First Example of Antiparasitic Activity Influenced by Thermochromism: Leishmanicidal Evaluation of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine Metal Complexes

Author(s): José M. Méndez-Arriaga*, Itziar Oyarzabal, Álvaro Martín-Montes, Judith García-Rodríguez, Miguel Quirós, Manuel Sánchez-Moreno

Journal Name: Medicinal Chemistry

Volume 16 , Issue 3 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: The World Health Organization catalogues illnesses such as Leishmaniasis as neglected diseases, due to low investment in new drugs to fight them. The search of novel and non-side effects anti-parasitic compounds is one of the urgent needs for the Third World. The use of triazolopyrimidines and their metallic complexes has demonstrated hopeful results in this field.

Objective: This work studies the antiparasitic efficacy of a series of 5,7-dimethyl-1,2,4- triazolo[1,5-a]pyrimidine first row transition metal complexes against three leishmania spp. strains.

Methods: The in vitro antiproliferation of promastigote forms of different strains of leishmania spp. (L. infantum, L. braziliensis and L donovani) and the cytotoxicity in macrophage host cells are reported here. The antiparasitic assays have been complemented with enzymatic tests to elucidate the mechanisms of action. New crystal structure description, thermal analysis, magnetic susceptibility and magnetization experiments have also been carried out in order to present a whole characterization of the studied compounds and interesting physical properties besides the biological tests.

Results: The results of antiproliferation screening and cytotoxicity show great antiparasitic efficacy in the studied complexes. The superoxide dismutase enzymatic assays exhibit a different behaviour according to the thermochromic triazolopyrimidine form tested.

Conclusion: Antiproliferative assays and enzymatic tests corroborate the synergetic leishmanicidal effect present in coordination triazolopyrimidine complexes. The changes in coordination sphere derived from thermochromism affect the physical properties as well as the biological efficacy.

Keywords: Leishmaniasis, anti-parasitic activity, enzymatic inhibition, bioinorganic chemistry, magnetism, triazolopyrimidine metal complexes.

