Current Computer-Aided Drug DesignCurrent Computer-Aided Drug DesignCurrent Computer-Aided Drug Design1573-40991875-6697Bentham Science64393210.2174/1573409919666230417135204ChemistryResearch ArticleEsters of Quinoxaline-7-Carboxylate 1,4-di-N-Oxide as Potential Inhibitors of Glycolytic Enzymes of Entamoeba histolytica: In silico ApproachZavala-OcampoLizethinfo@benthamscience.netSoto-SánchezJacquelineinfo@benthamscience.netPérez-MoraSalvadorinfo@benthamscience.netOspina-VillaJuaninfo@benthamscience.netLaboratorio de Productos Naturales, Facultad de Ciencias, Universidad Nacional Autónoma de MéxicoSección de Estudios de Posgrado e Investigación, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico NacionaSección de Estudios de Posgrado e Investigación, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico NacionalInstituto Colombiano de Medicina Tropical, Universidad CES, Sabaneta0102202420215516907012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1573-4099/article/view/643932

Background:Esters of quinoxaline-7-carboxylate 1,4-di-N-oxide (7-carboxylate QdNOs) derivatives are compounds that inhibit the growth of Entamoeba histolytica, the causative agent of amebiasis. Although these compounds cause changes in the redistribution of glycogen deposits within the parasite, it is unknown whether these compounds interact with enzymes of the glycolytic pathway.

Objective:The aim of this study was to test the binding affinity of these compounds to pyrophosphate- dependent phosphofructokinase (PPi-PFK), triosephosphate isomerase (TIM), and pyruvate phosphate dikinase (PPDK) from E. histolytica as a possible mechanism of action.

Methods:The molecular docking study of the 7-carboxylate QdNOs derivatives and the proteins was performed using AutoDock/Vina software. Molecular dynamics simulation was performed for 100 ns.

Results:Among all the selected compounds, T-072 exhibited the best binding affinity to EhPPi- PFK and EhTIM proteins, while T-006 interacted best with EhPPDK. ADMET analysis revealed that T-072 was non-toxic, while T-006 could become harmful to the host. In addition, molecular dynamics showed that T-072 has stable interaction with EhPPi-PFK and EhTIM.

Conclusion:Including all aspects, these data indicated that these compounds might inhibit the activity of key enzymes in energy metabolism leading to parasite death. Furthermore, these compounds may be a good starting point for the future development of new potent antiamebic agents.

PPi-PFKTIMPPDK&lti&ampgtEntamoeba histolytica&amplt/i&ampgtquinoxalinesmolecular dynamics.Quintanilla-Licea, R.; Vargas-Villarreal, J.; Verde-Star, M.J.; Rivas-Galindo, V.M.; Torres-Hernández, Á.D. Antiprotozoal activity against Entamoeba histolytica of flavonoids isolated from Lippia graveolens Kunth. Molecules, 2020, 25(11), 2464. doi: 10.3390/molecules25112464 PMID: 32466359Amoebiasis. Institut Pasteur. 