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Physicochemical characterization of two new Nitazoxanide analogs with antiparasitic activity

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Abstract

The low oral bioavailability of drugs can be principally attributed to their low solubility, low permeability, and low dissolution rate in the gastrointestinal tract. Considering the low lab-to-market success rate, it is highly important to evaluate these bioavailability factors in the early stages of drug discovery and development. In this work, some physicochemical properties of two new Nitazoxanide analogs (Compounds 1 and 2) were evaluated. Both compounds showed limited aqueous solubility in the pH range of the gastrointestinal tract (16 and 18 μg/mL, respectively), and Log P values were 1.01 and 1.44, for Compounds 1 and 2, respectively. These values indicate a slight affinity for lipid components. The compounds are comprised of a thiazole ring with basic character and an amide group with acidic character; as a result they present ampholytic behavior, with pKa values of 6.029 and 9.565 for Compound 1, and 4.945 and 8.127 for Compound 2. The apparent permeability was evaluated using an everted rat intestine and was quantified using a high performance liquid chromatography equipped with a UV–Vis detector. The results showed that permeability was limited for both compounds (1.15 × 10−5 cm/s for Compound 1 and 9.09 × 10−7 cm/s for Compound 2) when compared to furosemide (1.16 × 10−5 cm/s), a low permeability standard control. These new compounds were therefore classified as low permeability and low solubility (Class IV) according to the Biopharmaceutical Classification System.

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Acknowledgments

Part of this work was carried out at the Universidad of Guanajuato and RGV Analítica Industrial Research Laboratory. The authors acknowledge the support received by both institutions, whether as economic support PROMEP 2011 Program, as well as an internal grant from the Faculty of Pharmacy of Universidad Autónoma del Estado de Morelos, Universidad de Guanajuato and RGV Analítica Industrial Research Laboratory. Likewise, the support of the Dirección General de Apoyo a la Investigación y al Posgrado (DAIP) of Universidad de Guanajuato for the revision of the manuscript in English is appreciated.

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Authors and Affiliations

  1. Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, 62209, Morelos, Mexico

    Adriana Valladares-Méndez, Mirna García-Flores, Gabriel Navarrete-Vázquez & Julio C Rivera-Leyva

  2. RGV Analitica Industrial Research Laboratory, Yautepec, 62733, Morelos, Mexico

    Adriana Valladares-Méndez & Mirna García-Flores

  3. Departamento de Farmacia, Universidad de Guanajuato, Guanajuato, 36050, Guanajuato, Mexico

    Luis M. Orozco-Castellanos & Julio C Rivera-Leyva

  4. Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Mérida, 97310, Yucatán, Mexico

    Emanuel Hernandez-Nuñez

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  1. Adriana Valladares-Méndez
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  2. Mirna García-Flores
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  3. Gabriel Navarrete-Vázquez
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Correspondence to Julio C Rivera-Leyva.

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Valladares-Méndez, A., García-Flores, M., Navarrete-Vázquez, G. et al. Physicochemical characterization of two new Nitazoxanide analogs with antiparasitic activity. Med Chem Res 26, 9–18 (2017). https://doi.org/10.1007/s00044-016-1749-x

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