Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies

Amin Thawabteh, Filomena Lelario, Laura Scrano, Sabino A. Bufo, Stefanie Nowak, Maik Behrens, Antonella Di Pizio, Masha Y. Niv, Rafik Karaman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 HCl was the least and for guaifenesin dimethyl succinate was the highest. Functional heterologous expression of TAS2R14, 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 TAS2R14 homology model suggest that the decreased activity of the succinate derivatives may be caused by a clash with Phe247.

Original languageAmerican English
Pages (from-to)262-271
Number of pages10
JournalChemical Biology and Drug Design
Issue number3
StatePublished - Mar 2019

Bibliographical note

Publisher Copyright:
© 2018 John Wiley & Sons A/S


  • DFT calculations
  • acid-catalyzed ester hydrolysis
  • bitter taste
  • guaifenesin
  • molecular modeling
  • prodrugs


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