2015. Available from: www.pasteur.fr/en/medical-center/disease-sheets/amoebiasis-0Espinosa-Cantellano, M.; Martínez-Palomo, A. Pathogenesis of intestinal amebiasis: From molecules to disease. Clin. Microbiol. Rev., 2000, 13(2), 318-331. doi: 10.1128/CMR.13.2.318 PMID: 10756002Mi-ichi, F.; Ishikawa, T.; Tam, V.K.; Deloer, S.; Hamano, S.; Hamada, T.; Yoshida, H. Characterization of Entamoeba histolytica adenosine 5′-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis. PLoS Negl. Trop. Dis., 2019, 13(8), e0007633. doi: 10.1371/journal.pntd.0007633 PMID: 31425516Weir, C.B.; Le, J.K. Metronidazole; StatPearls Publishing: Treasure Island, FL, 2022.Wassmann, C.; Hellberg, A.; Tannich, E.; Bruchhaus, I. Metronidazole resistance in the protozoan parasite Entamoeba histolytica is associated with increased expression of iron-containing superoxide dismutase and peroxiredoxin and decreased expression of ferredoxin 1 and flavin reductase. J. Biol. Chem., 1999, 274(37), 26051-26056. doi: 10.1074/jbc.274.37.26051 PMID: 10473552Nagaraja, S.; Ankri, S. Target identification and intervention strategies against amebiasis. Drug Resist. Updat., 2019, 44, 1-14. doi: 10.1016/j.drup.2019.04.003 PMID: 31112766Saavedra, E.; Encalada, R.; Vázquez, C.; Olivos-García, A.; Michels, P.A.M.; Moreno-Sánchez, R. Control and regulation of the pyrophosphate-dependent glucose metabolism in Entamoeba histolytica. Mol. Biochem. Parasitol., 2019, 229, 75-87. doi: 10.1016/j.molbiopara.2019.02.002 PMID: 30772421Cheng, G.; Sa, W.; Cao, C.; Guo, L.; Hao, H.; Liu, Z.; Wang, X.; Yuan, Z. Quinoxaline 1,4-di-N-oxides: Biological activities and mechanisms of actions. Front. Pharmacol., 2016, 7, 64. doi: 10.3389/fphar.2016.00064 PMID: 27047380Soto-Sánchez, J.; Ospina-Villa, J.D. Current status of quinoxaline and quinoxaline 1,4‐di‐ N ‐oxides derivatives as potential antiparasitic agents. Chem. Biol. Drug Des., 2021, 98(4), 683-699. doi: 10.1111/cbdd.13921 PMID: 34289242Khatoon, H.; Abdulmalek, E. Novel synthetic routes to prepare biologically active quinoxalines and their derivatives: A synthetic review for the last two decades. Molecules, 2021, 26(4), 1055. doi: 10.3390/molecules26041055 PMID: 33670436Palos, I.; Luna-Herrera, J.; Lara-Ramírez, E.; Loera-Piedra, A.; Fernández-Ramírez, E.; Aguilera-Arreola, M.; Paz-González, A.; Monge, A.; Wan, B.; Franzblau, S.; Rivera, G. Anti-Mycobacterium tuberculosis activity of esters of quinoxaline 1,4-Di-N-oxide. Molecules, 2018, 23(6), 1453. doi: 10.3390/molecules23061453 PMID: 29914062Rivera, G.; Ahmad Shah, S.S.; Arrieta-Baez, D.; Palos, I.; Mongue, A.; Sánchez-Torres, L.E. Esters of quinoxaline 1`4-Di-N-oxide with cytotoxic activity on tumor cell lines based on NCI-60 panel. Iran. J. Pharm. Res., 2017, 16(3), 953-965. PMID: 29201086Chacón-Vargas, K.; Nogueda-Torres, B.; Sánchez-Torres, L.; Suarez-Contreras, E.; Villalobos-Rocha, J.; Torres-Martinez, Y.; Lara-Ramirez, E.; Fiorani, G.; Krauth-Siegel, R.; Bolognesi, M.; Monge, A.; Rivera, G. Trypanocidal activity