Synthesis and Antitrypanosomal Profile of Novel Hydrazonoyl Derivatives

Author(s): Natália N. Santiago, Giulianna P. de Alcântara, Juliana S. da Costa, Samir A. Carvalho, Juliana M.C. Barbosa, Kelly Salomão, Solange L. de Castro, Henrique M.G. Pereira, Edson F. da Silva*

Journal Name: Medicinal Chemistry

Volume 16 , Issue 4 , 2020

DOI : 10.2174/1573406415666190712115237

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Abstract:

Background: Approximately, 5-7 million people are infected with T. cruzi in the world, and approximately 10,000 people per year die of complications linked to this disease.

Methods: This work describes the construction of a new family of hidrazonoyl substituted derivatives, structurally designed exploring the molecular hybridization between megazol and nitrofurazone.

Results and Discussion: The compounds were evaluated for their in vitro activity against bloodstream trypomastigotes of Trypanosoma cruzi, etiological agent of Chagas disease, and for their potential toxicity to mammalian cells.

Conclusion: Among these hydrazonoyl derivatives, we identified the derivative (4) that showed trypanocidal activity (IC50/24 h = 15.0 µM) similar to Bz, the standard drug, and low toxicity to mammalian cells, reaching an SI value of 18.7.

Keywords: Hydrazonoyl, megazol, nitrofurazone, Chagas' disease, Trypanosoma cruzi, chemotherapy.