[1]
Alvar, J.; Vélez, I.D.; Bern, C.; Herrero, M.; Desjeux, P.; Cano, J.; Jannin, J.; den Boer, M. WHO leishmaniasis control team. PLoS One, 2012, 7e35671
[2]
World Health Organization. Control of the Leishmaniases, report of a WHO expert committee. World Health Organ. Tech. Rep. Ser., 2010, 949, 1-186.
[3]
Hotez, P.J.; Molyneux, D.H.; Fenwick, A.; Kumaresan, J.; Sachs, S.E.; Sachs, J.D.; Savioli, L. Control of neglected tropical diseases. N. Engl. J. Med., 2007, 357, 1018-1027.
[4]
Du, R.; Hotez, P.J.; Al-Salem, W.S.; Acosta-Serrano, A. Socioeconomic inequalities in neglected tropical diseases: A systematic review. PLoS Negl. Trop. Dis., 2016, 10(5)e0004546
[5]
Mishra, J.; Saxena, A. Chemotherapy of leishmaniasis: Past, present and future. Curr. Med. Chem., 2007, 14, 1153-1169.
[6]
Momeni, A.Z.; Reiszadae, M.R.; Aminjavaheri, R. Treatment of cutaneous leishmaniasis with a combination of allopurinol and low dose meglumine antimoniate. Int. J. Dermatol., 2002, 41, 441-443.
[7]
Palumbo, E. Current treatment for cutaneous leishmaniasis: A review. Am. J. Ther., 2009, 16, 178-182.
[8]
Croft, S.L.; Sundar, S.; Fairlamb, A.H. Drug resistance in leishmaniasis. Clin. Microbiol. Rev., 2006, 19, 111-126.
[9]
Natera, S.; Machuca, C.; Padrón-Nieves, M.; Romero, A.; Díaz, E.; Ponte-Sucre, A. Leishmania spp: Proficiency of drug-resistant parasites. Int. J. Antimicrob. Agents, 2007, 29, 637-642.
[10]
Frézard, F.; Demicheli, C.; Ribeiro, R.R. Pentavalent antimonials: New perspectives for old drugs. Molecules, 2009, 14, 2317-2336.
[11]
Salas, J.M.; Romero, M.A. Sánchez. M.P.; Quirós, M. Metal complexes of 1,2,4-triazolo[1,5-a]pyrimidine derivatives. Coord. Chem. Rev., 1999, 195, 1119-1142.
[12]
Fischer, G. Recent progress in 1,2,4-triazolo[1,5-a]pyrimidine chemistry. Adv. Heterocycl. Chem., 2008, 95, 143-219.
[13]
Astakhov, A.V.; Sokolov, A.N.; Pyatakov, D.A.; Shishkina, S.V.; Shishkin, O.V.; Chernyshev, V.M. Reactivity of 2-amino-1,2,4-triazolo[1,5-a]pyrimidines with various saturation of the pyrimidine ring towards electrophiles. Chem. Heterocycl. Compd., 2016, 51, 1039-1047.
[14]
Botros, S.; Khamil, O.M.; Kamel, M.M.; El-Dash, Y.S. Synthesis, characterization and cytotoxicity of substituted [1]Benzothieno[3,2-e][1,2,4]triazolo [4,3-a]pyrimidines. Acta Chim. Slov., 2017, 64(1), 102-116.
[15]
Wang, S.; Zhao, L.J.; Zheng, Y.C.; Shen, D.D.; Miao, E.F.; Qiao, X.P.; Zhao, L.J.; Liu, Y.; Huang, R.L.; Yu, B.; Liu, H.M. Design, synthesis and biological evaluation of [1,2,4]triazolo[1,5-a]pyrimidines as potent lysine specific demethylase 1 (LSD1/KDM1A) inhibitors. Eur. J. Med. Chem., 2017, 125, 940-951.
[16]
Birr, E.J. Synthesis of triazolopyrimidine compounds. Wiss. Z. Phot., 1952, 47, 2-27.
[17]
Bulow, C.; Haas, K. Synthetische Versuche zur Darstellung von Derivaten des heterokondensierten, heterocyclischen 1.3-Triazo-7.0′-pyrimidins. Chem. Ber., 1909, 42, 4638-4644.
[18]
Caballero, A.B.; Rodríguez-Diéguez, A.; Vidal, I.; Dobado, J.A.; Castillo, O.; Lezama, L.; Salas, J.M. Insights on the binding ability of a new adenine analog: 7-amine-1,2,4-triazolo[1,5-a]pyrimidine. Synthesis and magnetic study of the first copper(ii) complexes. Dalton Trans., 2012, 41(6), 1755-1764.
[19]
