تطوير دواء اولي مبتكر للاتوفاكوون? الدواء المضاد للملاريا: تصنيع كيميائي, تشخيص و تقييم القوى المحركه المخبريه
Novel Anti-malarial Atovaquone P rodrug: Synthesis,Characterization and in vitro Kinetics Study
بيسان وضاح امين الفتاش
Beesan Waddah Amin Alfattash
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Malaria is a global public health problem, resulting in tow million deaths per year .The majority of death cases are due to the most severe form of malaria caused by Plasmodium falciparum. As a result, efforts were directed toward the development of new effective medications intended for the treatment of this endemic disease. Atovaqoune is a new treatment option, showed an improvement in malaria treatment. Although Atovaqoune is an effective medication, it has its own limitations. Atovaqoune is highly lipophilic compound (water solubility < 0.2 µg/ mL), has low water solubility and low absorption, hence low bioavailability (< 10% in the fasted state). Accordingly, increasing atovaqoune aqueous solubility will improve its pharmacokinetic profile in particular bioavailability, thus improving its effectiveness and ability to administer the drug through different routs of administration. So that, our goal was to develop atovaqoune prod rug that possesses increased aqueous solubility by linking water soluble moiety to the 3- hydroxyl group, via chemical synthesis. Purification techniques including extraction, re-crystallization and column chromatography were used. Identity confirmation was done using, IR, NMR and LC/MS. Based on purity and identity results; in vitro kinetic studies using the HPLC instrument were performed at pH 2.2, 5.5 and 7.4. ATQ succinate (ProD1) has been successfully synthesized, purified and evaluated. T1/2 of ProD1 at pH 2.2, 5.5 and 7.4 is 28.8 days, 2.2 days, 3.2 days, respectively. It can be concluded from these data, that ProD1 is converted into ATQ in pH dependentmanner, and the hydrolysis of the prodrug follows first order kinetics, as the data plotted gives a straight line, and the Kobs is nearly constant. Concisely, modifying atovaqoune structure may result in enhancing its pharmacokinetic profile mainly absorption into body tissues, consequently increasing efficacy and ability to formulate atovaqoune in different dosage forms. Keywords: Malaria, drug resistance, atovaquone, bioavailability, prodrugs .