of quinoxaline 1,4 Di-N-oxide derivatives as trypanothione reductase inhibitors. Molecules, 2017, 22(2), 220. doi: 10.3390/molecules22020220 PMID: 28157150Villalobos-Rocha, J.C.; Sánchez-Torres, L.; Nogueda-Torres, B.; Segura-Cabrera, A.; García-Pérez, C.A.; Bocanegra-García, V.; Palos, I.; Monge, A.; Rivera, G. Anti-Trypanosoma cruzi and anti-leishmanial activity by quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives. Parasitol. Res., 2014, 113(6), 2027-2035. doi: 10.1007/s00436-014-3850-8 PMID: 24691716Chacón-Vargas, K.F.; Andrade-Ochoa, S.; Nogueda-Torres, B.; Juárez-Ramírez, D.C.; Lara-Ramírez, E.E.; Mondragón-Flores, R.; Monge, A.; Rivera, G.; Sánchez-Torres, L.E. Isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives induce regulated necrosis-like cell death on Leishmania (Leishmania) mexicana. Parasitol. Res., 2018, 117(1), 45-58. doi: 10.1007/s00436-017-5635-3 PMID: 29159705Palos, I.; Moo-Puc, R.; Vique-Sánchez, J.L.; Benítez-Cardoza, C.G.; Monge, A.; Villalobos-Rocha, J.C.; Paz-Gonzalez, A.D.; Rivera, G. Esters of quinoxaline-7-carboxylate-1,4-di- N -oxide as Trichomonas vaginalis triosephosphate isomerase inhibitors. Acta Pharm., 2021, 71(3), 485-495. doi: 10.2478/acph-2021-0032 PMID: 36654088Duque-Montaño, B.E.; Gómez-Caro, L.C.; Sanchez-Sanchez, M.; Monge, A.; Hernández-Baltazar, E.; Rivera, G.; Torres-Angeles, O. Synthesis and in vitro evaluation of new ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide against Entamoeba histolytica. Bioorg. Med. Chem., 2013, 21(15), 4550-4558. doi: 10.1016/j.bmc.2013.05.036 PMID: 23787289Soto-Sánchez, J.; Caro-Gómez, L.A.; Paz-González, A.D.; Marchat, L.A.; Rivera, G.; Moo-Puc, R.; Arias, D.G.; Ramírez-Moreno, E. Biological activity of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide against E. histolytica and their analysis as potential thioredoxin reductase inhibitors. Parasitol. Res., 2020, 119(2), 695-711. doi: 10.1007/s00436-019-06580-8 PMID: 31907668Benitez, D.; Cabrera, M.; Hernández, P.; Boiani, L.; Lavaggi, M.L.; Di Maio, R.; Yaluff, G.; Serna, E.; Torres, S.; Ferreira, M.E.; Vera de Bilbao, N.; Torres, E.; Pérez-Silanes, S.; Solano, B.; Moreno, E.; Aldana, I.; López de Ceráin, A.; Cerecetto, H.; González, M.; Monge, A. 3-Trifluoromethylquinoxaline N,N′-dioxides as anti-trypanosomatid agents. Identification of optimal anti-T. cruzi agents and mechanism of action studies. J. Med. Chem., 2011, 54(10), 3624-3636. doi: 10.1021/jm2002469 PMID: 21506600Álvarez, G.; Aguirre-López, B.; Varela, J.; Cabrera, M.; Merlino, A.; López, G.V.; Lavaggi, M.L.; Porcal, W.; Di Maio, R.; González, M.; Cerecetto, H.; Cabrera, N.; Pérez-Montfort, R.; de Gómez-Puyou, M.T.; Gómez-Puyou, A. Massive screening yields novel and selective Trypanosoma cruzi triosephosphate isomerase dimer-interface-irreversible inhibitors with anti-trypanosomal activity. Eur. J. Med. Chem., 2010, 45(12), 5767-5772. doi: 10.1016/j.ejmech.2010.09.034 PMID: 