Journal of Medicinal Chemistry p. 5002 - 5014 (2017)
Update date:2022-08-04
Topics:
Piizzi, Grazia
Parker, David T.
Peng, Yunshan
Dobler, Markus
Patnaik, Anup
Wattanasin, Som
Liu, Eugene
Lenoir, Francois
Nunez, Jill
Kerrigan, John
McKenney, David
Osborne, Colin
Yu, Donghui
Lanieri, Leanne
Bojkovic, Jade
Dzink-Fox, Joann
Lilly, Maria-Dawn
Sprague, Elizabeth R.
Lu, Yipin
Wang, Hongming
Ranjitkar, Srijan
Xie, Lili
Wang, Bing
Glick, Meir
Hamann, Lawrence G.
Tommasi, Ruben
Yang, Xia
Dean, Charles R.
Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-Acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.
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