Details
| Original language | English |
|---|---|
| Article number | 113797 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 226 |
| Early online date | 28 Aug 2021 |
| Publication status | Published - 15 Dec 2021 |
| Externally published | Yes |
Abstract
A short and divergent route towards new derivatives of 2-(trifluoromethyl)pyridines as potent inverse agonists of the bacterial target PqsR against Pseudomonas aeruginosa (PA) infections is described. This Gram-negative pathogen causes severe nosocomial infections and common antibiotic treatment options are rendered ineffective due to resistance issues. Based on an earlier identified optimized hit, we conducted derivatization and rigidification attempts employing two central building blocks. The western part of the molecule is built up via a 2-(trifluoromethyl)pyridine head group equipped with a terminal alkyne. The eastern section is then introduced through aryliode motifs exploiting Sonogashira as well as Suzuki-type chemistry. Subsequent modification provided quick access to an array of compounds, allowed for deep SAR insights, and enabled to optimize the hit scaffold into a lead structure of nanomolar potency combined with favorable in vitro ADME/T features.
Keywords
- Divergent synthesis, Hit-to-lead optimization, Pathoblocker, Pseudomonas aeruginosa, Quorum sensing
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Drug Discovery
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology
- Chemistry(all)
- Organic Chemistry
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In: European Journal of Medicinal Chemistry, Vol. 226, 113797, 15.12.2021.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Divergent synthesis and biological evaluation of 2-(trifluoromethyl)pyridines as virulence-attenuating inverse agonists targeting PqsR
AU - Schütz, Christian
AU - Hodzic, Amir
AU - Hamed, Mostafa
AU - Abdelsamie, Ahmed S.
AU - Kany, Andreas M.
AU - Bauer, Maximilian
AU - Röhrig, Teresa
AU - Schmelz, Stefan
AU - Scrima, Andrea
AU - Blankenfeldt, Wulf
AU - Empting, Martin
N1 - Funding information: The authors acknowledge the financial support by the German Centre for Infection Research ( DZIF ) through DZIF Flexible Funds TTU09.908 and the Helmholtz Association through Helmholtz Validation Fonds HVF-0054. Furthermore, the authors would like to thank T. Hesterkamp and M. Steindorff for their great help in coordinating and managing the project as well as M. Rösner for his valuable scientific input. We would also like to thank Simone Amann, Dennis Jener, Jeannine Jung, Tabea Schramm and Selina Wolter for conduction of routine assays. The authors acknowledge the financial support by the German Centre for Infection Research (DZIF) through DZIF Flexible Funds TTU09.908 and the Helmholtz Association through Helmholtz Validation Fonds HVF-0054. Furthermore, the authors would like to thank T. Hesterkamp and M. Steindorff for their great help in coordinating and managing the project as well as M. R?sner for his valuable scientific input. We would also like to thank Simone Amann, Dennis Jener, Jeannine Jung, Tabea Schramm and Selina Wolter for conduction of routine assays.
PY - 2021/12/15
Y1 - 2021/12/15
N2 - A short and divergent route towards new derivatives of 2-(trifluoromethyl)pyridines as potent inverse agonists of the bacterial target PqsR against Pseudomonas aeruginosa (PA) infections is described. This Gram-negative pathogen causes severe nosocomial infections and common antibiotic treatment options are rendered ineffective due to resistance issues. Based on an earlier identified optimized hit, we conducted derivatization and rigidification attempts employing two central building blocks. The western part of the molecule is built up via a 2-(trifluoromethyl)pyridine head group equipped with a terminal alkyne. The eastern section is then introduced through aryliode motifs exploiting Sonogashira as well as Suzuki-type chemistry. Subsequent modification provided quick access to an array of compounds, allowed for deep SAR insights, and enabled to optimize the hit scaffold into a lead structure of nanomolar potency combined with favorable in vitro ADME/T features.
AB - A short and divergent route towards new derivatives of 2-(trifluoromethyl)pyridines as potent inverse agonists of the bacterial target PqsR against Pseudomonas aeruginosa (PA) infections is described. This Gram-negative pathogen causes severe nosocomial infections and common antibiotic treatment options are rendered ineffective due to resistance issues. Based on an earlier identified optimized hit, we conducted derivatization and rigidification attempts employing two central building blocks. The western part of the molecule is built up via a 2-(trifluoromethyl)pyridine head group equipped with a terminal alkyne. The eastern section is then introduced through aryliode motifs exploiting Sonogashira as well as Suzuki-type chemistry. Subsequent modification provided quick access to an array of compounds, allowed for deep SAR insights, and enabled to optimize the hit scaffold into a lead structure of nanomolar potency combined with favorable in vitro ADME/T features.
KW - Divergent synthesis
KW - Hit-to-lead optimization
KW - Pathoblocker
KW - Pseudomonas aeruginosa
KW - Quorum sensing
UR - http://www.scopus.com/inward/record.url?scp=85114845624&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2021.113797
DO - 10.1016/j.ejmech.2021.113797
M3 - Article
VL - 226
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0009-4374
M1 - 113797
ER -