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 -