- Synthesis and structure–activity relationship study of novel quinazolinone-based inhibitors of MurA
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MurA is an intracellular bacterial enzyme that is essential for peptidoglycan biosynthesis, and is therefore an important target for antibacterial drug discovery. We report the synthesis, in silico studies and extensive structure–activity relationships of a series of quinazolinone-based inhibitors of MurA from Escherichia coli. 3-Benzyloxyphenylquinazolinones showed promising inhibitory potencies against MurA, in the low micromolar range, with an IC50 of 8?μM for the most potent derivative (58). Furthermore, furan-substituted quinazolinones (38, 46) showed promising antibacterial activities, with MICs from 1?μg/mL to 8?μg/mL, concomitant with their MurA inhibitory potencies. These data represent an important step towards the development of novel antimicrobial agents to combat increasing bacterial resistance.
- Hrast, Martina,Ro?man, Kaja,Juki?, Marko,Patin, Delphine,Gobec, Stanislav,Sova, Matej
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supporting information
p. 3529 - 3533
(2017/07/07)
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- CARBAMATE DERIVATIVES
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Compounds of formula (I) defined herein are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists and are useful for the prevention and/or treatment of diseases of the respiratory tract.
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Paragraph 0238-0241
(2015/12/30)
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- New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: Design, synthesis, crystal structures, and biological evaluation
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Mur ligases (MurC-MurF), a group of bacterial enzymes that catalyze four consecutive steps in the formation of cytoplasmic peptidoglycan precursor, are becoming increasingly adopted as targets in antibacterial drug design. Based on the crystal structure of MurD cocrystallized with thiazolidine-2,4-dione inhibitor I, we have designed, synthesized, and evaluated a series of improved glutamic acid containing 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2, 4-dione inhibitors of MurD with IC50 values up to 28 μM. Inhibitor 37, with an IC50 of 34 μM, displays a weak antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC 29212 with minimal inhibitory concentrations of 128 μg/mL. High-resolution crystal structures of MurD in complex with two new inhibitors (compounds 23 and 51) reveal details of their binding modes within the active site and provide valuable information for further structure-based optimization.
- Zidar, Nace,Toma?i?, Tihomir,?ink, Roman,Kova?, Andreja,Patin, Delphine,Blanot, Didier,Contreras-Martel, Carlos,Dessen, Andréa,Premru, Manica Müller,Zega, Anamarija,Gobec, Stanislav,Ma?i?, Lucija Peterlin,Kikelj, Danijel
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supporting information; experimental part
p. 5512 - 5523
(2011/12/15)
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