Synthesis of New Thiosemicarbazones and Semicarbazones Containing the 1,2,3-1H-triazole-isatin Scaffold: Trypanocidal, Cytotoxicity, Electrochemical Assays, and Molecular Docking

Author(s): Bianca N.M. Silva, Policarpo A. Sales Junior, Alvaro J. Romanha, Silvane M.F. Murta, Camilo H.S. Lima, Magaly G. Albuquerque, Eliane D'Elia, José G.A. Rodrigues, Vitor F. Ferreira, Fernando C. Silva, Angelo C. Pinto, Bárbara V. Silva*.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most important neglected diseases by the World Health Organization. The only drugs with proven efficacy against Chagas disease are benznidazole and nifurtimox, however both show adverse effects, poor clinical efficacy, and development of resistance. For these reasons, the search for new effective chemical entities is a challenge to research groups and the pharmaceutical industry.

Objective: Synthesis and evaluation of antitrypanosomal activities of a series of thiosemicarbazones and semicarbazones containing 1,2,3-1H triazole isatin scaffold.

Method: 5'-(4-alkyl/aryl)-1H-1,2,3-triazole-isatins were prepared by Huisgen 1,3-dipolar cycloaddition and the thiosemicarbazones and semicarbazones were obtained by the 1:1 reactions of the carbonylated derivatives with thiosemicarbazide and semicarbazide hydrochloride, respectively, in methanol, using conventional reflux or microwave heating. The compounds were assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Beyond the thio/semicarbazone derivatives, isatin and triazole synthetic intermediates were also evaluated for comparison.

Results: A series of compounds were prepared in good yields. Among the 37 compounds evaluated, 18 were found to be active, in particular thiosemicarbazones containing a non-polar saturated alkyl chain (IC50 = 24.1, 38.6, and 83.2 µM; SI = 11.6, 11.8, and 14.0, respectively). To further elucidate the mechanism of action of these new compounds, the redox behaviour of some active and inactive derivatives was studied by cyclic voltammetry. Molecular docking studies were also performed in two validated protein targets of Trypanosoma cruzi, i.e., cruzipain (CRZ) and phosphodiesterase C (TcrPDEC).

Conclusion: A class of thio/semicarbazones structurally simple and easily accessible was synthesized. Compounds containing thiosemicarbazone moieties showed the best results in the series, being more active than the corresponding semicarbazones. Our results indicated that the activity of these compounds does not originate from an oxidation-reduction pathway but probably from the interactions with trypanosomal enzymes.

Keywords: Chagas disease, Trypanosoma cruzi, 1, 2, 3-triazole, isatin, thiosemicarbazone, semicarbazone, trypanocidal.

