Identification of Novel Functionalized Carbohydrazonamides Designed as Chagas Disease Drug Candidates

Author(s): Mayara S.S. do Nascimento, Vitória R.F. Câmara, Juliana S. da Costa, Juliana M.C. Barbosa, Alessandra S.M. Lins, Kelly Salomão, Solange L. de Castro, Samir A. Carvalho, Edson F. da Silva, Carlos A.M. Fraga*

Journal Name: Medicinal Chemistry

Volume 16 , Issue 6 , 2020

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Abstract:

Background: Although several research efforts have been made worldwide to discover novel drug candidates for the treatment of Chagas disease, the nitroimidazole drug benznidazol remains the only therapeutic alternative in the control of this disease. However, this drug presents reduced efficacy in the chronic form of the disease and limited safety after long periods of administration, making it necessary to search for new, more potent and safe prototypes.

Objective: We described herein the synthesis and the trypanocidalaction of new functionalized carbohydrazonamides (2-10) against trypomastigote forms of Trypanosoma cruzi.

Methods: These compounds were designed through the application of molecular hybridization concept between two potent anti-T. cruzi prototypes, the nitroimidazole derivative megazol (1) and the cinnamyl N-acylhydrazone derivative (14) which have been shown to be twice as potent in vitro as benznidazole.

Results: The most active compounds were the (Z)-N'-((E)-3-(4-nitrophenyl)-acryloyl)-1-methyl-5- nitro-1H-imidazol-2-carbohydrazonamide (6) (IC50=9.50 μM) and the (Z)-N'-((E)-3-(4- hydroxyphe-nyl)-acryloyl)-1-methyl-5-nitro-1H-imidazol-2-carbohydrazonamide (8) (IC50=12.85 μM), which were almost equipotent to benznidazole (IC50=10.26 μM) used as standard drug. The removal of the amine group attached to the imine subunit in the corresponding N-acylhydrazone derivatives (11-13) resulted in less potent or inactive compounds. The para-hydroxyphenyl derivative (8) presented also a good selectivity index (SI = 32.94) when tested against mammalian cells from Swiss mice.

Conclusion: The promising trypanocidal profile of new carbohydrazonamide derivatives (6) and (8) was characterized. These compounds have proved to be a good starting point for the design of more effective trypanocidal drug candidates.

Keywords: Carbohydrazonamide, N-acythydrazone, molecular hybridization, trypanooldal activity, privileged structure, Chagas disease.

