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Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies
Author(s) -
Thawabteh Amin,
Lelario Filomena,
Scrano Laura,
Bufo Sabino A.,
Nowak Stefanie,
Behrens Maik,
Di Pizio Antonella,
Niv Masha Y.,
Karaman Rafik
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13409
Subject(s) - prodrug , chemistry , hydrolysis , nucleophile , combinatorial chemistry , stereochemistry , organic chemistry , biochemistry , catalysis
A respected number of drugs suffer from bitter taste which results in patient incompliance. With the aim of solving the bitterness of guaifenesin, dimethyl maleate, maleate, glutarate, succinate, and dimethyl succinate prodrugs were designed and synthesized. Molecular orbital methods were utilized for the design of the ester prodrugs. The density functional theory ( DFT ) calculations revealed that the hydrolysis efficiency of the synthesized prodrugs is significantly sensitive to the pattern of substitution on C=C bond and distance between the nucleophile and the electrophile. The hydrolysis of the prodrugs was largely affected by the pH of the medium. The experimental t 1/2 for the hydrolysis of guaifenesin dimaleate ester prodrugs in 1N HC l was the least and for guaifenesin dimethyl succinate was the highest. Functional heterologous expression of TAS 2R14, a broadly tuned bitter taste receptor responding to guaifenesin, and experiments using these prodrugs revealed that, while some of the prodrugs still activated the receptor similarly or even stronger than the parent substance, succinate derivatization resulted in the complete loss of receptor responses. The predicted binding modes of guaifenesin and its prodrugs to the TAS 2R14 homology model suggest that the decreased activity of the succinate derivatives may be caused by a clash with Phe247.