20889239Wierenga, R.K.; Kapetaniou, E.G.; Venkatesan, R. Triosephosphate isomerase: A highly evolved biocatalyst. Cell. Mol. Life Sci., 2010, 67(23), 3961-3982. doi: 10.1007/s00018-010-0473-9 PMID: 20694739Zomosa-Signoret, V.; Hernández-Alcántara, G.; Reyes-Vivas, H.; Martínez-Martínez, E.; Garza-Ramos, G.; Pérez-Montfort, R.; de Gómez-Puyou, M.T.; Gómez-Puyou, A. Control of the reactivation kinetics of homodimeric triosephosphate isomerase from unfolded monomers. Biochemistry, 2003, 42(11), 3311-3318. doi: 10.1021/bi0206560 PMID: 12641463Rodríguez-Romero, A.; Hernández-Santoyo, A.; del Pozo Yauner, L.; Kornhauser, A.; Fernández-Velasco, D.A. Structure and inactivation of triosephosphate isomerase from Entamoeba histolytica. J. Mol. Biol., 2002, 322(4), 669-675. doi: 10.1016/S0022-2836(02)00809-4 PMID: 12270704Deng, Z.; Huang, M.; Singh, K.; Albach, A.R.; Latshaw, P.S.; Chang, K.P.; Kemp, G.R. Cloning and expression of the gene for the active PPi-dependent phosphofructokinase of Entamoeba histolytica. Biochem. J., 1998, 329(3), 659-664. doi: 10.1042/bj3290659 PMID: 9445396Li, Z.J.; Phillips, N.F.B. Pyrophosphate-dependent phosphofructokinase from Giardia lamblia: Purification and characterization. Protein Expr. Purif., 1995, 6(3), 319-328. doi: 10.1006/prep.1995.1042 PMID: 7663168Mertens, E. ATP versus pyrophosphate: Glycolysis revisited in parasitic protists. Parasitol. Today, 1993, 9(4), 122-126. doi: 10.1016/0169-4758(93)90169-G PMID: 15463728Mertens, E. Pyrophosphate-dependent phosphofructokinase, an anaerobic glycolytic enzyme? FEBS Lett., 1991, 285(1), 1-5. doi: 10.1016/0014-5793(91)80711-B PMID: 1648508Li, Z.; Phillips, N.F.B. Involvement and identification of a lysine in the PPi-site of pyrophosphate-dependent phosphofructokinase from Giardia lamblia. Biochimie, 1997, 79(4), 221-227. doi: 10.1016/S0300-9084(97)83509-2 PMID: 9242987Nevalainen, L.; Hrdý, I.; Müller, M. Sequence of a Giardia lamblia gene coding for the glycolytic enzyme, pyruvate,phosphate dikinase. Mol. Biochem. Parasitol., 1996, 77(2), 217-223. doi: 10.1016/0166-6851(96)02604-7 PMID: 8813667Feng, X.M.; Cao, L.J.; Adam, R.D.; Zhang, X.C.; Lu, S.Q. The catalyzing role of PPDK in Giardia lamblia. Biochem. Biophys. Res. Commun., 2008, 367(2), 394-398. doi: 10.1016/j.bbrc.2007.12.139 PMID: 18167307Mertens, E.; Ladror, U.S.; Lee, J.A.; Miretsky, A.; Morris, A.; Rozario, C.; Kemp, R.G.; Müller, M. The pyrophosphate-dependent phosphofructokinase of the protist, Trichomonas vaginalis, and the evolutionary relationships of protist phosphofructokinases. J. Mol. Evol., 1998, 47(6), 739-750. doi: 10.1007/PL00006433 PMID: 9847416Rodriguez-Contreras, D.; Hamilton, N. Gluconeogenesis in Leishmania mexicana. J. Biol. Chem., 2014, 289(47), 32989-33000. doi: 10.1074/jbc.M114.569434 PMID: 25288791González-Marcano, E.; Acosta, H.; Mijares, A.; Concepción, J.L. Kinetic and molecular characterization of the pyruvate phosphate dikinase from Trypanosoma