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

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• 作者：Adriana Valladares-Méndez (1)
  Emanuel Hernández-Nú?ez (1) (2)
  Roberto Cedillo-Rivera (3)
  Rosa Moo-Puc (3)
  Elizabeth Barbosa-Cabrera (4)
  Luis M. Orozco-Castellanos (5)
  Julio C. Rivera-Leyva (1)
  Gabriel Navarrete-Vázquez (1)
  
• 关键词：Giardicidal activity ; Pharmacokinetics ; Oral administration ; Single dose ; Double peak
• 刊名：Medicinal Chemistry Research
• 出版年：2014
• 出版时间：June 2014
• 年：2014
• 卷：23
• 期：6
• 页码：3157-3164
• 全文大小：348 KB
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• 作者单位：Adriana Valladares-Méndez (1)
  Emanuel Hernández-Nú?ez (1) (2)
  Roberto Cedillo-Rivera (3)
  Rosa Moo-Puc (3)
  Elizabeth Barbosa-Cabrera (4)
  Luis M. Orozco-Castellanos (5)
  Julio C. Rivera-Leyva (1)
  Gabriel Navarrete-Vázquez (1)
  
  1. Facultad de Farmacia, Universidad Autónoma Del Estado de Morelos, 62209, Cuernavaca, Morelos, Mexico
  2. Facultad de Ingeniería, Universidad Autónoma de Yucatán, 97310, Mérida, Yucatán, Mexico
  3. Unidad de Investigación Médica Yucatán, Unidad Médica de Alta Especialidad, IMSS, 97000, Mérida, Yucatán, Mexico
  4. Sección de Estudios de Posgrado E Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340, México, DF, Mexico
  5. Departamento de Farmacia, Universidad de Guanajuato, 36050, Guanajuato, Guanajuato, Mexico
  
• ISSN：1554-8120

文摘

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. CC50?=?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.