Biochem. Physiol. B Biochem. Mol. Biol., 1996, 115(2), 281-285.
[http://dx.doi.org/10.1016/0305-0491(96)00112-5] [PMID: 8939007]
[108]
Goijman, S.G.; Frasch, A.C.C.; Stoppani, A.O.M. Damage of Trypanosoma cruzi deoxyribonucleic acid by nitroheterocyclic drugs. Biochem. Pharmacol., 1985, 34(9), 1457-1461.
[http://dx.doi.org/10.1016/0006-2952(85)90684-7] [PMID: 3888226]
[109]
Barreto-Bergter, E.; Hogge, L.; Steele da Cruz, F. Lipid alterations induced by nifurtimox in Trypanosoma cruzi. Mol. Biochem. Parasitol., 1986, 21(3), 221-226.
[http://dx.doi.org/10.1016/0166-6851(86)90127-1] [PMID: 3543670]
[110]
Díaz de Toranzo E.G.; Castro, J.A.; Franke de Cazzulo, B.M.; Cazzulo, J.J. Interaction of benznidazole reactive metabolites with nuclear and kinetoplastic DNA, proteins and lipids from Trypanosoma cruzi. Experientia, 1988, 44(10), 880-881.
[http://dx.doi.org/10.1007/BF01941187] [PMID: 3053234]
[111]
Maya, J.D.; Repetto, Y.; Agosín, M.; Ojeda, J.M.; Tellez, R.; Gaule, C.; Morello, A. Effects of nifurtimox and benznidazole upon glutathione and trypanothione content in epimastigote, trypomastigote and amastigote forms of Trypanosoma cruzi. Mol. Biochem. Parasitol., 1997, 86(1), 101-106.
[http://dx.doi.org/10.1016/S0166-6851(96)02837-X] [PMID: 9178272]
[112]
Hall, B.S.; Wilkinson, S.R. Activation of benznidazole by trypanosomal type I nitroreductases results in glyoxal formation. Antimicrob. Agents Chemother., 2012, 56(1), 115-123.
[http://dx.doi.org/10.1128/AAC.05135-11] [PMID: 22037852]
[113]
Panicucci, R.; McClelland, R.A. 4,5-Dihydro-4,5-dihydroxyimidazoles as products of the reduction of 2-nitroimidazoles. HPLC assay and demonstration of equilibrium transfer of glyoxal to guanine. Can. J. Chem., 1989, 67(12), 2128-2135.
[http://dx.doi.org/10.1139/v89-331]
[114]
Trochine, A.; Creek, D.J.; Faral-Tello, P.; Barrett, M.P.; Robello, C. Benznidazole biotransformation and multiple targets in Trypanosoma cruzi revealed by metabolomics. PLoS Negl. Trop. Dis., 2014, 8(5)e2844
[http://dx.doi.org/10.1371/journal.pntd.0002844] [PMID: 24853684]
[115]
Singh, R.; Manjunatha, U.; Boshoff, H.I.M.; Ha, Y.H.; Niyomrattanakit, P.; Ledwidge, R.; Dowd, C.S.; Lee, I.Y.; Kim, P.; Zhang, L.; Kang, S.; Keller, T.H.; Jiricek, J.; Barry, C.E., III PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science, 2008, 322(5906), 1392-1395.
[http://dx.doi.org/10.1126/science.1164571] [PMID: 19039139]
[116]
Dogra, M.; Palmer, B.D.; Bashiri, G.; Tingle, M.D.; Shinde, S.S.; Anderson, R.F.; O’Toole, R.; Baker, E.N.; Denny, W.A.; Helsby, N.A. Comparative bioactivation of the novel anti-tuberculosis agent PA-824 in Mycobacteria and a subcellular fraction of human liver. Br. J. Pharmacol., 2011, 162(1), 226-236.
[http://dx.doi.org/10.1111/j.1476-5381.2010.01040.x] [PMID: 20955364]
[117]
Fairlamb, A.H.; Gow, N.A.R.; Matthews, K.R.; Waters, A.P. Drug resistance in eukaryotic microorganisms. Nat. Microbiol., 2016, 1(7), 16092.
[http://dx.doi.org/10.1038/nmicrobiol.2016.92] [PMID: 27572976]
[118]
Andrade, S.G.; Magalhães, J.B.; Pontes, A.L. Evaluation of chemotherapy with benznidazole and nifurtimox in mice infected with Trypanosoma cruzi strains of different types. Bull. World Health Organ., 1985, 63(4), 721-726.