cruzi. Exp. Parasitol., 2016, 165, 81-87. doi: 10.1016/j.exppara.2016.03.023 PMID: 27003459Cosenza, L.W.; Bringaud, F.; Baltz, T.; Vellieux, F.M.D. Crystallization and preliminary crystallographic investigation of glycosomal pyruvate phosphate dikinase from Trypanosoma brucei. Acta Crystallogr. D Biol. Crystallogr., 2000, 56(12), 1688-1690. doi: 10.1107/S0907444900015298 PMID: 11092947González-Marcano, E.; Acosta, H.; Quiñones, W.; Mijares, A.; Concepción, J.L. Hysteresis of pyruvate phosphate dikinase from Trypanosoma cruzi. Parasitol. Res., 2021, 120(4), 1421-1428. doi: 10.1007/s00436-020-06934-7 PMID: 33098461Eubank, W.B.; Reeves, R.E. Analog inhibitors for the pyrophosphate-dependent phosphofructokinase of Entamoeba histolytica and their effect on culture growth. J. Parasitol., 1982, 68(4), 599-602. doi: 10.2307/3280916 PMID: 6288907Bruchhaus, I.; Jacobs, T.; Denart, M.; Tannich, E. Pyrophosphate-dependent phosphofructokinase of Entamoeba histolytica: Molecular cloning, recombinant expression and inhibition by pyrophosphate analogues. Biochem. J., 1996, 316(1), 57-63. doi: 10.1042/bj3160057 PMID: 8645233Saavedra-Lira, E.; Ramirez-Silva, L.; Perez-Montfort, R. Expression and characterization of recombinant pyruvate phosphate dikinase from Entamoeba histolytica. Biochim. Biophys. Acta Protein Struct. Mol. Enzymol., 1998, 1382(1), 47-54. doi: 10.1016/S0167-4838(97)00139-8 PMID: 9507062Saavedra-Lira, E.; Pérez-Montfort, R. Energy production in Entamoeba histolytica: New perspectives in rational drug design. Arch. Med. Res., 1996, 27(3), 257-264. PMID: 8854380Stephen, P.; Vijayan, R.; Bhat, A.; Subbarao, N.; Bamezai, R.N.K. Molecular modeling on pyruvate phosphate dikinase of Entamoeba histolytica and in silico virtual screening for novel inhibitors. J. Comput. Aided Mol. Des., 2008, 22(9), 647-660. doi: 10.1007/s10822-007-9130-2 PMID: 17710553Juárez-Saldivar, A.; Barbosa-Cabrera, E.; Lara-Ramírez, E.E.; Paz-González, A.D.; Martínez-Vázquez, A.V.; Bocanegra-García, V.; Palos, I.; Campillo, N.E.; Rivera, G. Virtual screening of FDA-approved drugs against triose phosphate isomerase from Entamoeba histolytica and Giardia lamblia identifies inhibitors of their trophozoite growth phase. Int. J. Mol. Sci., 2021, 22(11), 5943. doi: 10.3390/ijms22115943 PMID: 34073021Saidin, S.; Othman, N.; Noordin, R. In vitro testing of potential Entamoeba histolytica pyruvate phosphate dikinase inhibitors. Am. J. Trop. Med. Hyg., 2017, 97(4), 1204-1213. doi: 10.4269/ajtmh.17-0132 PMID: 28820699Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717. doi: 10.1038/srep42717 PMID: 28256516Deng, Z.; Wang, X.; Kemp, R.G. Site-directed mutagenesis of the fructose 6-phosphate binding site of the pyrophosphate-dependent phosphofructokinase of Entamoeba histolytica. Arch. Biochem. Biophys., 2000, 380(1), 56-62. doi: 10.1006/abbi.2000.1881 PMID: 10900132Radchenko, E.V.; Dyabina, A.S.; Palyulin, V.A.; Zefirov, N.S. Prediction of human intestinal