Computer-assisted design for atenolol prodrugs for the use in aqueous formulations Karaman, Rafik Dajani, Khuloud Hallak, Hussein 2018-09-22T08:58:37Z 2018-09-22T08:58:37Z 2011-07-23
dc.description.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). en_US
dc.description.sponsorship The Karaman Co. is thanked for support of our computational facilities. Special thanks are also given to Angi Karaman, Donia Karaman, Rowan Karaman and Nardene Karaman for technical assistance. en_US
dc.identifier.issn 1610-2940
dc.language.iso en_US en_US
dc.publisher Springer-Verlag en_US
dc.subject Amide hydrolysis en_US
dc.subject Anti-hypertensive agents en_US
dc.subject Atenolol prodrugs en_US
dc.subject DFT calculations en_US
dc.subject Enzyme catalysis en_US
dc.subject Intramolecular acid-catalyzed hydrolysis en_US
dc.subject Maleamic acid amide derivatives en_US
dc.subject Strain effects en_US
dc.title Computer-assisted design for atenolol prodrugs for the use in aqueous formulations en_US
dc.type Article en_US
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