[1]
Rassi, A., Jr; Rassi, A.; Marcondes de Rezende, J. American trypanosomiasis (Chagas disease). Infect. Dis. Clin. North Am., 2012, 26(2), 275-291.
[http://dx.doi.org/10.1016/j.idc.2012.03.002] [PMID: 22632639]
[2]
Rassi, A., Jr; Rassi, A.; Marin-Neto, J.A. Chagas disease. Lancet, 2010, 375(9723), 1388-1402.
[http://dx.doi.org/10.1016/S0140-6736(10)60061-X] [PMID: 20399979]
[3]
DNDi. Disponível em Available at:. www.dndi.org/diseasesprojects/chagas/
[4]
Dias, L.C.; Dessoy, M.A.; Silva, J.J.N.; Thiemann, O.H.; Oliva, G.; Andricupolo, A.D. Chemotherapy of Chagas’ disease: State of the art and perspectives for the development of new drugs. Quim. Nova, 2009, 32(9), 2444-2457.
[http://dx.doi.org/10.1590/S0100-40422009000900038]
[5]
Shikanai-Yasuda, M.A.; Carvalho, N.B. Oral transmission of Chagas disease. Clin. Infect. Dis., 2012, 54(6), 845-852.
[http://dx.doi.org/10.1093/cid/cir956] [PMID: 22238161]
[6]
Wilkinson, S.R.; Bot, C.; Kelly, J.M.; Hall, B.S. Trypanocidal activity of nitroaromatic prodrugs: current treatments and future perspectives. Curr. Top. Med. Chem., 2011, 11(16), 2072-2084.
[http://dx.doi.org/10.2174/156802611796575894] [PMID: 21619510]
[7]
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]
[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]
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]
[10]
Enanga, B.; Ariyanayagam, M.R.; Stewart, M.L.; Barrett, M.P. Activity of megazol, a trypanocidal nitroimidazole, is associated with DNA damage. Antimicrob. Agents Chemother., 2003, 47(10), 3368-3370.
[http://dx.doi.org/10.1128/AAC.47.10.3368-3370.2003] [PMID: 14506061]
[11]
Berkelhammer, G.; Asato, G. 2-Amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3, 4-thiadiazole: a new antimicrobial agent. Science, 1968, 162(3858), 1146.
[http://dx.doi.org/10.1126/science.162.3858.1146] [PMID: 4880722]
[12]
Filardi, L.S.; Brener, Z. A nitroimidazole-thiadiazole derivative with curative action in experimental Trypanosoma cruzi infections. Ann. Trop. Med. Parasitol., 1982, 76(3), 293-297.
[http://dx.doi.org/10.1080/00034983.1982.11687544] [PMID: 6812514]
[13]
Duarte, C.D.; Barreiro, E.J.; Fraga, C.A.M. Privileged structures: a useful concept for the rational design of new lead drug candidates. Mini Rev. Med. Chem., 2007, 7(11), 1108-1119.
[http://dx.doi.org/10.2174/138955707782331722] [PMID: 18045214]
[14]
Fraga, C.A.M.; Barreiro, E.J. Medicinal chemistry of N acylhydrazones: new lead-compounds of analgesic, antiinflammatory and antithrombotic drugs. Curr. Med. Chem., 2006, 13(2), 167-198.
[http://dx.doi.org/10.2174/092986706775197881] [PMID: 16472212]
[15]
Thota, S.; Rodrigues, D.A.; Pinheiro, P.S.M.; Lima, L.M.; Fraga, C.A.M.; Barreiro, E.J. N-Acylhydrazones as drugs. Bioorg. Med. Chem. Lett., 2018, 28(17), 2797-2806.
[http://dx.doi.org/10.1016/j.bmcl.2018.07.015] [PMID: 30006065]
[16]
Li, R.; Chen, X.; Gong, B.; Selzer, P.M.; Li, Z.; Davidson, E.; Kurzban, G.; Miller, R.E.; Nuzum, E.O.; McKerrow, J.H.; Fletterick, R.J.; Gillmor, S.A.; Craik, C.S.; Kuntz, I.D.; Cohen, F.E.; Kenyon, G.L. Structure-based design of parasitic protease inhibitors. Bioorg. Med. Chem., 1996, 4(9), 1421-1427.
[http://dx.doi.org/10.1016/0968-0896(96)00136-8] [PMID: 8894100]
[17]
McGrath, M.E.; Eakin, A.E.; Engel, J.C.; McKerrow, J.H.; Craik, C.S.; Fletterick, R.J. The crystal structure of cruzain: a therapeutic target for Chagas’ disease. J. Mol. Biol., 1995, 247(2), 251-259.
[http://dx.doi.org/10.1006/jmbi.1994.0137] [PMID: 7707373]
[18]
Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E.J.; Fraga, C.A.M. Molecular hybridization: a useful tool in the design of new drug prototypes. Curr. Med. Chem., 2007, 14(17), 1829-1852.
[http://dx.doi.org/10.2174/092986707781058805] [PMID: 17627520]
[19]
Carvalho, S.A.; Feitosa, L.O.; Soares, M.; Costa, T.E.M.M.; Henriques, M.G.; Salomão, K.; de Castro, S.L.; Kaiser, M.; Brun, R.; Wardell, J.L.; Wardell, S.M.S.V.; Trossini, G.H.G.; Andricopulo, A.D.; da Silva, E.F.; Fraga, C.A.M. Design and synthesis of new (E)-cinnamic N-acylhydrazones as potent antitrypanosomal agents. Eur. J. Med. Chem., 2012, 54, 512-521.