absorption of drug compounds. Russ. Chem. Bull., 2016, 65(2), 576-580. doi: 10.1007/s11172-016-1340-0Mi-ichi, F.; Yousuf, M.A.; Nakada-Tsukui, K.; Nozaki, T. Mitosomes in Entamoeba histolytica contain a sulfate activation pathway. Proc. Natl. Acad. Sci., 2009, 106(51), 21731-21736. doi: 10.1073/pnas.0907106106 PMID: 19995967Matt, J.; Duchêne, M. Molecular and biochemical characterization of Entamoeba histolytica fructokinase. Parasitol. Res., 2015, 114(5), 1939-1947. doi: 10.1007/s00436-015-4383-5 PMID: 25700717Kumari, P.; Idrees, D.; Rath, P.P.; Vijayan, R.; Gourinath, S. Biochemical and biophysical characterization of the smallest pyruvate kinase from Entamoeba histolytica. Biochim. Biophys. Acta. Proteins Proteomics, 2020, 1868(1), 140296. doi: 10.1016/j.bbapap.2019.140296 PMID: 31676451Pineda, E.; Encalada, R.; Vázquez, C.; Néquiz, M.; Olivos-García, A.; Moreno-Sánchez, R.; Saavedra, E. In vivo identification of the steps that control energy metabolism and survival of Entamoeba histolytica. FEBS J., 2015, 282(2), 318-331. doi: 10.1111/febs.13131 PMID: 25350227Brimacombe, K.R.; Walsh, M.J.; Liu, L.; Vásquez-Valdivieso, M.G.; Morgan, H.P.; McNae, I.; Fothergill-Gilmore, L.A.; Michels, P.A.M.; Auld, D.S.; Simeonov, A.; Walkinshaw, M.D.; Shen, M.; Boxer, M.B. Identification of ML251, a potent inhibitor of T. brucei and T. cruzi Phosphofructokinase. ACS Med. Chem. Lett., 2014, 5(1), 12-17. doi: 10.1021/ml400259d PMID: 24900769Zinsser, V.L.; Hoey, E.M.; Trudgett, A.; Timson, D.J. Biochemical characterisation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) from the liver fluke, Fasciola hepatica. Biochim. Biophys. Acta. Proteins Proteomics, 2014, 1844(4), 744-749. doi: 10.1016/j.bbapap.2014.02.008 PMID: 24566472Dax, C.; Duffieux, F.; Chabot, N.; Coincon, M.; Sygusch, J.; Michels, P.A.M.; Blonski, C. Selective irreversible inhibition of fructose 1,6-bisphosphate aldolase from Trypanosoma brucei. J. Med. Chem., 2006, 49(5), 1499-1502. doi: 10.1021/jm050237b PMID: 16509566Reeves, R.E.; South, D.J.; Blytt, H.J.; Warren, L.G. Pyrophosphate:D-fructose 6-phosphate 1-phosphotransferase. A new enzyme with the glycolytic function of 6-phosphofructokinase. J. Biol. Chem., 1974, 249(24), 7737-7741. doi: 10.1016/S0021-9258(19)42029-2 PMID: 4372217Moreno-Sánchez, R.; Marín-Hernández, A.; Gallardo-Pérez, J.C.; Quezada, H.; Encalada, R.; Rodríguez-Enríquez, S.; Saavedra, E. Phosphofructokinase type 1 kinetics, isoform expression and gene polymorphisms in cancer cells. J. Cell. Biochem., 2011, 113(5), 1692-1703. doi: 10.1002/jcb.24039 PMID: 22213537Fernandes, P.M.; Kinkead, J.; McNae, I.W.; Bringaud, F.; Michels, P.A.M.; Walkinshaw, M.D. The kinetic characteristics of human and trypanosomatid phosphofructokinases for the reverse reaction. Biochem. J., 2019, 476(2), 179-191. doi: 10.1042/BCJ20180635 PMID: 30404924Moreno-Viguri, E.; Pérez-Silanes, S. Quinoxaline 1,4-di- N -oxide derivatives: Interest in the treatment of