[1]
(a) Altclas, J.D.; Barcan, L.; Nagel, C.; Lattes, R.; Riarte, A. Organ transplantation and Chagas disease. JAMA, 2008, 299(10), 1134.
[http://dx.doi.org/10.1001/jama.299.10.1134-a] [PMID: 18334687]
(b) Dias, J.C.P.; Amato Neto, V. Prevention concerning the different alternative routes for transmission of Trypanosoma cruzi in Brazil. Rev. Soc. Bras. Med. Trop., 2011, 44(Suppl. 2), 68-72.
[http://dx.doi.org/10.1590/S0037-86822011000800011] [PMID: 21584360]
[2]
(a) Schmunis, G.A.; Yadon, Z.E. Chagas disease: A Latin American health problem becoming a world health problem. Acta Trop., 2010, 115(1-2), 14-21.
[http://dx.doi.org/10.1016/j.actatropica.2009.11.003] [PMID: 19932071]
(b) Jackson, Y.; Varcher Herrera, M.; Gascon, J. Economic crisis and increased immigrant mobility: New challenges in managing Chagas disease in Europe. Bull. World Health Organ., 2014, 92(10), 771-772.
[http://dx.doi.org/10.2471/BLT.13.134072] [PMID: 25378732]
[3]
Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Wkly. Epidemiol. Rec., 2015, 90(6), 33-43.
[PMID: 25671846]
[4]
Salomão, K.; Menna-Barreto, R.F.; de Castro, S.L. Stairway to heaven or hell? Perspectives and limitations of chagas disease chemotherapy. Curr. Top. Med. Chem., 2016, 16(20), 2266-2289.
[http://dx.doi.org/10.2174/1568026616666160413125049] [PMID: 27072716]
[5]
Patterson, S.; Fairlamb, A.H. Current and future prospects of nitro-compounds as drugs for Trypanosomiasis and Leishmaniasis. Curr. Med. Chem., 2019, 26, 4454-4475.
[http://dx.doi.org/10.2174/0929867325666180426164352]
[6]
World Health Organization. 19th Model List of Essential Medicines.,. http://www.who.int/medicines/publications/essentialmedi-cines/en/2018.
[7]
(a) Bahia, M.T.; de Andrade, I.M.; Martins, T.A.; do Nascimento, Á.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]
(b) 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]
(c) Simões-Silva, M.R.; De Araújo, J.S.; Oliveira, G.M.; Demarque, K.C.; Peres, R.B.; D’Almeida-Melo, I.; Batista, D.G.J.; Da Silva, C.F.; Cardoso-Santos, C.; Da Silva, P.B.; Batista, M.M.; Bahia, M.T.; Soeiro, M.N.C. Drug repurposing strategy against Trypanosoma cruzi infection: In vitro and in vivo assessment of the activity of metronidazole in mono- and combined therapy. Biochem. Pharmacol., 2017, 145, 46-53.
[http://dx.doi.org/10.1016/j.bcp.2017.08.025] [PMID: 28870526]
(d) Barreira, F.; Blum, B. Update on DNDi clinical studies: BENDITA e FEXI 012., https://www.dndi.org/wp-content/uploads/2018/07/2018Newsletter_Chagas_ING.pdf
[8]
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]
[9]
(a) Chauvière, G.; Bouteille, B.; Enanga, B.; de Albuquerque, C.; Croft, S.L.; Dumas, M.; Périé, J. Synthesis and biological activity of nitro heterocycles analogous to Megazol, a Trypanocidal lead. J. Med. Chem., 2003, 46(3), 427-440.
[PMID: 12540242]
(b) 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]
(c) 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]
[10]
(a) Maya, J.D.; Bollo, S.; Nuñez-Vergara, L.J.; Squella, J.A.; Repetto, Y.; Morello, A.; Périé, J.; Chauvière, G. Trypanosoma cruzi: effect and mode of action of nitroimidazole and nitrofuran derivatives. Biochem. Pharmacol., 2003, 65(6), 999-1006.
[http://dx.doi.org/10.1016/S0006-2952(02)01663-5] [PMID: 12623132]
(b) 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]
[11]
(a) 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]
(b) Poli, P.; Aline de Mello, M.; Buschini, A.; Mortara, R.A.; Northfleet de Albuquerque, C.; da Silva, S.; Rossi, C.; Zucchi, T.M.A.D. Cytotoxic and genotoxic effects of megazol, an anti-Chagas’ disease drug, assessed by different short-term tests. Biochem. Pharmacol., 2002, 64(11), 1617-1627.
[http://dx.doi.org/10.1016/S0006-2952(02)01390-4] [PMID: 12429351]
[12]
(a) Boechat, N.; Carvalho, A.S.; Fernandez-Ferreira, E.; Soares, R.O.; Souza, A.S.; Gibaldi, D.; Bozza, M.; Pinto, A.C. Novel nitroimidazoles with trypanocidal and cell growth inhibition activities. Cytobios, 2001, 105(409), 83-90.
[PMID: 11393774]
(b) Carvalho, S.A.; da Silva, E.F.; Santa-Rita, R.M.; de Castro, S.L.; Fraga, C.A.M. Synthesis and antitrypanosomal profile of new functionalized 1,3,4-thiadiazole-2-arylhydrazone derivatives, designed as non-mutagenic megazol analogues. Bioorg. Med. Chem. Lett., 2004, 14(24), 5967-5970.
[http://dx.doi.org/10.1016/j.bmcl.2004.10.007] [PMID: 15546709]
(c) Carvalho, S.A.; Lopes, F.A.S.; Salomão, K.; Romeiro, N.C.; Wardell, S.M.V.S.; de Castro, S.L.; da Silva, E.F.; Fraga, C.A.M. Studies toward the structural optimization of new brazilizone-related trypanocidal 1,3,4-thiadiazole-2-arylhydrazone derivatives. Bioorg. Med. Chem., 2008, 16(1), 413-421.
[http://dx.doi.org/10.1016/j.bmc.2007.09.027] [PMID: 17904851]
(d) Carvalho, A.S.; Menna-Barreto, R.F.S.; Romeiro, N.C.; de Castro, S.L.; Boechat, N. Design, synthesis and activity against Trypanosoma cruzi of azaheterocyclic analogs of megazol. Med. Chem., 2007, 3(5), 460-465.
[http://dx.doi.org/10.2174/157340607781745519] [PMID: 17897071]
(e) Salomão, K.; de Souza, E.M.; Carvalho, S.A.; da Silva, E.F.; Fraga, C.A.M.; Barbosa, H.S.; de Castro, S.L. In vitro and in vivo activities of 1,3,4-thiadiazole-2-arylhydrazone derivatives of megazol against Trypanosoma cruzi. Antimicrob. Agents Chemother., 2010, 54(5), 2023-2031.
