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Medicinal Chemistry

Author(s): Fady N. Akladios, Scott D. Andrew, Samantha J. Boog, Carmen de Kock, Richard K. Haynes and Christopher J. Parkinson*

DOI: 10.2174/1573406414666180525132204

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The Evaluation of Metal Co-ordinating Bis-Thiosemicarbazones as Potential Anti-malarial Agents

Page: [51 - 58] Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Background: The emergence of resistance to the artemisinins which are the current mainstays for antimalarial chemotheraphy has created an environment where the development of new drugs acting in a mechanistally discrete manner is a priority.

Objective: The goal of this work was to synthesize ane evaluate bis-thiosemicarbazones as potential antimalarial agents.

Methods: Fifteen compounds were generated using two condensation protocols and evaluated in vitro against the NF54 (CQ sensitive) strain of Plasmodium falciparum. A preliminary assessment of the potential for human toxicity was conducted in vitro against the MRC5 human lung fibroblast line.

Results: The activity of the bis-thiosemicarbazones was highly dependent on the nature of the arene at the core of the structure. The inclusion of a non-coordinating benzene core resulted in inactive compounds, while the inclusion of a pyridyl core resulted in compounds of moderate or potent antimalarial activity (4 compounds showing IC50 < 250 nM).

Conclusion: Bis-thiosemicarbazones containing a central pyridyl core display potent antimalarial activity in vitro. Sequestration and activation of ferric iron appears to play a significant role in this activity. Ongoing studies are aimed at further development of this series as potential antimalarials.

Keywords: Malaria, Plasmodium, thiosemicarbazone, metal coordination, iron, copper, reactive oxygen.