Méndez-Arriaga, J.M.; Oyarzabal, I.; Escolano, G.; Rodríguez-Diéguez, A.; Sánchez-Moreno, M.; Salas, J.M. In vitro leishmanicidal and trypanocidal evaluation and magnetic properties of 7-amino-1,2,4-triazolo[1,5-a]pyrimidine Cu (II) complexes. J. Inorg. Biochem., 2018, 180, 26-32.
[20]
Caballero, A.B.; Rodríguez-Diéguez, A.; Quirós, M.; Lezama, L.; Salas, J.M. New copper(II), nickel(II) and zinc(II) complexes with1,2,4-triazolo[1,5-a]pyrimidines and the chelating ligand 1,3-propanediamine:An unexpected coordination behavior for the 7-amine-derivative. Inorg. Chim. Acta, 2011, 378(1), 194-201.
[21]
Méndez-Arriaga, J.M.; Esteban-Parra, G.M.; Juárez, M.J.; Rodríguez-Diéguez, A.; Sánchez-Moreno, M.; Salas, J.M. Antiparasitic activity against trypanosomatid diseases and novel metal complexes derived from the first time characterized 5-phenyl-1,2,4-triazolo[1,5-a]pyrimidi-7(4H)-one. J. Inorg. Biochem., 2017, 175, 217-224.
[22]
Magán, R.; Marín, C.; Rosales, M.J.; Salas, J.M.; Sánchez-Moreno, M. Therapeutic potential of new Pt(II) and Ru(III) triazole-pyrimidine complexes against Leishmania donovani. Pharmacology, 2005, 73, 41-48.
[23]
Martinez, A.; Carreon, T.; Iniguez, E.; Anzellotti, A.; Sanchez, A.; Tyan, M.; Sattler, A.; Herrera, L.; Maldonado, R.A.; Sanchez-Delgado, R.A. Searching for new chemotherapies for tropical diseases: Ruthenium–clotrimazole complexes display high in vitro activity against Leishmania major and Trypanosoma cruzi and low toxicity toward normal mammalian cells. J. Med. Chem., 2012, 55, 3867-3877.
[24]
Navarro, P.; Sanchez-Moreno, M.; Marín, C.; García-España, E.; Ramírez-Macías, I.; Olmo, F.; Rosales, M.J.; Gómez-Contreras, C.; Yunta, M.J.R.; Gutierrez-Sanchez, R. In vitro leishmanicidal activity of pyrazole-containing polyamine macrocycles which inhibit the Fe-SOD enzyme of leishmania infantum and Leishmania braziliensis species. Parasitology, 2014, 141, 1031-1043.
[25]
Fandzloch, M.; Méndez-Arriaga, J.M.; Sánchez-Moreno, M.; Wojtczak, A.; Jezierska, J.; Sitkowski, J.; Wisniewska, J.; Salas, J.M.; Łakomska, I. Strategies for overcoming tropical disease by ruthenium complexes with purine analog: Application against Leishmania spp. and Trypanosoma cruzi. J. Inorg. Biochem., 2017, 176, 144-155.
[26]
Sánchez-Delgado, R.A.; Anzellotti, A. Metal complexes as chemotherapeutic agents against tropical diseases: trypanosomiasis, malaria and leishmaniasis. Mini Rev. Med. Chem., 2004, 4(1), 23-30.
[27]
Łakomska, I.; Fandzloch, M. Application of 1,2,4-triazolo[1,5-a]pyrimidines for the design of coordination compounds with interesting structures and new biological properties. Coord. Chem. Rev., 2016, 328, 221-241.
[28]
Salas, J.M.; Caballero, A.B.; Esteban-Parra, G.M.; Méndez-Arriaga, J.M. Leishmanicidal and trypanocidal activity of metal complexes with 1,2,4-triazolo[1,5-a]pyrimidines: insights on their therapeutic potential against leishmaniasis and chagas disease. Curr. Med. Chem., 2017, 24(25), 2796-2806.
[29]
Łakomska, I.; Fandzloch, M.; Wojtczak, A. Dimeric ruthenium-triazolopyrimidine complex: Synthesis and structural characterization. Inorg. Chem. Commun., 2014, 49, 24-26.
[30]
