Prodrugs of Acyclovir - A Computational Approach
Date
2012-02-12
Authors
Karaman, Rafik
Dajani, Khuloud K.
Qtait, Alaa
Khamis, Mustafa
Journal Title
Journal ISSN
Volume Title
Publisher
John Wiley & Sons
Abstract
Density functional theory calculation results demonstrated
that the efficiency of the acid-catalyzed
hydrolysis of Kirby’s acid amides 1–15 is strongly
dependent on the substitution on the C–C double
bond and the nature of the amide N-alkyl group.
Further, the results established that while in the
gas phase the hydrolysis rate-limiting step is the
tetrahedral intermediate formation in polar solvents
such as water, the rate-limiting step could
be either the formation or the collapse of the tetrahedral
intermediate depending on the substitution
on the C–C double bond and on the amide
nitrogen substituent. Based on a linear correlation
between the calculated and experimental effective
molarities, the study on the systems reported
herein could provide a good basis for designing
prodrug systems that are less hydrophilic than
their parental drugs and can be used, in different
dosage forms, to release the parent drug in a
controlled manner. For example, based on the
calculated log effective molarities values, the predicted
t1/2 (a time needed for 50% of the reactant
to be hydrolyzed to products) for acyclovir
prodrugs, ProD 1–4, was 29.2 h, 6097 days,
4.6 min, and 8.34 h, respectively. Hence, the rate
by which acyclovir prodrug releases acyclovir can
be determined according to the structural features
of the linker (Kirby’s acid amide moiety).
Description
Keywords
acyclovir prodrugs , bioavailability of acyclovir , density functional theory calculations , intramolecular amide hydrolysis , maleamic acid amides