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61.
Maria-Agustina Rossi Veronica Martinez Philip Hinchliffe Maria F. Mojica Valerie Castillo Diego M. Moreno Ryan Smith Brad Spellberg George L. Drusano Claudia Banchio Robert A. Bonomo James Spencer Alejandro J. Vila Graciela Mahler 《Chemical science》2021,12(8):2898
Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro (e.g., Ki = 0.44 μM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(ii) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than d/l-captopril. Unexpectedly, MMTZ binding features a thioether–π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ, and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur–π interactions can be exploited for general ligand design in medicinal chemistry.Metallo-β-lactamases (MBLs) are major culprits of resistance to carbapenems in bacteria. A series of thiazolidines are potent MBL inhibitors, restoring the activity of carbapenems. Metal binding and sulphur–π interactions are key to inhibition. 相似文献
62.
Dr. Jean-Pierre Kahane 《Monatshefte für Mathematik》1982,93(4):289-292
Given a non-empty closed subsetF of the unit circle |z|=1, and a Möbius transformationM(z) of the unit disc |z|1, such thatM(0)0, there exists a functionf(z) holomorphic in the unit disc,F being the singular set at the boundary, whose Taylor coefficients tend to zero while the Taylor coefficients off(M(z)), do not tend to zero. 相似文献
63.
Pascal Brunerie Jean-Pierre Clrier Huguette Petit Grard Lhommet 《Journal of heterocyclic chemistry》1986,23(4):1183-1188
The reaction of acyl chlorides with cyclic five-membered β-enaminoesters gave exclusively N-acylated products while reaction of acyl chlorides with cyclic seven-membered β-enaminoesters gave only C-acylated products. In the case of cyclic six-membered β-enaminoesters, the reaction of acyl chlorides gave a mixture of N-acylated and C-acylated products. 相似文献
64.
Herv Bouchard Jean-Pierre Pulicani Marc Vuilhorgne Jean-Dominique Bourzat Alain Commer on 《Tetrahedron letters》1994,35(52):9713-9716
A new route to semisynthetic 19-nor-7β, 8β-methylene taxoids, such as compound 8, from the 7-O-trifluoromethanesulfonyl derivative 6 is reported. Evidence for a dissociation of the triflate to form a carbocation at C-7 under the reaction conditions is presented. Electrochemical reduction of the cyclopropane taxoid 8 gives, besides the expected 10-dehydroxy-cyclopropane analog 10, the 7-membered C-ring derivative 11. 相似文献
65.
Leclaire J Dagiral R Fery-Forgues S Coppel Y Donnadieu B Caminade AM Majoral JP 《Journal of the American Chemical Society》2005,127(45):15762-15770
The synthesis of a new family of phosphorus dendrimers built from an octasubstituted metal-free phthalocyanine core is described up to generation 5. This core is used as a sensor and a probe for analyzing the properties of the internal structure and the influence of each structural part (core, branches, surface) upon the whole structure. UV-visible spectra show both a hyperchromic and bathochromic effect on the Q-bands with increasing generation, indicating that the chromophore is more isolated, and that the dendritic shell mimics a highly polar solvent. There is no evidence for aggregation, except for generation 0, showing again the isolation of the core. However, the dendritic shell is permeable to aqueous acids and bases, as demonstrated by the reversible splitting of the Q-band in an acidic medium (neutral form of the phthalocyanine) and the single Q-band in a basic medium (dianionic form), even for generation 4. The fluorescence quantum yield for the neutral form increases with increasing generation. The dianionic form of generation 0 is poorly fluorescent, whereas generations 3 and 4 (G3 and G4) exhibit better fluorescence. The cores of G3 and G4 are highly sensitive optical sensors for H3O+ and OH-. These experiments are carried out in THF/water mixtures, and the influence of water on the structure has been checked. The hydrodynamic radius of generation 4 is measured by NMR diffusion (pulse gradient spin-echo) experiments. R(H) varies from 35.4 A at 4 mol % of water to 32.5 A at 64 mol % of water in THF, indicating the hydrophobic nature of these dendrimers. 相似文献
66.
67.
An efficient one-step synthesis of 1,1-dipfienyl-1-silacyclopent-3-ene 1 is reported. 相似文献
68.
Readily available tricyclo[3.2.2.02,4]non-6-en-8-one is converted into the tricyclo ring system of the aristolane sesquiterpenes via an alkoxide accelerated [3, 3]-sigmatropic rearrangement. 相似文献
69.
Bromonitromethane, triethyl orthoformate and aniline react together, in a one-flask procedure, to afford the title compound. 相似文献
70.
Brecht Van Hooreweder David Moens Rene Boonen Jean-Pierre Kruth Paul Sas 《Polymer Testing》2013,32(5):972-981
This paper describes the influence of dynamic tension/compression loading on notched and unnotched nylon specimens fabricated by Injection Molding (IM) and Selective Laser Sintering (SLS). The main objective of this work is to analyze and describe the differences in material structure and fatigue properties of as-built nylon parts produced by IM and SLM from the same polyamide 12 powder. The differences in dimensional quality, density, surface roughness, crystal structure and crystallinity are systematically measured and linked to the mechanical fatigue properties. The fatigue properties of the unnotched SLS specimens are found to be equal to those of the unnotched IM specimens. The presence of pores in the sintered samples does not lead to rapid failure, and the microvoid coalescence failure mechanism is delayed. The notched specimens show more brittle failure and increased fatigue resistance which is caused by local notch-strengthening. The results enable improved understanding of the difference in material structure and fatigue behavior of selective laser sintered and injection molded polyamide. 相似文献