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Abstract

DESIGN, SYNTHESIS, CHARACTERIZATION AND IN VITRO KINETIC STUDY OF NOVEL ANTIBACTERIALS PRODRUGS

Rafik Karaman*, Ghadeer Dokmak, Omar Hamarsheh and Donia Karaman

ABSTRACT

A number of marketed antibacterial drugs suffer several problems, such as bitter sensation and low stability which lead to patient incompliance. The prodrug approach is considered the most promising and extremely exciting method to overcome such problems. Based on our previously reported density functional theory (DFT) calculations, amoxicillin ProD 1-2 and cephalexin ProD 1-2 were designed, synthesized and fully characterized. The intraconversion kinetics for amoxicillin ProD 1-2 and cephalexin ProD 1-2 were carried out in different aqueous media and the kobs and t1/2 values for the four prodrugs were calculated from a linear regression equation obtained from the plot of log concentration of the residual prodrug versus time. Kinetic studies in 1N HCl, pH 2.5 and pH 5 were selected to examine the intraconversion for the prodrugs to their active parent drugs. The intraconversion of the prodrugs to their active parent drugs 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. On the other hand, the 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. 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. In vitro binding test revealed that the four antibacterial prodrugs were bitterless and it is believed that the lack of the bitter sensation is due to the disability of the prodrugs to interact with the active sites of the tested bitter taste receptors.

Keywords: Prodrugs, bitterness, antibacterials, amoxicillin, cephalexin, enzyme model, DFT calculations, Kirby‘s N-alkylmaleamic acids


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