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
N1 - Funding Information:
Acknowledgments This study was taken in part from the PhD Thesis of A. Valladares-Mendez, and it was supported in part by internal funds from Facultad de Farmacia, UAEM and Universidad de Guanajuato. We are in debt to Johnatan Cauich Chan, from the UADY, for his technical assistance with antiprotozoal susceptibility assays. A. Valladares-Méndez thanks Consejo Nacional de Ciencia y Tecnología (CONACyT) for the fellowship (Registration No. 164413) during the realization of this study.
Funding Information:
Funding Financial support in part by internal funds from Facultad de Farmacia, UAEM, Universidad de Guanajuato and PROMEP (Project: F-PROMEP-38/Rev-03SEP-23-005). This study was taken in part from the PhD thesis of A. Valladares-Méndez.
PY - 2014/6
Y1 - 2014/6
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.
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.
KW - Double peak
KW - Giardicidal activity
KW - Oral administration
KW - Pharmacokinetics
KW - Single dose
UR - http://www.scopus.com/inward/record.url?scp=84898870401&partnerID=8YFLogxK
U2 - 10.1007/s00044-013-0893-9
DO - 10.1007/s00044-013-0893-9
M3 - Artículo
SN - 1054-2523
VL - 23
SP - 3157
EP - 3164
JO - Medicinal Chemistry Research
JF - Medicinal Chemistry Research
IS - 6
ER -