Graphical Abstract

[1]
World Malaria Report, 2016. World Health Organization: Geneva; Available at: www.who.int
[2]
Miller, L.H.; Ackerman, H.C.; Su, X.Z.; Wellems, T.E. Malaria biology and disease pathogenesis: insights for new treatments. Nat. Med., 2013, 19, 156-167.
[3]
Arley, F.; Witkowski, B.; Amaratunga, C.; Beghain, J.; Langlois, A.C.; Khim, N.; Khim, S.; Duru, V.; Boichier, C.; Ma, L.; Lim, P.; Leang, R.; Duong, S.; Sreng, S.; Suon, S.; Chuor, C.M.; Bout, D.M.; Menard, S.; Rogers, W.O.; Genton, B.; Fandeur, T.; Miotto, O.; Ringwald, P.; Le Bras, J.; Berry, A.; Barale, J.C.; Fairhurst, R.M.; Benoit-Vical, F.; Mercereau-Puijalon, O.; Menard, D. A molecular marker of artemisinin-resistant malaria. Nature, 2014, 505, 50-55.
[4]
St Laurent, B.; Miller, B.; Burton, T.A.; Amaratunga, C.; Men, S.; Sovannaroth, S.; Fay, M.P.; Miotto, O.; Gwadz, R.W.; Anderson, J.M.; Fairhurst, R.M. Artemisinin-resistant Plasmodium falciparum clinical isolates can infect diverse mosquito vectors of Southeast Asia and Africa. Nat. Commun., 2015, 6, 8614.
[5]
Dondorp, A.M.; Fairhurst, R.M.; Slutsker, L.; MacArthur, J.R.; Bremen, J.G.; Guerin, P.J.; Wellems, T.E.; Ringwald, P.; Newman, R.D.; Plowe, C.V. The threat of artemisinin-resistant malaria. N. Engl. J. Med., 2011, 365, 1073-1075.
[6]
Phillips, M.A.; Burrows, J.N.; Manyando, C.; van Huijsduijnen, R.H.; Van Voorhis, W.C.; Wells, T.N.C. Malaria. Nat. Rev. Disease Primers., 2017, 3, 1-24. (article number 17050).
[7]
Gamo, F.J.; Sanz, L.M.; Vidal, J.; de Cozar, C.; Alvarez, E.; Lavandera, J.L.; Vanderwall, D.E.; Green, D.V.; Kumar, V.; Hasan, S.; Brown, J.R.; Peishoff, C.E.; Cardon, L.R.; Garcia-Bustos, J.F. Thousands of chemical starting points for antimalarial lead identification. Nature, 2010, 465, 305-310.
[8]
Phyo, A.; Jittamala, P.; Nosten, F.H.; Pukrittayakamee, S.; Imwong, M.; White, N.J.; Duparc, S.; Macintyre, F.; Baker, M.; Möhrle, J.J. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect. Dis., 2016, 16, 61-69.
[9]
White, N.J.; Duong, T.T.; Uthaisin, C.; Nosten, F.; Phyo, A.P.; Hanboonkunupakarn, B.; Pukrittayakamee, S.; Jittamala, P.; Chuthasmit, K.; Cheung, M.S.; Feng, Y.; Li, R. Magnusson, Marc Sultan, M.; Wieser, D.; Xun, X.; Zhao, R.; Diagana, T.T.; Pertel, P.; Leong, F.J. Antimalarial activity of KAF156 in falciparum and vivax malaria. N. Engl. J. Med., 2016, 375, 1152-1160.
[10]
White, N.J.; Pukrittayakamee, S.; Phyo, A.P.; Rueangweerayut, R.; Nosten, F.H.; Jittamala, P.; Jeeyapant, A.; Jain, J.P.; Lefèvre, G.; Li, R.; Magnusson, B.; Diagana, T.T.; Leong, F.J. Spiroindolone KAE609 for falciparum and vivax malaria. N. Engl. J. Med., 2014, 371, 403-410.
[11]
Gu, H.M.; Lu, B.F.; Qu, Z.X. Antimalarial activity of 25 derivatives of artemisinin against chloroquine-resistant Plasmodium berghei. Acta Pharmacol. Sinica., 1980, 1, 48-50.
[12]
Wozencraft, A.O.; Croft, S.L.; Sayers, G. Impairment of macrophage functions after ingestion of Plasmodium falciparum -infected erythrocytes or isolated malarial pigment. Immunology, 1985, 56, 523-531.
[13]
Clark, I.A.; Cowden, W.B.; Butcher, G.A. Free oxygen radicals in malaria. Lancet, 1983, i, 234.
[14]
Bachur, N.R.; Gordon, S.L. A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Gee, M.V. Cancer Res., 1978, 38, 1745-1750.
[15]
Haynes, R.K.; Cheu, K-W.; Chan, H-W.; Wong, H-N.; Li, K-Y.; Tang, M.M-K.; Chen, M.J.; Guo, Z-F.; Guo, Z-H.; Sinniah, K.; Witte, A.B.; Coghi, P.; Monti, D. Interactions between artemisinins and other antimalarial drugs in relation to the cofactor model – a unifying proposal for drug action. ChemMedChem, 2012, 7, 2204-2226.
[16]
Zhang, Y.; Konig, I.; Schirmer, R.H. Glutathione reductase deficient erythrocytes as host cells for malaria parasites. Biochem. Pharmacol., 1988, 37, 861-865.
[17]
Zhang, Y.A.; Hempelmann, E.; Schirmer, R.H. Glutathione reductase inhibitors as potential antimalarial drugs. Effects of nitrosoureas on Plasmodium falciparum in vitro. Biochem. Pharmacol., 1988, 37, 855-860.
[18]
Vennerstrom, J.L.; Eaton, J.W. Oxidants, oxidant drugs and malaria. J. Med. Chem., 1988, 31, 1269-1277.
[19]
Chou, A.C.; Chevli, R.; Fitch, C.D. Ferriprotoporphyrin IX fulfills the criteria for identification as the chloroquine receptor of malaria parasites. Biochemistry, 1980, 19, 1543-1549.
[20]
Slater, A.F.G.; Cerami, A. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature, 1992, 355, 167-169.
[21]
Dorn, A.; Vippagunta, S.R.; Matile, H.; Jaquet, C.; Vennerstrom, J.L.; Ridley, R.G. An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials. Biochem. Pharmacol., 1998, 55, 727-736.
