Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition

Simone Di Micco; Stefania Terracciano; Dafne Ruggiero; Marianna Potenza; Maria C Vaccaro; Katrin Fischer; Oliver Werz; Ines Bruno; Giuseppe Bifulco

doi:10.3389/fchem.2021.676631

Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition

Front Chem. 2021 May 7:9:676631. doi: 10.3389/fchem.2021.676631. eCollection 2021.

Authors

Simone Di Micco¹, Stefania Terracciano², Dafne Ruggiero², Marianna Potenza², Maria C Vaccaro², Katrin Fischer³, Oliver Werz³, Ines Bruno², Giuseppe Bifulco²

Affiliations

¹ European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy.
² Dipartimento di Farmacia, University degli Studi di Salerno, Fisciano, Italy.
³ Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany.

Abstract

We report the implementation of our in silico/synthesis pipeline by targeting the glutathione-dependent enzyme mPGES-1, a valuable macromolecular target in both cancer therapy and inflammation therapy. Specifically, by using a virtual fragment screening approach of aromatic bromides, straightforwardly modifiable by the Suzuki-Miyaura reaction, we identified 3-phenylpropanoic acid and 2-(thiophen-2-yl)acetic acid to be suitable chemical platforms to develop tighter mPGES-1 inhibitors. Among these, compounds 1c and 2c showed selective inhibitory activity against mPGES-1 in the low micromolar range in accordance with molecular modeling calculations. Moreover, 1c and 2c exhibited interesting IC₅₀ values on A549 cell lines compared to CAY10526, selected as reference compound. The most promising compound 2c induced the cycle arrest in the G₀/G₁ phase at 24 h of exposure, whereas at 48 and 72 h, it caused an increase of subG₀/G₁ fraction, suggesting an apoptosis/necrosis effect.

Keywords: Suzuki-Miyaura cross-coupling; anti-inflammatory drugs; anticancer agents; fragment-based approach; mPGES-1 inhibitors.