chagas disease. Revista Virtual de Química, 2013, 5(6), 1101-1119. doi: 10.5935/1984-6835.20130080Yang, X.; Yin, X.; Liu, J.; Niu, Z.; Yang, J.; Shen, B. Essential role of pyrophosphate homeostasis mediated by the pyrophosphate-dependent phosphofructokinase in Toxoplasma gondii. PLoS Pathog., 2022, 18(2), e1010293. doi: 10.1371/journal.ppat.1010293 PMID: 35104280Téllez-Valencia, A.; Olivares-Illana, V.; Hernández-Santoyo, A.; Pérez-Montfort, R.; Costas, M.; Rodríguez-Romero, A.; López-Calahorra, F.; Tuena de Gómez-Puyou, M.; Gómez-Puyou, A. Inactivation of triosephosphate isomerase from Trypanosoma cruzi by an agent that perturbs its dimer interface. J. Mol. Biol., 2004, 341(5), 1355-1365. doi: 10.1016/j.jmb.2004.06.056 PMID: 15321726Schliebs, W.; Thanki, N.; Eritja, R.; Wierenga, R. Active site properties of monomeric triosephosphate isomerase (monoTIM) as deduced from mutational and structural studies. Protein Sci., 1996, 5(2), 229-239. doi: 10.1002/pro.5560050206 PMID: 8745400Tellez, L.A.; Blancas-Mejia, L.M.; Carrillo-Nava, E.; Mendoza-Hernández, G.; Cisneros, D.A.; Fernández-Velasco, D.A. Thermal unfolding of triosephosphate isomerase from Entamoeba histolytica: Dimer dissociation leads to extensive unfolding. Biochemistry, 2008, 47(44), 11665-11673. doi: 10.1021/bi801360k PMID: 18837510Téllez-Valencia, A.; Ávila-Ríos, S.; Pérez-Montfort, R.; Rodríguez-Romero, A.; de Gómez-Puyou, T.M.; López-Calahorra, F.; Gómez-Puyou, A. Highly specific inactivation of triosephosphate isomerase from Trypanosoma cruzi. Biochem. Biophys. Res. Commun., 2002, 295(4), 958-963. doi: 10.1016/S0006-291X(02)00796-9 PMID: 12127988Vázquez-Jiménez, L.K.; Moreno-Herrera, A.; Juárez-Saldivar, A.; González-González, A.; Ortiz-Pérez, E.; Paz-González, A.D.; Palos, I.; Ramírez-Moreno, E.; Rivera, G. Recent advances in the development of triose phosphate isomerase inhibitors as antiprotozoal agents. Curr. Med. Chem., 2022, 29(14), 2504-2529. doi: 10.2174/0929867328666210913090928 PMID: 34517794Ferraro, F.; Corvo, I.; Bergalli, L.; Ilarraz, A.; Cabrera, M.; Gil, J.; Susuki, B.M.; Caffrey, C.R.; Timson, D.J.; Robert, X.; Guillon, C.; Freire, T.; Álvarez, G. Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity. Sci. Rep., 2020, 10(1), 2587. doi: 10.1038/s41598-020-59460-y PMID: 32054976Enriquez-Flores, S.; Rodriguez-Romero, A.; Hernandez-Alcantara, G.; De la Mora-De la Mora, I.; Gutierrez-Castrellon, P.; Carvajal, K.; Lopez-Velazquez, G.; Reyes-Vivas, H. Species-specific inhibition of Giardia lamblia triosephosphate isomerase by localized perturbation of the homodimer. Mol. Biochem. Parasitol., 2008, 157(2), 179-186. doi: 10.1016/j.molbiopara.2007.10.013 PMID: 18077010Vique-Sánchez, J.L.; Jiménez-Pineda, A.; Benítez-Cardoza, C.G. Amoebicidal effect of 5,5′‐(4‐nitrophenyl)methylenebis‐6‐hydroxy‐2‐mercapto‐3‐methyl‐4(3 H)‐pyrimidinone), a new drug against Entamoeba histolytica. Arch. Pharm., 2021, 354(2), 2000263. doi: 10.1002/ardp.202000263 