In vitro and In Vivo Evaluation of Quinoxaline 1,4-di-N-oxide Against Giardia lamblia

Author(s): Elizabeth Barbosa-Cabrera, Rosa Moo-Puc, Antonio Monge, Alma Delia Paz-González, Virgilio Bocanegra-García, Gildardo Rivera*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 4 , 2020

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Graphical Abstract:


Background: Giardiasis is an important public health problem. However, its pharmacological treatment is limited mainly to two drugs, metronidazole and nitazoxanide.

Objectives: Screening four series of esters (methyl, ethyl, isopropyl and n-propyl) of quinoxaline-7- carboxylate 1,4-di-N-oxide in in vitro and in vivo models as antigiardiasis agents.

Methods: Briefly, 4 × 104 trophozoites of G. lamblia were incubated for 48 h at 37 °C with different concentrations of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide, albendazole, metronidazole and nitazoxanide. Afterwards, trophozoites were counted and the half maximal inhibitory concentration (IC50) was calculated by Probit analysis. The in vivo antigiardial activity of the compounds was demonstrated using experimental infections of G. lamblia in suckling female CD-1 mice.

Results: Compound T-069 with a thienyl, a trifluoromethyl and an isopropyl group at R1-, R2- and R3-position, respectively, on the quinoxaline 1,4-di-N-oxide ring in an in vitro model showed an IC50 value of 0.0014 µM, and 3502 and 1108 times more giardicidal activity than nitazoxanide and metronidazole in an in vivo model.

Conclusion: Isopropyl ester of quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives showed better giardicidal activity than the reference drugs; therefore, these compounds are good candidates to develop new pharmacological treatment for giardiasis.

Keywords: Biological evaluation, drugs, esters, giardiasis, antiprotozoal, quinoxaline 1, 4-di-N-oxide.