Caballero, A.B.; Rodríguez-Diéguez, A.; Quirós, M.; Salas, J.M.; Huertas, O.; Ramírez-Macías, I.; Sánchez-Moreno, M. Triazolopyrimidine compounds containing first-row transition metals and their activity against the neglected infectious Chagas disease and leishmaniasis. Eur. J. Med. Chem., 2014, 85, 526-534.
[31]
Rodríguez-Arce, E.; Machado, I.; Rodríguez, B.; Lapier, M.; Zúñiga, M.C.; Maya, J.D.; Olea-Azar, C.; Otero, L.; Gambino, D. Rhenium(I) tricarbonyl compounds of bioactive thiosemicarbazones: Synthesis, characterization and activity against Trypanosoma cruzi. J. Inorg. Biochem., 2017, 170, 125-133.
[32]
Marutescu, L.; Calu, M.; Chifiriuc, C.; Bleotu, C.; Daniliuc, C.G.; Falcescu, D.; Kamerzan, C.M.; Badea, M.; Olar, R. Synthesis, Physico-chemical characterization, crystal structure and influence on microbial and tumor cells of some Co(II) complexes with 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine. Molecules, 2017, 22, 1233.
[33]
Bruker Apex2, Instructions manual. Bruker AXS Inc., Madison, Wisconsin, USA 2004.
[34]
Sheldrick, G.M. SADABS, Program for Empirical Adsorption Correction; Institute for Inorganic Chemistry, University of Gottingen: Germany, 1996.
[35]
Sheldrick, G.M. Crystal structure refinement with SHELXS. Acta Cryst., 2015, C71, 3-8.
[36]
Romero, M.A.; Salas, J.M.; Quirós, M.; Sánchez, M.P.; Romero, J.; Martín, D. Structural and magnetic studies on a bromine-bridged copper(II) dimer with 5,7-Dimethyl[1,2,4]triazolo[1,5-a]pyrimidine. Inorg. Chem., 1994, 33, 5477-5481.
[37]
Romero, M.A.; Salas, J.M.; Quirós, M. Cobalt(II) complexes of 5,7-dimethyl[1,2,4]-triazolo-[1,5-a]-pyrimidine. Spectroscopic characterization, XRD study and antimicrobial activity. Transition Met. Chem., 1993, 18, 595-598.
[38]
González, P.; Marín, C.; Rodríguez-González, I.; Hitos, A.B.; Rosales, M.J.; Reina, M.; Díaz, J.G.; González-Coloma, A.; Sánchez-Moreno, M. Cobalt(II) complexes of 5,7-dimethyl[1,2,4]-triazolo-[1,5-a]-pyrimidine. Spectroscopic characterization, XRD study and antimicrobial activity. Int. J. Antimicrob. Agents, 2005, 25, 136-141.
[39]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72, 248-254.
[40]
Beyer, W.F.; Fridovich, I. Assaying for superoxide dismutase activity: Some large consequences of minor changes in conditions. Anal. Biochem., 1987, 161, 559-566.
[41]
Salas, J.M.; Romero, M.A.; Rahmani, A.; Faure, R. Dichlorobis(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-N3)zinc(II). Acta Cryst., 1994, C50, 510-512.
[42]
Chilton, N.F.; Anderson, R.P.; Turner, L.D.; Soncini, A.; Murray, K.S. PHI: A powerful new program for the analysis of anisotropic monomeric and exchange-coupled polynuclear d- and f-block complexes. I. Comput. Chem., 2013, 34, 1164-1175.
[43]
Rojo, T.; Arriortua, N.I.; Ruiz, J.; Darriet, J.; Villeneuve, G.; Beltran-Porter, D. Magnetostructural correlations in parallel square-planar chloride bridged copper(II) dimers: structure, dynamic nuclear magnetic resonance study, and magnetic properties of [Cu2(terpy)2Cl2][PF6]2. Dalton Trans., 1987, 285-291.
[44]
Torres-García, P.; Luna-Giles, F.; Bernalte-García, A.; Platas-Iglesias, C.; Esteban-Gómez, D.; Viñuelas-Zahínos, E. Effects of the substituents of pyrazole/thiazine ligands on the magnetic properties of chloro-bridged Cu(II) complexes. New J. Chem., 2017, 41, 8818-8827.
