Computer-assisted design for atenolol prodrugs for the use in aqueous formulations
Date
2011-07-23
Authors
Karaman, Rafik
Dajani, Khuloud
Hallak, Hussein
Journal Title
Journal ISSN
Volume Title
Publisher
Springer-Verlag
Abstract
Based on stability studies on the drugs atenolol
and propranolol and some of their derivatives it is believed
that increasing the lipophilicity of the drug will lead to an
increase in the stability of its aqueous solutions and will
provide a prodrug system with the potential for releasing
atenolol in a controlled manner. Using DFT theoretical
calculations we have calculated an intramolecular acid
catalyzed hydrolysis in nine maleamic (4-amino-4-oxo-
2butenoic) acids (Kirby’s N-alkylmaleamic acids), 1–9. The
DFT calculations confirmed that the acid-catalyzed hydrolysis
mechanism in these systems involves: (1) a proton
transfer from the hydroxyl of the carboxyl group to the
adjacent amide carbonyl carbon, (2) an approach of the
carboxylate anion toward the protonated amide carbonyl
carbon to form a tetrahedral intermediate; and (3) a collapse
of the tetrahedral intermediate into products. Furthermore,
DFT calculations in different media revealed that the
reaction rate-limiting step depends on the reaction medium.
In aqueous medium the rate-limiting step is the collapse of
the tetrahedral intermediate whereas in the gas phase the
formation of the tetrahedral intermediate is the rate-limiting
step. Furthermore, the calculations establish that the acidcatalyzed
hydrolysis efficiency is largely sensitive to the
pattern of substitution on the carbon-carbon double bond. Based on the experimental t1/2 (the time needed for the
conversion of 50% of the reactants to products) and EM
(effective molarity) values for processes 1–9 we have
calculated the t1/2 values for the conversion of the two
prodrugs to the parental drug, atenolol. The calculated t1/2
values for ProD 1–2 are predicted to be 65.3 hours and 11.8
minutes, respectively. Thus, the rate by which atenolol
prodrug undergoes cleavage to release atenolol can be
determined according to the nature of the linker of the
prodrug (Kirby’s N-alkylmaleamic acids 1–9).
Description
Keywords
Amide hydrolysis , Anti-hypertensive agents , Atenolol prodrugs , DFT calculations , Enzyme catalysis , Intramolecular acid-catalyzed hydrolysis , Maleamic acid amide derivatives , Strain effects