[1]
Drugs for Neglected Diseases Initiative (DNDi). http://www.dndi.org/diseases-projects/chagas/ (Accessed April 12, 2018).
[2]
Chagas Disease (American trypanosomiasis). World Health Organization (WHO).. http://www.who.int/mediacentre/factsheets/ fs340/en/ (Accessed April 12, 2018).
[3]
Coura, J.R.; Dias, J.C.P. Epidemiology, control and surveillance of Chagas disease - 100 years after its discovery. Mem. Inst. Oswaldo Cruz, 2009, 104(Suppl. 1), 31-40.
[4]
Norman, F.F.; Lopez-Velez, R. Chagas disease and breast-feeding. Emerg. Infect. Dis., 2013, 19, 1561-1566.
[5]
Angheben, A.; Boix, L.; Buonfrate, D.; Gobbi, F.; Bisoffi, Z.; Pupella, S.; Gandini, G.; Aprili, G. Chagas disease and transfusion medicine: a perspective from non-endemic countries. Blood Transfus., 2015, 13, 540-550.
[6]
Drugs for Neglected Diseases Initiative (DNDi). http://www.dndi. org/diseases-projects/chagas/chagas-current-treatments/ (Accessed April 12 2018).
[7]
Coura, J.R.; de Castro, S.L. A critical review on CD chemotherapy. Mem. Inst. Oswaldo Cruz, 2002, 97, 3-24.
[8]
Castro, J.A.; De Mecca, M.M.; Bartel, L.C. Toxic side effects of drugs used to treat CD (American trypanosomiasis). Hum. Exp. Toxicol., 2006, 25, 471-479.
[9]
Jannin, J.; Villa, L. An overview of CD treatment. Mem. Inst. Oswaldo Cruz, 2007, 102(Suppl. 1), 95-97.
[10]
Murta, S.M.F.; Gazzinelli, R.T. Brener, Z.; Romanha, A.J. Molecular characterization of susceptible and naturally resistant strains of Trypanosoma cruzi to benznidazole and nifurtimox. Mol. Biol. Parasitol, 1998, 93, 203-214.
[11]
Drugs for Neglected Diseases initiative (DNDi). http://www.dndi. org/diseases-projects/chagas/chagas-current-treatments/ (Accessed April 12, 2018).
[12]
Machado, F.S.; Tanowitz, H.B.; Teixeira, M.M. New drugs for neglected infectious diseases: Chagas’ disease. Br. J. Pharmacol., 2010, 160, 258-259.
[13]
Silva, B.N.M.; Silva, B.V.; Silva, F.C.; Gonzaga, D.T.; Ferreira, V.F.; Pinto, A.C. Synthesis of novel isatin-type 5′-(4-Alkyl/Aryl-1H-1,2,3-triazoles) via 1,3-dipolar cycloaddition reactions. J. Braz. Chem. Soc., 2013, 24, 1-5.
[14]
Silva, B.N.M.; Pinto, A.C.; Silva, F.C.; Ferreira, V.F.; Silva, B.V. Ultrasound-assisted synthesis of isatin-type 5′-(4-alkyl/aryl-1H-1,2,3-triazoles) via 1,3-dipolar cycloaddition reactions. J. Braz. Chem. Soc., 2016, 27, 2378-2382.
[15]
Chiyanzu, I.; Hansell, E.; Gut, J.; Rosenthal, P.J.; McKerrowb, R.J.; Chibale, K. Synthesis and evaluation of isatins and thiosemicarbazone derivatives against cruzain, falcipain-2 and rhodesain. Bioorg. Med. Chem. Lett., 2003, 13, 3527-3530.
[16]
Guedes, P.M.M.; Urbina, J.A.; Lana, M.; Afonso, L.C.C.; Veloso, V.M.; Tafuri, W.L.; Machado-Coelho, G.L.L.; Chiari, E.; Bahia, M.T. Activity of the new triazole derivative albaconazole against Trypanosoma (Schizotrypanum) cruzi in dog hosts. Antimicrob. Agents. Chemother., 2004, 48, 4286-4292.
[17]
de Andrade, P.; Galo, O.A.; Carvalho, M.R.; Lopes, C.D.; Carneiro, Z.A.; Sesti-Costa, R.; de Melo, E.B.; Silva, J.S.; Carvalho, I. 1,2,3-Triazole-based analogue of benznidazole displays remarkable activity against Trypanosoma cruzi. Bioorg. Med. Chem, 2015, 23, 6815-6826.