[45]
Boča, R. Zero-field splitting in metal complexes. Coord. Chem. Rev., 2004, 248, 757-815. and references cited therein.
[46]
Titiš, J.; Boča, R. Magnetostructural D correlations in hexacoordinated cobalt(II) complexes. Inorg. Chem., 2011, 50, 11838-11845.
[47]
Colacio, E.; Ruiz, J.; Ruiz, E.; Cremades, E.; Krzystek, J.; Carretta, S.; Cano, J.; Guidi, T.; Wernsdorfer, W.; Brechin, E.K. Slow magnetic relaxation in a CoII–YIII Single‐ion magnet with positive axial zero-field splitting. Angew. Chem. Int. Ed., 2013, 52, 9130-9134.
[48]
Herchel, R.; Vahovska, L.; Potočňak, I.; Travniček, Z. Slow magnetic relaxation in octahedral cobalt(II) field-induced single-ion magnet with positive axial and large rhombic anisotropy. Inorg. Chem., 2014, 53, 5896-5898.
[49]
Smolko, L.; Černák, J.; Dušek, M.; Miklovič, J.; Titiš, J.; Boča, R. Three tetracoordinate Co(II) complexes [Co(biq)X2] (X = Cl, Br, I) with easy-plane magnetic anisotropy as field-induced single-molecule magnets. Dalton Trans., 2015, 44, 17565-17571.
[50]
Idešicová, M.; Titiš, J.; Krzystek, J.; Boča, R. Zero-field splitting in pseudotetrahedral Co(II) complexes: A Magnetic, high-frequency and -field EPR, and computational study. Inorg. Chem., 2013, 52, 9409-9417.
[51]
Caballero, A.B.; Salas, J.M.; Sánchez-Moreno, M. Metal based therapeutics for leishmaniasis. In: Leishmaniasis – Trends in Epidemiology, Diagnosis and Treatment, in Leishmaniasis: Trends in Epidemiology, Diagnosis and Treatment; David M. , Claborn, Ed.; IntechOpen Chapter 20, 2014.
[52]
Tavares, J.; Ouaissi, A.; Kong Thoo Lin, P.; Loureiro, I.; Kaur, S.; Roy, N.; Cordeiro da Silva, A. Bisnaphthalimidopropyl derivatives as inhibitors of Leishmania SIR2 related protein 1. ChemMedChem, 2010, 5, 140-147.
[53]
Cleghorn, L.A.; Woodland, A.; Collie, I.T.; Torrie, L.S.; Norcross, N.; Luksch, T.; Mpamhanga, C.; Walker, R.G.; Mottram, J.C.; Brenk, R.; Frearson, J.A.; Gilbert, I.H.; Wyatt, P.G. Identification of Inhibitors of the Leishmania cdc2-Related protein kinase CRK3. ChemMedChem, 2011, 6, 2214-2224.
[54]
Toro, M.A.; Sánchez-Murcia, P.A.; Moreno, D.; Ruiz-Santaquiteria, M.; Alzate, J.F.; Negri, A.; Camarasa, M.J.; Gago, F.; Velázquez, S.; Jiménez-Ruiz, A. Probing the dimerization interface of Leishmania infantum trypanothione reductase with site-directed mutagenesis and short peptides. ChemBioChem, 2013, 14(10), 1212-1217.
[55]
Ruiz-Santaquiteria, M.; Sánchez-Murcia, P.A.; Toro, M.A.; de Lucio, H.; Gutiérrez, K.J.; de Castro, S.; Carneiro, F.A.C.; Gago, F.; Jiménez-Ruiz, A.; Camarasa, M.J.; Velázquez, S. First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity. Eur. J. Med. Chem., 2017, 135, 49-59.
[56]
Miller, A.F. Superoxide dismutases: Active sites that save, but a protein that kills. Curr. Opin. Chem. Biol., 2004, 8, 162-168.
[57]
Turrens, J.F. Oxidative stress and antioxidant defenses: a target for the treatment of diseases caused by parasitic protozoa. Mol. Asp Med., 2004, 25, 211-220.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 3
Year: 2020
Published on: 16 April, 2020
Page: [422 - 430]
Pages: 9
DOI: 10.2174/1573406415666190401120607
Price: $65

Article Metrics

PDF: 16
HTML: 3