التركيب الكيميائي والخصائص والقوى المحركة المخبرية لدوائيْن أوليّيْن جديديْن مبتكريْن من مضادات البكتيريا؛ الأموكسيلين والسيفالكسين
Synthesis, Characterization and In Vitro Kinetics of Amoxicillin and Cephalexin Antibacterial Prodrugs
غدير عبد مطر دقماق
GHADEER ABED MATAR DOKMAK
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Marketed antibacterial drugs suffer several problems, such as bitter taste and low stability which lead to patient incompliance. Prodrug technology for solving such problems is extremely exciting. Based on previously reported density functional theory calculations, amoxicillin ProD 1-2 and cephalexin ProD 1-2 were designed and synthesized. For the intraconversion of both antibacterial prodrugs the kobs and t1/2 values in different media were calculated from the linear regression equation obtained from the correlation of log concentration of the residual prodrug versus time. At constant temperature and pH the hydrolysis reaction for the above mentioned prodrugs displayed strict first order kinetics as the kobs was quite constant and a straight line was obtained. Kinetic studies in 1N HCl, pH 2.5 and pH 5 were selected to examine the intraconversion of both prodrugs to their parent drugs. The acid-catalyzed hydrolysis of the prodrugs was found to be much higher in 1N HCl than in pH 2.5 and pH 5. The experimental t1/2 values of amoxicillin ProD 1 in 1N HCl, pH 2.5 and pH 5 were 2.5, 7 and 81 hours respectively and for cephalexin ProD 1 in 1 N HCl and pH 2.5 were 2 and 14 hours respectively. In contrast, t1/2 values of amoxicillin ProD 2 in 1N HCl and pH 2.5 were 8 and 44 hours respectively and for cephalexin ProD 2 in 1 N HCl was 6 hours. On the other hand, at pH 7.4, the four prodrugs were quite stable and no release of the parent drugs was observed. At pH 5 the hydrolysis of the prodrugs was too slow. The four antibacterial prodrugs were found to be bitterless. The bitter taste masking by the prodrugs is believed to be via altering the ability of the drug to interact with bitter taste receptors.