[18]
Pelosi, G.; Bisceglie, F.; Bignami, F.; Ronzi, P.; Schiavone, P.; Re, M.C.; Casoli, C.; Pilotti, E. Antiretroviral activity of thiosemicarbazone metal complexes. J. Med. Chem., 2010, 53, 8765-8769.
[19]
Parul, N.; Subhangkar, N.; Arun, M. Antimicrobial activity of diferent thiosemicarbazone compounds against microbial pathogens. IRJP, 2012, 3, 350-363.
[20]
Kalinowski, D.S.; Quach, P.; Richardson, D.R. Thiosemicarbazones: the new wave in cancer treatment. Future Med. Chem, 2009, 1, 1143-1151.
[21]
de Oliveira, R.B.; Souza-Fagundes, E.M.; Soares, R.P.P.; Andrade, A.A.; Krettli, A.U.; Zani, C.L. Synthesis and antimalarial activity of semicarbazone and thiosemicarbazone derivatives. Eur. J. Med. Chem., 2008, 43, 1983-1988.
[22]
Soares, R.O.A.; Echevarria, A.; Bellieny, M.S.; Pinho, R.T.; Leo, R.M.M.; Seguis, W.S.; Machado, G.M.; Canto-Cavalheiro, M.M.; Leon, L.L. Evaluation of thiosemicarbazones and semicarbazones as potential agents anti-Trypanosoma cruzi. Exp. Parasitol., 2011, 129, 381-387.
[23]
Moreira, D.R.M.; Oliveira, A.D.T.; Gomes, P.A.T.M.; Simone, C.A.; Villela, F.S.; Ferreira, R.S.; Silva, A.C.; Santos, T.A.R.; Castro, M.C.A.B.; Pereira, V.R.A.; Leite, A.C.L. Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death. Eur. J. Med. Chem., 2014, 75, 467-478.
[24]
Alves, M.A.; Queiroz, A.C.; Alexandre-Moreira, M.S.; Varela, J.; Cerecetto, H.; González, M.; Doriguetto, A.C.; Landre, I.M.; Barreiro, E.J.; Lima, L.M. Design, synthesis and in vitro trypanocidal and leishmanicidal activities of novel semicarbazone derivatives. Eur. J. Med. Chem., 2015, 100, 24-33.
[25]
Silva, B.V.; Silva, B.N.M. Thio- and semicarbazones: Hope in the search for treatment of Leishmaniasis and Chagas disease. Med. Chem., 2017, 13, 110-126.
[26]
Calvet, C.M.; Vieira, D.F.; Choi, J.Y.; Kellar, D.; Cameron, M.D.; Siqueira-Neto, J.L.; Gut, J.; Johnston, J.B.; Lin, L.; Khan, S.; McKerrow, J.H.; Roush, W.R.; Podust, L.M. 4‑Aminopyridyl-based CYP51 inhibitors as anti-Trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency. J. Med. Chem., 2014, 57, 6989-7005.
[27]
Romanha, A.J.; De Castro, S.L.; Soeiro, M.D.N.C.; Lannes-Vieira, J.; 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-Júnior, L.H.; Romero, L.I.; Bahia, M.T.; Lotrowska, M.; Soares, M.; Andrade, S.G.; Armstrong, T.; Degrave, W.; Andrade, Z.A. In vitro and in vivo experimental models for drug screening and development for Chagas disease. Mem. Inst. Oswaldo Cruz, 2010, 105, 233-238.
[28]
Pires, C.L.; Rodrigues, S.D.; Bristot, D.; Gaeta, H.H.; Toyama, D.O.; Farias, W.R.L.; Toyama, M.H. Evaluation of macroalgae sulfated polysaccharides on the Leishmania (L.) amazonensis promastigote. Mar. Drugs, 2013, 11, 934-943.
[29]
Maximiano, F.P.; Costa, G.H.Y.; Souza, J.; Cunha-Filho, M.S.S. Caracterização físico-química do fármaco antichagásico benznidazol. Quim. Nova, 2010, 33, 1714-1719.
[30]
Scholz, F. (Ed.). Electroanalytical methods (Guide to experiments and applications), 2th ed.; London New York: Springer Heidelberg Dordrecht, 2009.