[http://dx.doi.org/10.1016/j.ejmech.2012.05.041] [PMID: 22727447]
[20]
Di, L.; Fish, P.V.; Mano, T. Bridging solubility between drug discovery and development. Drug Discov. Today, 2012, 17(9-10), 486-495.
[http://dx.doi.org/10.1016/j.drudis.2011.11.007] [PMID: 22138563]
[21]
Lebedev, A.V.; Lebedeva, A.B.; Sheludyakov, V.D.; Kovaleva, E.A.; Ustinova, O.L.; Kozhevnikov, I.B. Competitive formation of β-amino acids, propenoic, and ylidenemalonic acids by the Rodionov reaction from malonic acid, aldehydes, and ammonium acetate in alcoholic medium. Russ. J. Gen. Chem., 2005, 75(7), 1113-1124.
[http://dx.doi.org/10.1007/s11176-005-0377-9]
[22]
Singh, G.; Bali, S.; Singh, A.K. Palladium(0) complexes of (P,P) and (P,N) ligands immobilized on silica gel as catalysts in selective Heck type carbon–carbon coupling reactions. Polyhedron, 2007, 26, 897-903.
[http://dx.doi.org/10.1016/j.poly.2006.09.043]
[23]
Szymanski, W.; Wu, B.; Weiner, B.; de Wildeman, S.; Feringa, B.L.; Janssen, D.B. Phenylalanine aminomutase-catalyzed addition of ammonia to substituted cinnamic acids: a route to enantiopure alpha- and β-amino acids. J. Org. Chem., 2009, 74(23), 9152-9157.
[http://dx.doi.org/10.1021/jo901833y] [PMID: 19894731]
[24]
Klein, J.; Bergmann, E.D. The reaction of acetals with malonic acid and its derivatives. A contribution to the knowledge of the Knoevenagel-Doebner reaction. J. Am. Chem. Soc., 1957, 79, 2452-2452.
[http://dx.doi.org/10.1021/ja01570a037]
[25]
Zhang, L.; Peng, Z.; Yao, L.; Chunhong, F.; Fengzhen, L.; Xuan, L. Photoalignment of liquid crystals by cinnamate polyelectrolyte layer-by-layer ultrathin film. Appl. Surf. Sci., 2007, 253, 3372-3377.
[http://dx.doi.org/10.1016/j.apsusc.2006.05.050]
[26]
Pearl, I.A.; Beyer, D.L. Reactions of vanillin and its derived compounds. XI. Cinnamic acids derived from vanillin and its related compounds. J. Org. Chem., 1951, 16, 216-220.
[http://dx.doi.org/10.1021/jo01142a008]
[27]
Knoevenagel, E. Condensation von Malondiure mit Aromatiachen Aldehyden durch Ammoniak und Amine. Ber. Dtsch. Chem. Ges., 1898, 31(3), 2596-2619.
[http://dx.doi.org/10.1002/cber.18980310308]
[28]
Doebner, O. Synthesis of sorbic acid. Chem. Ber., 1900, 33, 2140-2142.
[http://dx.doi.org/10.1002/cber.190003302121]
[29]
Zhang, X.; Breslav, M.; Grimm, J.; Guan, K.; Huang, A.; Liu, F.; Maryanoff, C.A.; Palmer, D.; Patel, M.; Qian, Y.; Shaw, C.; Sorgi, K.; Stefanick, S.; Xu, D. A new procedure for preparation of carboxylic acid hydrazides. J. Org. Chem., 2002, 67(26), 9471-9474.
[http://dx.doi.org/10.1021/jo026288n] [PMID: 12492358]
[30]
Vanellel, P.; Maldonadol, J.; Jentzera, O.; Crozet, M.P.; Savomins, B.; Delmass, F.; Gasquet, M.; David, T.P. Fonctionnalisation du méthyl-1-formyl-2-nitro-5-imidazole et recherche de propriétés antiparasitaires. Eur. J. Med. Chem., 1990, 25(4), 321-325.
[http://dx.doi.org/10.1016/0223-5234(90)90115-J]
[31]
Messeder, J.C.; Tinoco, L.W.; Figueroa-Villar, J.D.; Souza, E.M.; Santa Rita, R.; de Castro, S.L. Aromatic guanyl hydrazones: Synthesis, structural studies and in vitro activity against Trypanosoma cruzi. Bioorg. Med. Chem. Lett., 1995, 5(24), 3079-3084.
[http://dx.doi.org/10.1016/0960-894X(95)00541-5]
[32]
Romanha, A.J.; de Castro, S.L.; Soeiro, M.N.; Lannes-Vieira, L.; Ribeiro, I.; Talvani, A.; Bourdin, B.; Blum, B.; Olivieri, B.; Zani, C.; Spadafora, C.; Chiari, E.; Chatelain, E.; Chaves, G.; Calzada, J.E.; Bustamante, J.M.; Freitas-Junior, L.H.; Romero, L.I.; Bahia, M.T.; Lotrowska, M.; Soares, M.; Andrade, S.G.; Armstrong, T.; Degrave, W.; Andrade, Z.A. Experimental in vitro and in vivo models for drug screening and development for Chagas disease. Mem. Inst. Oswaldo Cruz, 2010, 105(2), 233-238.
[http://dx.doi.org/10.1590/S0074-02762010000200022] [PMID: 20428688]


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Article Details

VOLUME: 16
ISSUE: 6
Year: 2020
Published on: 07 September, 2020
Page: [774 - 783]
Pages: 10
DOI: 10.2174/1573406415666190627103013
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