α-Amino diphenyl phosphonates as novel inhibitors of Escherichia coli ClpP protease

Carlos Moreno-Cinos, Elisa Sassetti, Irene G. Salado, Gesa Witt, Siham Benramdane, Laura Reinhardt, Cristina D. Cruz, Jurgen Joossens, Pieter Van der Veken, Heike Brötz-Oesterhelt, Päivi Sirpa Marjaana Tammela, Mathias Winterhalter, Philip Gribbon, Björn Windshügel, Koen Augustyns

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

Increased Gram-negative bacteria resistance to antibiotics is becoming a global problem, and new classes of antibiotics with novel mechanisms of action are required. The caseinolytic protease subunit P (ClpP) is a serine protease conserved among bacteria that is considered as an interesting drug target. ClpP function is involved in protein turnover and homeostasis, stress response, and virulence among other processes. The focus of this study was to identify new inhibitors of Escherichia coli ClpP and to understand their mode of action. A focused library of serine protease inhibitors based on diaryl phosphonate warheads was tested for ClpP inhibition, and a chemical exploration around the hit compounds was conducted. Altogether, 14 new potent inhibitors of E. coli ClpP were identified. Compounds 85 and 92 emerged as most interesting compounds from this study due to their potency and, respectively, to its moderate but consistent antibacterial properties as well as the favorable cytotoxicity profile.
Originalspråkengelska
TidskriftJournal of Medicinal Chemistry
Volym62
Utgåva2
Sidor (från-till)774-797
Antal sidor24
ISSN0022-2623
DOI
StatusPublicerad - 24 jan 2019
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 317 Farmaci
  • 116 Kemi

Citera det här

Moreno-Cinos, C., Sassetti, E., Salado, I. G., Witt, G., Benramdane, S., Reinhardt, L., ... Augustyns, K. (2019). α-Amino diphenyl phosphonates as novel inhibitors of Escherichia coli ClpP protease. Journal of Medicinal Chemistry, 62(2), 774-797. https://doi.org/10.1021/acs.jmedchem.8b01466