[31]
Pérez-Silanes, S.; Devarapally, G.; Torres, E.; Moreno-Viguri, E.; Aldana, I.; Monge, A.; Crawford, P.W. Cyclic voltammetric study of some anti-chagas-active 1,4-dioxidoquinoxalin-2-yl ketone derivatives. Helv. Chim. Acta, 2013, 96, 217-227.
[32]
Tonin, L.T.D.; Barbosa, V.A.; Bocca, C.C.; Ramos, E.R.F.; Nakamura, C.V.; Costa, W.F.; Basso, E.A.B.; Nakamura, T.U.; Sarragioto, M.H. Comparative study of the trypanocidal activity of the methyl 1-nitrophenyl-1,2,3,4-9H-tetrahydro-b-carboline-3-carboxy-late derivatives and benznidazole using theoretical calculations and cyclic voltammetry. Eur. J. Med. Chem., 2009, 44, 1745-1750.
[33]
Fernández, M.; Arce, E.R.; Sarniguet, C.; Morais, T.S.; Tomaz, A.I.; Azar, C.O.; Figueroa, R.; Maya, J.D.; Medeiros, A.; Comini, M.; Garcia, M.H.; Otero, L.; Gambino, D. Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites. J. Inorg. Biochem., 2015, 153, 306-314.
[34]
Oliveira, S.C.B.; Fernandes, I.P.G.; Silva, B.V.; Pinto, A.C.; Oliveira-Brett, A.M. Isatin nitro-derivatives redox behavior. J. Electroanal. Chem., 2013, 689, 207-215.
[35]
Diculescu, V.C.; Kumbhat, S.; Oliveira-Brett, A.M. Electrochemical behaviour of isatin at a glassy carbon electrode. . Anal. Chim. Acta, 2006, 575, 190-197.
[36]
Gupta, A.K.; Sindal, R.S. A comparative study of electrochemical reduction of isatin and its synthesized Schiff bases at HMDE J. Chem. Sci, 2009, 121, 347-351.
[37]
Lokesh, S.V.; Satpati, A.K.; Sherigara, B.S. Electrochemical Behavior of 1,2,4-Triazole and benzotriazole at glassy carbon electrode in acidic media T. O. Elec. J., 2010, 2, 15-21.
[38]
Pieretti, S.; Haanstra, J.R.; Mazet, M.; Perozzo, R.; Bergamini, C.; Prati, F.; Fato, R.; Lenaz, G.; Capranico, G.; Brun, R.; Bakker, B.M.; Michels, P.A.M.; Scapozza, L.; Bolognesi, M.L.; Cavalli, A. Naphthoquinone derivatives exert their antitrypanosomal activity via a multi-target mechanism. PLoS Negl. Trop. Dis., 2013, 7, e2012.
[39]
Scotti, L. Filho, F.J.; de Moura, R.O Ribeiro, F.F.; Ishiki, H.; da Silva, M.S.; Filho, J.M.; Scotti, M. T. Multi-target drugs for neglected diseases. Curr. Pharm. Des., 2016, 22, 3135-3163.
[40]
Bolognesi, M.L. Multi-target-directed ligands as innovative tools to combat trypanosomatid diseases. Curr. Top. Med. Chem., 2011, 11, 2824-2833.
[41]
Chiyanzu, I.; Hansell, E.; Gut, J.; Rosenthal, P.J.; McKerrow, J.H.; Chibale, K. Synthesis and evaluation of isatins and thiosemicarbazone derivatives against cruzain, falcipain-2 and rhodesain. Bioorg. Med. Chem. Lett., 2003, 13, 3527-3530.
[42]
Scotti, M.T.; Scotti, L.; Ishiki, H.M.; Peron, L.M.; de Rezende, L.; do Amaral, A.T. Variable-selection approaches to generate QSAR models for a set of antichagasic semicarbazones and analogues. Chemom. Intell. Lab. Syst., 2016, 154, 137-149.
[43]
Nagarsenkar, A.; Guntuku, L.; Guggilapu, S.D.; Bai, K.D.; Gannoju, S.; Naidu, V.G.M.; Bathini, N.B. Synthesis and apoptosis inducing studies of triazole linked 3-benzylidene isatin derivatives. Eur. J. Med. Chem., 2016, 124, 782-793.
[44]
