Synthesis, in vitro and in vivo giardicidal activity, and pharmacokinetic profile of a new nitazoxanide analog

Adriana Valladares-Méndez, Emanuel Hernández-Núñez, Roberto Cedillo-Rivera, Rosa Moo-Puc, Elizabeth Barbosa-Cabrera, Luis M. Orozco-Castellanos, Julio C. Rivera-Leyva, Gabriel Navarrete-Vázquez

Research output: Contribution to journalArticle

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Abstract

4-Nitro-N-(5-nitro-1,3-thiazol-2-yl)benzamide (1), a new nitazoxanide analog, was synthesized; its chemical structure was confirmed by 1H, 13C NMR, and HRMS. In this study, we evaluated the in vitro activity of compound 1 against Giardia lamblia trophozoites, as well as its in vivo giardicidal activity in a CD-1 mouse model. A pharmacokinetic study in Wistar rats evaluated compound 1 disposition after intravenous (IV) and oral administration of 3.3 and 150 mg/kg, respectively. Compound 1 inhibited G. lamblia growth in vitro with a median inhibitory concentration (IC50) of 0.78 ± 0.01 μM, and thus was more effective than metronidazole (IC50 = 5.36 ± 0.23 μM), the drug of choice against this parasite. An evaluation of cytotoxicity using VERO cells showed that compound 1 was less cytotoxic than metronidazole (CC50 = 685.98 vs. CC 50 = 68 μM, respectively), with a favorable selectivity index (SI = 879). In vivo, we found that 97.2 % of parasite load was eliminated after intragastric administration of compound 1 (75 mg/kg). An analysis of the oral pharmacokinetic profile revealed a double peak of maximum concentration. Pharmacokinetic parameters indicated an absolute bioavailability approaching 33 %, a prolonged half-life, a large distribution volume, and slow clearance. This pharmacokinetic behavior of compound 1 makes it a promising candidate for the treatment of infections caused by both intestinal and systemic parasites. © 2013 Springer Science+Business Media New York.
Original languageAmerican English
Pages (from-to)3157-3164
Number of pages2840
JournalMedicinal Chemistry Research
DOIs
StatePublished - 1 Jan 2014

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nitazoxanide
Pharmacokinetics
Giardia lamblia
Metronidazole
Inhibitory Concentration 50
Parasites
Parasite Load
Trophozoites
Cytotoxicity
Intravenous Administration
Biological Availability
Oral Administration
Half-Life
Wistar Rats
Rats
Nuclear magnetic resonance
In Vitro Techniques
Growth
Infection

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Valladares-Méndez, A., Hernández-Núñez, E., Cedillo-Rivera, R., Moo-Puc, R., Barbosa-Cabrera, E., Orozco-Castellanos, L. M., ... Navarrete-Vázquez, G. (2014). Synthesis, in vitro and in vivo giardicidal activity, and pharmacokinetic profile of a new nitazoxanide analog. Medicinal Chemistry Research, 3157-3164. https://doi.org/10.1007/s00044-013-0893-9
Valladares-Méndez, Adriana ; Hernández-Núñez, Emanuel ; Cedillo-Rivera, Roberto ; Moo-Puc, Rosa ; Barbosa-Cabrera, Elizabeth ; Orozco-Castellanos, Luis M. ; Rivera-Leyva, Julio C. ; Navarrete-Vázquez, Gabriel. / Synthesis, in vitro and in vivo giardicidal activity, and pharmacokinetic profile of a new nitazoxanide analog. In: Medicinal Chemistry Research. 2014 ; pp. 3157-3164.
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Valladares-Méndez, A, Hernández-Núñez, E, Cedillo-Rivera, R, Moo-Puc, R, Barbosa-Cabrera, E, Orozco-Castellanos, LM, Rivera-Leyva, JC & Navarrete-Vázquez, G 2014, 'Synthesis, in vitro and in vivo giardicidal activity, and pharmacokinetic profile of a new nitazoxanide analog', Medicinal Chemistry Research, pp. 3157-3164. https://doi.org/10.1007/s00044-013-0893-9

Synthesis, in vitro and in vivo giardicidal activity, and pharmacokinetic profile of a new nitazoxanide analog. / Valladares-Méndez, Adriana; Hernández-Núñez, Emanuel; Cedillo-Rivera, Roberto; Moo-Puc, Rosa; Barbosa-Cabrera, Elizabeth; Orozco-Castellanos, Luis M.; Rivera-Leyva, Julio C.; Navarrete-Vázquez, Gabriel.