[PMID: 3936634]
[119]
Filardi, L.S.; Brener, Z. Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease. Trans. R. Soc. Trop. Med. Hyg., 1987, 81(5), 755-759.
[http://dx.doi.org/10.1016/0035-9203(87)90020-4] [PMID: 3130683]
[120]
Andrade, S.G.; Rassi, A.; Magalhaes, J.B.; Ferriolli Filho, F.; Luquetti, A.O. Specific chemotherapy of Chagas disease: a comparison between the response in patients and experimental animals inoculated with the same strains. Trans. R. Soc. Trop. Med. Hyg., 1992, 86(6), 624-626.
[http://dx.doi.org/10.1016/0035-9203(92)90156-7] [PMID: 1287919]
[121]
Neal, R.A.; van Bueren, J. Comparative studies of drug susceptibility of five strains of Trypanosoma cruzi in vivo and in vitro. Trans. R. Soc. Trop. Med. Hyg., 1988, 82(5), 709-714.
[http://dx.doi.org/10.1016/0035-9203(88)90208-8] [PMID: 3075357]
[122]
Moreno, M.; D’ávila, D.A.; Silva, M.N.; Galvão, L.M.C.; Macedo, A.M.; Chiari, E.; Gontijo, E.D.; Zingales, B. Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease. Mem. Inst. Oswaldo Cruz, 2010, 105(7), 918-924.
[http://dx.doi.org/10.1590/S0074-02762010000700014] [PMID: 21120364]
[123]
Murta, S.M.; Ropert, C.; Alves, R.O.; Gazzinelli, R.T.; Romanha, A.J. In-vivo treatment with benznidazole enhances phagocytosis, parasite destruction and cytokine release by macrophages during infection with a drug-susceptible but not with a derived drug-resistant Trypansoma cruzi population. Parasite Immunol., 1999, 21(10), 535-544.
[http://dx.doi.org/10.1046/j.1365-3024.1999.00251.x] [PMID: 10610497]
[124]
Lewis, M.D.; Francisco, A.F.; Taylor, M.C.; Jayawardhana, S.; Kelly, J.M. Host and parasite genetics shape a link between Trypanosoma cruzi infection dynamics and chronic cardiomyopathy. Cell. Microbiol., 2016, 18(10), 1429-1443.
[http://dx.doi.org/10.1111/cmi.12584] [PMID: 26918803]
[125]
Tarleton, R.L. Chagas disease: a role for autoimmunity? Trends Parasitol., 2003, 19(10), 447-451.
[http://dx.doi.org/10.1016/j.pt.2003.08.008] [PMID: 14519582]
[126]
Lewis, M.D.; Fortes Francisco, A.; Taylor, M.C.; Burrell-Saward, H.; McLatchie, A.P.; Miles, M.A.; Kelly, J.M. Bioluminescence imaging of chronic Trypanosoma cruzi infections reveals tissue-specific parasite dynamics and heart disease in the absence of locally persistent infection. Cell. Microbiol., 2014, 16(9), 1285-1300.
[http://dx.doi.org/10.1111/cmi.12297] [PMID: 24712539]
[127]
Henriques, C.; Henriques-Pons, A.; Meuser-Batista, M.; Ribeiro, A.S.; de Souza, W. In vivo imaging of mice infected with bioluminescent Trypanosoma cruzi unveils novel sites of infection. Parasit. Vectors, 2014, 7, 89.
[http://dx.doi.org/10.1186/1756-3305-7-89] [PMID: 24589192]
[128]
Campos, M.C.; Leon, L.L.; Taylor, M.C.; Kelly, J.M. Benznidazole-resistance in Trypanosoma cruzi: evidence that distinct mechanisms can act in concert. Mol. Biochem. Parasitol., 2014, 193(1), 17-19.
[http://dx.doi.org/10.1016/j.molbiopara.2014.01.002] [PMID: 24462750]
[129]
Mejia, A.M.; Hall, B.S.; Taylor, M.C.; Gómez-Palacio, A.; Wilkinson, S.R.; Triana-Chávez, O.; Kelly, J.M. Benznidazole-resistance in Trypanosoma cruzi is a readily acquired trait that can arise independently in a single population. J. Infect. Dis., 2012, 206(2), 220-228.