Fernicola, S.; Torquati, I.; Paiardini, A.; Giardina, G.; Rampioni, G.; Messina, M.; Leoni, L.; Del Bello, F.; Petrelli, R.; Rinaldo, S.; Cappellacci, L.; Cutruzzolà, F. Synthesis of triazole-linked analogues of c-di-GMP and their interactions with diguanylate cyclase. J. Med. Chem., 2015, 58, 8269-8284.
[45]
Lipeeva, A.V.; Pokrovsky, M.A.; Baev, D.S.; Shakirov, M.M.; Bagryanskaya, I.Y.; Tolstikova, T.G.; Pokrovsky, A.G.; Shults, E.E. Synthesis of 1H-1,2,3-triazole linked aryl(arylamidomethyl)- dihydrofurocoumarin hybrids and analysis of their cytotoxicity. Eur. J. Med. Chem., 2015, 100, 119-128.
[46]
Mareddy, J.; Nallapati, S.B.; Anireddy, J.; Devi, Y.P.; Mangamoori, L.N.; Kapavarapu, R.; Pal, S. Synthesis and biological evaluation of nimesulide based new class of triazole derivatives as potential PDE4B inhibitors against cancer cells. Bioorg. Med. Chem. Lett., 2013, 23, 6721-6727.
[47]
King-Keller, S.; Li, M.; Smith, A.; Zheng, S.; Kaur, G.; Yang, X.; Wang, B.; Docampo, R. Chemical validation of phosphodiesterase C as a chemotherapeutic target in Trypanosoma cruzi, the etiological agent of Chagas’ disease. Antimicrob. Agents Chemother., 2010, 54, 3738-3745.
[48]
Wiggers, H.J.; Rocha, J.R.; Fernandes, W.B.; Sesti-Costa, R.; Carneiro, Z.A.; Cheleski, J.; da Silva, A.B.F.; Juliano, L.; Cezari, M.H.S.; Silva, J.S.; McKerrow, J.H.; Montanari, C.A. Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay. PLoS Negl. Trop. Dis., 2013, 7, e2370.
[49]
Wang, H.; Kunz, S.; Chen, G.; Seebeck, T.; Wan, Y.; Robinson, H.; Martinelli, S.; Ke, H. Biological and structural characterization of Trypanosoma cruzi phosphodiesterase C and implications for design of parasite selective inhibitors. J. Biol. Chem., 2012, 287, 11788-11797.
[50]
Kontoyianni, M.; McClellan, L.M.; Sokol, G.S. Evaluation of docking performance: comparative data on docking algorithms. J. Med. Chem., 2004, 47, 558-565.
[51]
Buckner, F.S.; Verlinde, C.L.M.J.; La Flamme, A.C.; Van Voorhis, W.C. Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing β-galactosidase. Antimicrob. Agents Chemother., 1996, 40, 2592-2597.
[52]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28, 235-242.
[53]
Dewar, M.J.S. Zoebisch, E.G.; Healy, E.F.; Stewart, J.J.P. AM1: A new general purpose quantum mechanical molecular model. J. Am. Chem. Soc., 1985, 107, 3902-3909.
[54]
Halgren, T.A. Merck molecular force field. I. Basis, form, scope, parameterization and performance of MMFF94. J. Comput. Chem., 1996, 17, 490-519.
[55]
Rocha, G.B.; Freire, R.O.; Simas, A.M.; Stewart, J.J.P. RM1: a reparameterization of AM1 for H, C, N, O, P, S, F, Cl, Br, and I. J. Comput. Chem., 2006, 27, 1101-1111.
[56]
Shao, Y. et al. Advances in methods and algorithms in a modern quantum chemistry program package. Phys. Chem. Chem. Phys., 2006, 8, 3172-3191.
[57]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30, 2785-2791.
[58]
Accelrys Discovery Studio Visualizer (v.3.1) freeware (Accelrys Software Inc; BIOVIA, San Diego, CA, USA).


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [240 - 256]
Pages: 17
DOI: 10.2174/1573406414666180912120502
Price: $58

Article Metrics

PDF: 39
HTML: 7