Physicochemical characterization of two new Nitazoxanide analogs with antiparasitic activity

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• 作者：Adriana Valladares-Méndez ; Mirna García-Flores…
• 关键词：Nitazoxanide analogs ; Physicochemical characterization ; Apparent permeability ; Aqueous solubility ; Biopharmaceutical properties
• 刊名：Medicinal Chemistry Research
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：26
• 期：1
• 页码：9-18
• 全文大小：
• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Cell Biology;
• 出版者：Springer US
• ISSN：1554-8120
• 卷排序：26

文摘

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.