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

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Moreno-Cinos , C , Sassetti , E , Salado , I G , Witt , G , Benramdane , S , Reinhardt , L , Cruz , C D , Joossens , J , Van der Veken , P , Brötz-Oesterhelt , H , Tammela , P S M , Winterhalter , M , Gribbon , P , Windshügel , B & Augustyns , K 2019 , ' α-Amino diphenyl phosphonates as novel inhibitors of Escherichia coli ClpP protease ' , Journal of Medicinal Chemistry , vol. 62 , no. 2 , pp. 774-797 . https://doi.org/10.1021/acs.jmedchem.8b01466

Title: α-Amino diphenyl phosphonates as novel inhibitors of Escherichia coli ClpP protease
Author: Moreno-Cinos, Carlos; Sassetti, Elisa; Salado, Irene G.; Witt, Gesa; Benramdane, Siham; Reinhardt, Laura; Cruz, Cristina D.; Joossens, Jurgen; Van der Veken, Pieter; Brötz-Oesterhelt, Heike; Tammela, Päivi Sirpa Marjaana; Winterhalter, Mathias; Gribbon, Philip; Windshügel, Björn; Augustyns, Koen
Contributor: University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, Drug Research Program
Date: 2019-01-24
Language: eng
Number of pages: 24
Belongs to series: Journal of Medicinal Chemistry
ISSN: 0022-2623
URI: http://hdl.handle.net/10138/308651
Abstract: 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.
Subject: 317 Pharmacy
116 Chemical sciences
BETA-LACTONES
LISTERIA-MONOCYTOGENES
PLASMINOGEN-ACTIVATOR
STAPHYLOCOCCUS-AUREUS
POTENT INHIBITORS
SERINE-PROTEASE
VIRULENCE
CHYMOTRYPSIN
ANALOGS
ACID
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