Design, Synthesis, Characterization and In-Vitro Kinetic Study of Novel Antibacterials Prodrugs
Date
2015-10-30
Authors
Karaman, Rafik
Dokmak, Ghadeer
Hamarsheh, Omar
Karaman, Donia
Journal Title
Journal ISSN
Volume Title
Publisher
WJPR,Tara Pal,WJPR
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.
Description
Keywords
Prodrugs , bitterness , antibacterials , amoxicillin , cephalexin , enzyme model , DFT calculations , Kirby‘s N-alkylmaleamic acids