In: Medicinal Chemistry Research, 01.01.2014, p. 3157-3164.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis, in vitro and in vivo giardicidal activity, and pharmacokinetic profile of a new nitazoxanide analog

AU - Valladares-Méndez, Adriana

AU - Hernández-Núñez, Emanuel

AU - Cedillo-Rivera, Roberto

AU - Moo-Puc, Rosa

AU - Barbosa-Cabrera, Elizabeth

AU - Orozco-Castellanos, Luis M.

AU - Rivera-Leyva, Julio C.

AU - Navarrete-Vázquez, Gabriel

PY - 2014/1/1

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N2 - 4-Nitro-N-(5-nitro-1,3-thiazol-2-yl)benzamide (1), a new nitazoxanide analog, was synthesized; its chemical structure was confirmed by 1H, 13C NMR, and HRMS. In this study, we evaluated the in vitro activity of compound 1 against Giardia lamblia trophozoites, as well as its in vivo giardicidal activity in a CD-1 mouse model. A pharmacokinetic study in Wistar rats evaluated compound 1 disposition after intravenous (IV) and oral administration of 3.3 and 150 mg/kg, respectively. Compound 1 inhibited G. lamblia growth in vitro with a median inhibitory concentration (IC50) of 0.78 ± 0.01 μM, and thus was more effective than metronidazole (IC50 = 5.36 ± 0.23 μM), the drug of choice against this parasite. An evaluation of cytotoxicity using VERO cells showed that compound 1 was less cytotoxic than metronidazole (CC50 = 685.98 vs. CC 50 = 68 μM, respectively), with a favorable selectivity index (SI = 879). In vivo, we found that 97.2 % of parasite load was eliminated after intragastric administration of compound 1 (75 mg/kg). An analysis of the oral pharmacokinetic profile revealed a double peak of maximum concentration. Pharmacokinetic parameters indicated an absolute bioavailability approaching 33 %, a prolonged half-life, a large distribution volume, and slow clearance. This pharmacokinetic behavior of compound 1 makes it a promising candidate for the treatment of infections caused by both intestinal and systemic parasites. © 2013 Springer Science+Business Media New York.

AB - 4-Nitro-N-(5-nitro-1,3-thiazol-2-yl)benzamide (1), a new nitazoxanide analog, was synthesized; its chemical structure was confirmed by 1H, 13C NMR, and HRMS. In this study, we evaluated the in vitro activity of compound 1 against Giardia lamblia trophozoites, as well as its in vivo giardicidal activity in a CD-1 mouse model. A pharmacokinetic study in Wistar rats evaluated compound 1 disposition after intravenous (IV) and oral administration of 3.3 and 150 mg/kg, respectively. Compound 1 inhibited G. lamblia growth in vitro with a median inhibitory concentration (IC50) of 0.78 ± 0.01 μM, and thus was more effective than metronidazole (IC50 = 5.36 ± 0.23 μM), the drug of choice against this parasite. An evaluation of cytotoxicity using VERO cells showed that compound 1 was less cytotoxic than metronidazole (CC50 = 685.98 vs. CC 50 = 68 μM, respectively), with a favorable selectivity index (SI = 879). In vivo, we found that 97.2 % of parasite load was eliminated after intragastric administration of compound 1 (75 mg/kg). An analysis of the oral pharmacokinetic profile revealed a double peak of maximum concentration. Pharmacokinetic parameters indicated an absolute bioavailability approaching 33 %, a prolonged half-life, a large distribution volume, and slow clearance. This pharmacokinetic behavior of compound 1 makes it a promising candidate for the treatment of infections caused by both intestinal and systemic parasites. © 2013 Springer Science+Business Media New York.

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