[22]
Meshnick, S.R. Is haemozoin a target for antimalarial drugs? Ann. Trop. Med. Parasitol., 1996, 90, 367-372.
[23]
Mabeza, G.F.; Loyevsky, M.; Gordeuk, V.R.; Weiss, G. Iron chelation therapy for malaria: a review. Pharmacol. Therap., 1999, 81, 53-75.
[24]
Hershko, C.; Peto, T.E. Deferoxamine inhibition of malaria is independent of host iron status. J. Exp. Med., 1988, 168, 375-387.
[25]
Gordeuk, V.R.; Thuma, P.E.; Brittenham, G.M.; Zulu, S.; Simwanza, G.; Mahangu, A.; Flesch, G.; Parry, D. Iron chelation with desferrioxamine B in adults with asymptomatic Plasmodium falciparum parasitemia. Blood, 1992, 79, 308-312.
[26]
Gordeuk, V.R.; Thuma, P.E.; McLaren, C.E.; Biemba, G.; Zulu, S.; Poltera, A.A.; Askin, J.E.; Brittenham, G.M. Transferrin saturation and recovery from coma in cerebral malaria. Blood, 1995, 85, 3297-3301.
[27]
Pradines, B.; Tall, A.; Ramiandrosa, F.; Spiegel, A.; Sokhna, C.; Fusai, T.; Mosnier, J.; Daries, W.; Trape, J.F.; Kunesch, G.; Parzy, D.; Rogier, C.J. In vitro activity of iron-binding compounds against Senegalese isolates of Plasmodium falciparum. J. Antimicrob. Chemother., 2006, 57, 1093-1099.
[28]
Walcourt, A.; Loyevsky, M.; Lovejoy, D.B.; Gordeuk, V.R.; Richardson, D.R. Novel aroylhydrazone and thiosemicarbazone iron chelators with anti-malarial activity against chloroquine-resistant and -sensitive parasites. Int. J. Biochem. Cell Biol., 2004, 36, 401-407.
[29]
Melnyk, P.; Leroux, V.; Sergheraert, C.; Grellier, P. Design, synthesis and in vitro antimalarial activity of an acylhydrazone library. Bioorg. Med. Chem. Lett., 2006, 16, 31-35.
[30]
Tsafack, A.; Loyevsky, M.; Ponka, P.; Ioav Cabantchik, Z. Mode of action of iron(III) chelators as antimalarials. IV. Potentiation of desferal action by benzoyl and isonicotinoyl hydrazone derivatives. J. Lab. Clin. Med., 1996, 127, 574-582.
[31]
Ferrer, P.; Tripathi, A.K.; Clark, M.A.; Hand, C.C.; Reinhoff, H.Y., Jr; Sullivan, D.J., Jr Antimalarial iron chelator, FBS0701, shows asexual and gametocyte Plasmodium falciparum activity and single dose cure in a murine malaria model. PLoS One, 2012, 7, e37171.
[http://dx.doi.org/10.1371/journal.pone.0037171]
[32]
Ferrer, P.; Vega-Rodriguez, J.; Tripathi, A.K.; Jacobs-Lorena, M.; Sullivan, D.J., Jr Antimalarial iron chelator FBS0701 blocks transmission by Plasmodium falciparum gametocyte activation inhibition. Antimicrob. Agents Chemother., 2015, 59, 1418-1426.
[33]
Akladios, F.N.; Andrew, S.D.; Parkinson, C.J. Cytotoxic activity of expanded coordination bis-thiosemicarbazones and copper complexes thereof. J. Biol. Inorg. Chem., 2016, 21, 931-944.
[34]
Pedrido, R.; Bermejo, M.R.; Romero, M.J.; Vázquez, M.; González-Noya, A.M.; Maneiro, M.; Rodríguez, M.J.; Fernández, M.I. Synthesis and X-ray characterisation of metal complexes with the pentadentate thiosemicarbazone ligand bis (4-N-methylthiosemi-carbazone)-2,6-diacetylpyridine. The first pentacoordinate lead(II) complex with a pentagonal geometry. Dalton Transactions., 2005, 572-579.
[35]
Kinfe, H.H.; Belay, Y.H. Synthesis and biological evaluation of novel thiosemicarbazone-triazole hybrid compounds as antimalarial agents. S. Afr. J. Chem., 2013, 66, 130-135.
[36]
Kulandaivelu, U.; Padmini, V.G.; Suneetha, K.; Shireesha, B.; Vidyasagar, J.V.; Rao, T.R.; Jayaveera, K.N.; Basu, A.; Jayaprakash, V. Synthesis, antimicrobial and anticancer activity of new thiosemicarbazone derivatives. Archiv. der Pharmazie. , 2011, 344, 84-90.
[37]
Asahi, H.; Tolba, M.E.M.; Tanabe, M.; Sugano, S.; Abe, K.; Kawamoto, F. Perturbation of copper homeostasis is instrumental in early developmental arrest of intraerythrocytic Plasmodium falciparum. BMC Microbiol., 2014, 14, 167-177.
[38]
Lai, H.; Sasaki, T.; Singh, N.P. Targeted treatment of cancer with artemisinin aand artemisinin-tagged iron carrying compounds. Expert Opin. Ther. Targets, 2005, 9, 995-1007.
[39]
Miller, M.J.; Walz, A.J.; Zhu, H.; Wu, C.; Moraski, G.; Mollman, U.; Tristani, E.M.; Crumbliss, A.L.; Ferdig, M.T.; Checkley, L.; Edwards, R.L.; Boshoff, H.I. Design, synthesis and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria. J. Am. Chem. Soc., 2011, 133, 2076-2079.
[40]
Trager, W.; Jensen, J.B. Human malaria parasite in continuous culture. Science, 1976, 193(4254), 673-675.
[41]
Makler, M.T.; Ries, J.M.; Williams, J.A.; Bancroft, J.E.; Piper, R.C.; Gibbins, B.L.; Hinrichs, D.J. Parasite lactate dehydrogenase as an assay for Plasmodium falciparum drug sensitivity. Am. J. Trop. Med. Hyg., 1993, 48, 739-741.