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α-Amino Diphenyl Phosphonates as Novel Inhibitors of Escherichia coli ClpP Protease

: Moreno-Cinos, C.; Sassetti, E.; Salado, I.G.; Witt, G.; Benramdane, S.; Reinhardt, L.; Cruz, C.D.; Joossens, J.; Veken, P. Van der; Brötz-Oesterhe, H.; Tammela, P.; Winterhalter, M.; Gribbon, P.; Windshügel, B.; Augustyns, K.


Journal of medicinal chemistry 62 (2019), Nr.2, S.774-797
ISSN: 0022-2623
ISSN: 1520-4804
Deutsche Forschungsgemeinschaft DFG
SFB 766
Deutsche Forschungsgemeinschaft DFG
GRK 1708
Fraunhofer IME ()

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.