[http://dx.doi.org/10.1093/infdis/jis331] [PMID: 22551809]
[130]
Mejía-Jaramillo, A.M.; Fernández, G.J.; Palacio, L.; Triana-Chávez, O. Gene expression study using real-time PCR identifies an NTR gene as a major marker of resistance to benzonidazole in Trypanosoma cruzi. Parasit. Vectors, 2011, 4, 169.
[http://dx.doi.org/10.1186/1756-3305-4-169] [PMID: 21892937]
[131]
Murta, S.M.F.; Krieger, M.A.; Montenegro, L.R.; Campos, F.F.M.; Probst, C.M.; Avila, A.R.; Muto, N.H.; de Oliveira, R.C.; Nunes, L.R.; Nirdé, P.; Bruna-Romero, O.; Goldenberg, S.; Romanha, A.J. Deletion of copies of the gene encoding old yellow enzyme (TcOYE), a NAD(P)H flavin oxidoreductase, associates with in vitro-induced benznidazole resistance in Trypanosoma cruzi. Mol. Biochem. Parasitol., 2006, 146(2), 151-162.
[http://dx.doi.org/10.1016/j.molbiopara.2005.12.001] [PMID: 16442642]
[132]
Andrade, H.M.; Murta, S.M.F.; Chapeaurouge, A.; Perales, J.; Nirdé, P.; Romanha, A.J. Proteomic analysis of Trypanosoma cruzi resistance to Benznidazole. J. Proteome Res., 2008, 7(6), 2357-2367.
[http://dx.doi.org/10.1021/pr700659m] [PMID: 18435557]
[133]
Portal, P.; Fernández Villamil, S.; Alonso, G.D.; De Vas, M.G.; Flawiá, M.M.; Torres, H.N.; Paveto, C. Multiple NADPH-cytochrome P450 reductases from Trypanosoma cruzi suggested role on drug resistance. Mol. Biochem. Parasitol., 2008, 160(1), 42-51.
[http://dx.doi.org/10.1016/j.molbiopara.2008.03.007] [PMID: 18455247]
[134]
Nogueira, F.B.; Ruiz, J.C.; Robello, C.; Romanha, A.J.; Murta, S.M.F. Molecular characterization of cytosolic and mitochondrial tryparedoxin peroxidase in Trypanosoma cruzi populations susceptible and resistant to benznidazole. Parasitol. Res., 2009, 104(4), 835-844.
[http://dx.doi.org/10.1007/s00436-008-1264-1] [PMID: 19018566]
[135]
Temperton, N.J.; Wilkinson, S.R.; Meyer, D.J.; Kelly, J.M. Overexpression of superoxide dismutase in Trypanosoma cruzi results in increased sensitivity to the trypanocidal agents gentian violet and benznidazole. Mol. Biochem. Parasitol., 1998, 96(1-2), 167-176.
[http://dx.doi.org/10.1016/S0166-6851(98)00127-3] [PMID: 9851615]
[136]
Nogueira, F.B.; Krieger, M.A.; Nirdé, P.; Goldenberg, S.; Romanha, A.J.; Murta, S.M. Increased expression of iron-containing superoxide dismutase-A (TcFeSOD-A) enzyme in Trypanosoma cruzi population with in vitro-induced resistance to benznidazole. Acta Trop., 2006, 100(1-2), 119-132.
[http://dx.doi.org/10.1016/j.actatropica.2006.10.004] [PMID: 17113553]
[137]
Trochine, A.; Alvarez, G.; Corre, S.; Faral-Tello, P.; Durán, R.; Batthyany, C.I.; Cerecetto, H.; González, M.; Robello, C. Trypanosoma cruzi chemical proteomics using immobilized benznidazole. Exp. Parasitol., 2014, 140, 33-38.
[http://dx.doi.org/10.1016/j.exppara.2014.03.013] [PMID: 24632192]
[138]
Garavaglia, P.A.; Laverrière, M.; Cannata, J.J.; García, G.A. Putative role of the aldo-keto reductase from Trypanosoma cruzi in benznidazole metabolism. Antimicrob. Agents Chemother., 2016, 60(5), 2664-2670.
[http://dx.doi.org/10.1128/AAC.02185-15] [PMID: 26856844]
[139]
Campos, M.C.; Castro-Pinto, D.B.; Ribeiro, G.A.; Berredo-Pinho, M.M.; Gomes, L.H.; da Silva Bellieny, M.S.; Goulart, C.M.; Echevarria, A.; Leon, L.L. P-glycoprotein efflux pump plays an important role in Trypanosoma cruzi drug resistance. Parasitol. Res., 2013, 112(6), 2341-2351.