Leitsch, D. Drug Resistance in the microaerophilic parasite Giardia lamblia. Curr. Trop. Med. Rep., 2015, 2(3), 128-135.
[] [PMID: 26258002]
Ansell, B.R.; McConville, M.J.; Ma’ayeh, S.Y.; Dagley, M.J.; Gasser, R.B.; Svärd, S.G.; Jex, A.R. Drug resistance in Giardia duodenalis. Biotechnol. Adv., 2015, 33(6 Pt 1), 888-901.
[] [PMID: 25922317]
Duplessis, C.A.; Gutierrez, R.L.; Porter, C.K. Review: Chronic and persistent diarrhea with a focus in the returning traveler. Trop. Dis. Travel Med. Vaccines, 2017, 3, 9.
[] [PMID: 28883979]
Lalle, M.; Hanevik, K. Treatment-refractory giardiasis: Challenges and solutions. Infect. Drug Resist., 2018, 11, 1921-1933.
[] [PMID: 30498364]
Upcroft, P.; Upcroft, J.A. Drug targets and mechanisms of resistance in the anaerobic protozoa. Clin. Microbiol. Rev, 2001, 14(1), 150-164.
[] [PMID: 11148007]
Cano, P.A.; Islas-Jácome, A.; González-Marrero, J.; Yépez-Mulia, L.; Calzada, F.; Gámez-Montaño, R. Synthesis of 3-tetrazolylmethyl-4H-chromen-4-ones via Ugi-azide and biological evaluation against Entamoeba histolytica, Giardia lamblia and Trichomona vaginalis. Bioorg. Med. Chem., 2014, 22(4), 1370-1376.
[] [PMID: 24468633]
Galeh, T.M.; Kazemi, A.; Mahami-Oskouei, M.; Baradaran, B.; Spotin, A.; Sarafraz, S.; Karamat, M. Introducing nitazoxanide as a promising alternative treatment for symptomatic to metronidazole-resistant giardiasis in clinical isolates. Asian Pac. J. Trop. Med., 2016, 9(9), 887-892.
[] [PMID: 27633304]
Jampilek, J. Recent advances in design of potential quinoxaline anti-infectives. Curr. Med. Chem., 2014, 21(38), 4347-4373.
[] [PMID: 25312209]
Balderas-Renteria, I.; Gonzalez-Barranco, P.; Garcia, A.; Banik, B.K.; Rivera, G. Anticancer drug design using scaffolds of β-lactams, sulfonamides, quinoline, quinoxaline and natural products. Drugs advances in clinical trials. Curr. Med. Chem., 2012, 19(26), 4377-4398.
[] [PMID: 22709002]
Patel, N.B.; Patel, J.N.; Purohit, A.C.; Patel, V.M.; Rajani, D.P.; Moo-Puc, R.; Lopez-Cedillo, J.C.; Nogueda-Torres, B.; Rivera, G. In vitro and in vivo assessment of newer quinoxaline-oxadiazole hybrids as antimicrobial and antiprotozoal agents. Int. J. Antimicrob. Agents, 2017, 50(3), 413-418.
[] [PMID: 28687457]
Cheng, 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.
[] [PMID: 27047380]
Villalobos-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.
[] [PMID: 24691716]
Chacón-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.
[] [PMID: 29159705]
Quiliano, M.; Pabón, A.; Ramirez-Calderon, G.; Barea, C.; Deharo, E.; Galiano, S.; Aldana, I. New hydrazine and hydrazide quinoxaline 1,4-di-N-oxide derivatives: In silico ADMET, antiplasmodial and antileishmanial activity. Bioorg. Med. Chem. Lett., 2017, 27(8), 1820-1825.
[] [PMID: 28291694]
Duque-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.
[] [PMID: 23787289]
Gómez-Caro, L.C.; Sánchez-Sánchez, M.; Bocanegra-García, V.; Monge, A.; Rivera, G. Synthesis of quinoxaline 1,4-di-N-oxide derivatives on solid support using room temperature and microwave-assisted solvent-free procedures. Quim. Nova, 2011, 34, 1147-1151.
Hernández-Núñez, E.; Tlahuext, H.; Moo-Puc, R.; Torres-Gómez, H.; Reyes-Martínez, R.; Cedillo-Rivera, R.; Nava-Zuazo, C.; Navarrete-Vazquez, G. Synthesis and in vitro trichomonicidal, giardicidal and amebicidal activity of N-acetamide(sulfonamide)-2-methyl-4-nitro-1H-imidazoles. Eur. J. Med. Chem., 2009, 44(7), 2975-2984.
[] [PMID: 19208443]
Cedillo-Rivera, R.; Enciso-Moreno, J.A.; Martínez-Palomo, A.; Ortega Pierres, G. Isolation and axenization of Giardia lamblia isolates from symptomatic and asymptomatic patients in Mexico. Arch. Invest. Med. (Mex.), 1991, 22(1), 79-85.
[PMID: 1819980]
Barbosa, E.; Calzada, F.; Campos, R. In vivo antigiardial activity of three flavonoids isolated of some medicinal plants used in Mexican traditional medicine for the treatment of diarrhea. J. Ethnopharmacol., 2007, 109(3), 552-554.
[] [PMID: 17052875]
Navarrete-Vázquez, G.; Cedillo, R.; Hernández-Campos, A.; Yépez, L.; Hernädez-Luis, F.; Valdez, J.; Morales, R.; Cortés, R.; Hernández, M.; Castillo, R. Synthesis and antiparasitic activity of 2-(trifluoromethyl)-benzimidazole derivatives. Bioorg. Med. Chem. Lett., 2001, 11(2), 187-190.
[] [PMID: 11206455]
Valdez, J.; Cedillo, R.; Hernández-Campos, A.; Yépez, L.; Hernández-Luis, F.; Navarrete-Vázquez, G.; Tapia, A.; Cortés, R.; Hernández, M.; Castillo, R. Synthesis and antiparasitic activity of 1H-benzimidazole derivatives. Bioorg. Med. Chem. Lett., 2002, 12(16), 2221-2224.
[] [PMID: 12127542]
Torres-Gómez, H.; Hernández-Núñez, E.; León-Rivera, I.; Guerrero-Alvarez, J.; Cedillo-Rivera, R.; Moo-Puc, R.; Argotte-Ramos, R. Rodríguez-Gutiérrez, Mdel.C.; Chan-Bacab, M.J.; Navarrete-Vázquez, G. Design, synthesis and in vitro antiprotozoal activity of benzimidazole-pentamidine hybrids. Bioorg. Med. Chem. Lett., 2008, 18(11), 3147-3151.
[] [PMID: 18486471]
Anderson, V.R.; Curran, M.P. Nitazoxanide: A review of its use in the treatment of gastrointestinal infections. Drugs, 2007, 67(13), 1947-1967.
[] [PMID: 17722965]
Shakya, A.; Bhat, H.R.; Ghosh, S.K. update on nitazoxanide: A multifunctional chemotherapeutic agent. Curr. Drug Discov. Technol., 2018, 15(3), 201-213.
[] [PMID: 28748751]

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Article Details

Year: 2020
Published on: 25 April, 2020
Page: [428 - 433]
Pages: 6
DOI: 10.2174/1570180816666190618115854

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