[http://dx.doi.org/10.1128/AAC.01241-09] [PMID: 20231395]
[13]
(a) Brener, Z. Atividade terapêuutica do 5-nitro-2-furaldeido- semicarbazona (nitrofurazona) em esquemas de duração prolongada na infecção experimental do camundongo pelo Trypanosoma cruzi. Rev. Inst. Med. Trop. São Paulo, 1961, 3, 43-49.
(b) Andrade, Z.A.; Brenner, Z. Action of nitrofurazone (5-nitro-2-furaldehyde-semi-carbazone) on the intracellular forms of Trypanosoma cruzi in experimental Chagas’ disease. Rev. Inst. Med. Trop. São Paulo, 1969, 11, 222-228.
[PMID: 4980992]
[14]
(a) de Ferreira, H.O. Acute form of Chagas’ disease treated by nitrofurazone. Rev. Inst. Med. Trop. São Paulo, 1961, 3, 287-289.
[PMID: 13892538]
(b) Rassi, A.; Ferreira, H.O. Tentativas de tratamento específico da fase aguda da doença de Chagas com nitrofuranos em esquemas de duração prolongada. Rev. Soc. Bras. Med. Trop., 1971, 5, 235-262.
[http://dx.doi.org/10.1590/S0037-86821971000500001]
(c) Coura, J.R.; Ferreira, L.F.; Silva, J. Experiências com nitrofurazona na fase crônica da doença de Chagas. Hosp. (Lond.), 1962, 62, 957-964.
[PMID: 14023410]
(d) Cançado, J.R.; Marra, U.D.; Brener, Z. Clinical Therapeutic trial of 5-nitro-2-furaldehyde-semicarbazone (nitrofurazone) in the chronic form of Chagas disease. Rev. Inst. Med. Trop. São Paulo, 1964, 6, 12-16.
[PMID: 14146399]
[15]
Trossini, G.H.; Malvezzi, A. T-do Amaral, A.; Rangel-Yagui, C.O.; Izidoro, M.A.; Cezari, M.H.; Juliano, L.; Chin, C.M.; Menezes, C.M.; Ferreira, E.I. Cruzain inhibition by hydroxymethylnitrofurazone and nitrofurazone: investigation of a new target in Trypanosoma cruzi. J. Enzyme Inhib. Med. Chem., 2010, 25(1), 62-67.
[http://dx.doi.org/10.3109/14756360902941058] [PMID: 20030510]
[16]
Ferreira, L.G.; Andricopulo, A.D. Targeting cysteine proteases in trypanosomatid disease drug discovery. Pharmacol. Ther., 2017, 180, 49-61.
[http://dx.doi.org/10.1016/j.pharmthera.2017.06.004] [PMID: 28579388]
[17]
Bollo, S.; Núñez-Vergara, L.J.; Bontá, M.; Chauviere, G.; Squella, J.A. Cyclic voltammetric studies on nitro radical anion formation from megazol and some related nitroimidazole derivatives. J. Electroanal. Chem. (Lausanne Switz.), 2001, 511(1/2), 46-54.
[http://dx.doi.org/10.1016/S0022-0728(01)00557-5]
[18]
Pinto, A.V.; Pinto, C.N. Pinto, Mdo.C.; Rita, R.S.; Pezzella, C.A.; de Castro, S.L. Trypanocidal activity of synthetic heterocyclic derivatives of active quinones from Tabebuia sp. Arzneimittelforschung, 1997, 47(1), 74-79.
[PMID: 9037448]
[19]
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-Barreto, R.F.S.; Salomão, K.; De Castro, S.L.; Silva Júnior, E.N. On the investigation of hybrid quinones: synthesis, electrochemical studies and evaluation of trypanocidal activity. RSC Advances, 2015, 5, 78047.
[http://dx.doi.org/10.1039/C5RA16213K]
[20]
(a) Albright, J.D.; Shepherd, R.G. 1,2-Disubstituted-5-nitroimidazoles. US Patent 3, 652,555,. 1972.
(b) da Silva, R.B.; Loback, V.B.; Salomão, K.; de Castro, S.L.; Wardell, J.L.; Wardell, S.M.S.V.; Costa, T.E.M.M.; Penido, C.; Henriques, Md.; Carvalho, S.A.; da Silva, E.F.; Fraga, C.A.M. Synthesis and trypanocidal activity of novel 2,4,5-triaryl-N-hydroxylimidazole derivatives. Molecules, 2013, 18(3), 3445-3457.
[http://dx.doi.org/10.3390/molecules18033445] [PMID: 23503118]
[21]
Macco, A.A.; Godefroi, E.F.; Drouen, J.J.M. 2-(2-Imidazolyl) acetophenones. Preparation and some reactions antonius A. J. Org. Chem., 1975, 40, 2.
[22]
(a) Edrees, M.M.; Farghaly, T.A.; El-Hag, F.A.; Abdalla, M.M. Antimicrobial, antitumor and 5α-reductase inhibitor activities of some hydrazonoyl substituted pyrimidinones. Eur. J. Med. Chem., 2010, 45(12), 5702-5707.
[http://dx.doi.org/10.1016/j.ejmech.2010.09.026] [PMID: 20933305]
(b) Yoder, C.H.; Kennedy, S.; Snavely, F.A. Geometric isomerism in the phenylhydrazones of some. α-dicarbonyl compounds. J. Org. Chem., 1978, 43, 1077-1079.
[http://dx.doi.org/10.1021/jo00400a010]
[23]
Sparr, C.; Schweizer, W.B.; Senn, H.M.; Gilmour, R. The fluorine-iminium ion gauche effect: proof of principle and application to asymmetric organocatalysis. Angew. Chem. Int. Ed. Engl., 2009, 48(17), 3065-3068.
[http://dx.doi.org/10.1002/anie.200900405] [PMID: 19322862]
[24]
van Niel, M.B.; Collins, I.; Beer, M.S.; Broughton, H.B.; Cheng, S.K.; Goodacre, S.C.; Heald, A.; Locker, K.L.; MacLeod, A.M.; Morrison, D.; Moyes, C.R.; O’Connor, D.; Pike, A.; Rowley, M.; Russell, M.G.; Sohal, B.; Stanton, J.A.; Thomas, S.; Verrier, H.; Watt, A.P.; Castro, J.L. Fluorination of 3-(3-(piperidin-1-yl)propyl) indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles. J. Med. Chem., 1999, 42(12), 2087-2104.
[http://dx.doi.org/10.1021/jm981133m] [PMID: 10377215]
[25]
Smith, D.A.; van de Waterbeemd, H.; Walker, D.K. Methods and Principles in Medicinal Chemistry, 31; Wiley-VCH: Weinheim, 2006.
[26]
Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science, 2007, 317(5846), 1881-1886.
[http://dx.doi.org/10.1126/science.1131943] [PMID: 17901324]


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VOLUME: 16
ISSUE: 4
Year: 2020
Published on: 21 May, 2020
Page: [487 - 494]
Pages: 8
DOI: 10.2174/1573406415666190712115237
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