[http://dx.doi.org/10.1007/s00436-013-3398-z] [PMID: 23572046]
[140]
Murta, S.M.F.; dos Santos, W.G.; Anacleto, C.; Nirdé, P.; Moreira, E.S.A.; Romanha, A.J. Drug resistance in Trypanosoma cruzi is not associated with amplification or overexpression of P-glycoprotein (PGP) genes. Mol. Biochem. Parasitol., 2001, 117(2), 223-228.
[http://dx.doi.org/10.1016/S0166-6851(01)00350-4] [PMID: 11606233]
[141]
Maina, N.; Maina, K.J.; Mäser, P.; Brun, R. Genotypic and phenotypic characterization of Trypanosoma brucei gambiense isolates from Ibba, South Sudan, an area of high melarsoprol treatment failure rate. Acta Trop., 2007, 104(2-3), 84-90.
[http://dx.doi.org/10.1016/j.actatropica.2007.07.007] [PMID: 17765860]
[142]
Likeufack, A.C.L.; Brun, R.; Fomena, A.; Truc, P. Comparison of the in vitro drug sensitivity of Trypanosoma brucei gambiense strains from West and Central Africa isolated in the periods 1960-1995 and 1999-2004. Acta Trop., 2006, 100(1-2), 11-16.
[http://dx.doi.org/10.1016/j.actatropica.2006.09.003] [PMID: 17078916]
[143]
Jeganathan, S.; Sanderson, L.; Dogruel, M.; Rodgers, J.; Croft, S.; Thomas, S.A. The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-cerebrospinal fluid barriers. J. Pharmacol. Exp. Ther., 2011, 336(2), 506-515.
[http://dx.doi.org/10.1124/jpet.110.172981] [PMID: 21057057]
[144]
Wyllie, S.; Foth, B.J.; Kelner, A.; Sokolova, A.Y.; Berriman, M.; Fairlamb, A.H. Nitroheterocyclic drug resistance mechanisms in Trypanosoma brucei. J. Antimicrob. Chemother., 2016, 71(3), 625-634.
[http://dx.doi.org/10.1093/jac/dkv376] [PMID: 26581221]
[145]
Chung, M.C.; Bosquesi, P.L.; dos Santos, J.L. A prodrug approach to improve the physico-chemical properties and decrease the genotoxicity of nitro compounds. Curr. Pharm. Des., 2011, 17(32), 3515-3526.
[http://dx.doi.org/10.2174/138161211798194512] [PMID: 22074424]
[146]
Deavall, D.G.; Martin, E.A.; Horner, J.M.; Roberts, R. Drug-induced oxidative stress and toxicity. J. Toxicol., 2012, 2012645460.
[http://dx.doi.org/10.1155/2012/645460] [PMID: 22919381]
[147]
Balasubramanian, B.; Pogozelski, W.K.; Tullius, T.D. DNA strand breaking by the hydroxyl radical is governed by the accessible surface areas of the hydrogen atoms of the DNA backbone. Proc. Natl. Acad. Sci. USA, 1998, 95(17), 9738-9743.
[http://dx.doi.org/10.1073/pnas.95.17.9738] [PMID: 9707545]
[148]
Mortelmans, K.; Zeiger, E. The Ames Salmonella/microsome mutagenicity assay. Mutat. Res., 2000, 455(1-2), 29-60.
[http://dx.doi.org/10.1016/S0027-5107(00)00064-6] [PMID: 11113466]
[149]
Collins, A.R. Measuring oxidative damage to DNA and its repair with the comet assay. Biochim. Biophys. Acta, 2014, 1840(2), 794-800.
[http://dx.doi.org/10.1016/j.bbagen.2013.04.022] [PMID: 23618695]
[150]
Hayashi, M. The micronucleus test-most widely used in vivo genotoxicity test. Genes Environ., 2016, 38, 18.
[http://dx.doi.org/10.1186/s41021-016-0044-x] [PMID: 27733885]
[151]
Araldi, R.P.; de Melo, T.C.; Mendes, T.B.; de Sá Júnior, P.L.; Nozima, B.H.; Ito, E.T.; de Carvalho, R.F.; de Souza, E.B.; de Cassia Stocco, R. Using the comet and micronucleus assays for genotoxicity studies: A review. Biomed. Pharmacother., 2015, 72, 74-82.
[http://dx.doi.org/10.1016/j.biopha.2015.04.004] [PMID: 26054678]