PMID: 33017058Ye, D.; Wei, M.; McGuire, M.; Huang, K.; Kapadia, G.; Herzberg, O.; Martin, B.M.; Dunaway-Mariano, D. Investigation of the catalytic site within the ATP-grasp domain of Clostridium symbiosum pyruvate phosphate dikinase. J. Biol. Chem., 2001, 276(40), 37630-37639. doi: 10.1074/jbc.M105631200 PMID: 11468288Avila-Bonilla, R.G.; López-Sandoval, Á.; Soto-Sánchez, J.; Marchat, L.A.; Rivera, G.; Medina-Contreras, O.; Ramírez-Moreno, E. Proteomic and functional analysis of the effects of quinoxaline derivatives on Entamoeba histolytica. Front. Cell. Infect. Microbiol., 2022, 12, 887647. doi: 10.3389/fcimb.2022.887647 PMID: 35832378Malik, A.; Dalal, V.; Ankri, S.; Tomar, S. Structural insights into Entamoeba histolytica arginase and structure‐based identification of novel non‐amino acid based inhibitors as potential antiamoebic molecules. FEBS J., 2019, 286(20), 4135-4155. doi: 10.1111/febs.14960 PMID: 31199070Probst, A.; Nguyen, T.N.; El-Sakkary, N.; Skinner, D.; Suzuki, B.M.; Buckner, F.S.; Gelb, M.H.; Caffrey, C.R.; Debnath, A. Bioactivity of farnesyltransferase inhibitors against Entamoeba histolytica and Schistosoma mansoni. Front. Cell. Infect. Microbiol., 2019, 9, 180. doi: 10.3389/fcimb.2019.00180 PMID: 31192168Rodrigues, J.H.S.; Ueda-Nakamura, T.; Corrêa, A.G.; Sangi, D.P.; Nakamura, C.V. A quinoxaline derivative as a potent chemotherapeutic agent, alone or in combination with benznidazole, against Trypanosoma cruzi. PLoS One, 2014, 9(1), e85706. doi: 10.1371/journal.pone.0085706 PMID: 24465654Williams, C.F.; Vacca, A.R.; Dunham, L.; Lloyd, D.; Coogan, M.P.; Evans, G.; Graz, M.; Cable, J. The redox-active drug metronidazole and thiol-depleting garlic compounds act synergistically in the protist parasite Spironucleus vortens. Mol. Biochem. Parasitol., 2016, 206(1-2), 20-28. doi: 10.1016/j.molbiopara.2016.03.001 PMID: 26968264Planer, J.D.; Hulverson, M.A.; Arif, J.A.; Ranade, R.M.; Don, R.; Buckner, F.S. Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. PLoS Negl. Trop. Dis., 2014, 8(7), e2977. doi: 10.1371/journal.pntd.0002977 PMID: 25033456Zahid, M.S.H.; Johnson, M.M.; Tokarski, R.J., II; Satoskar, A.R.; Fuchs, J.R.; Bachelder, E.M.; Ainslie, K.M. Evaluation of synergy between host and pathogen-directed therapies against intracellular Leishmania donovani. Int. J. Parasitol. Drugs Drug Resist., 2019, 10, 125-132. doi: 10.1016/j.ijpddr.2019.08.004 PMID: 31493763Sun, Y.; Chen, D.; Pan, Y.; Qu, W.; Hao, H.; Wang, X.; Liu, Z.; Xie, S. Nanoparticles for antiparasitic drug delivery. Drug Deliv., 2019, 26(1), 1206-1221. doi: 10.1080/10717544.2019.1692968 PMID: 31746243de Oliveira, J.K.; Ueda-Nakamura, T.; Corrêa, A.G.; Petrilli, R.; Lopez, R.F.V.; Nakamura, C.V.; Auzely-Velty, R. Liposome-based nanocarrier loaded with a new quinoxaline derivative for the treatment of cutaneous leishmaniasis. Mater. Sci. Eng. C, 2020, 110(110720), 110720. doi: 10.1016/j.msec.2020.110720 PMID: 32204033