- Design, synthesis, and antibacterial evaluation of novel derivatives of NPS-2143 for the treatment of methicillin-resistant S. aureus (MRSA) infection
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Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant global health challenge due to the emergence of strains exhibiting resistance to nearly all classes of antibiotics. This necessitates the rapid development of novel antimicrobials to circumvent this critical problem. Screening of compounds based on phenotypes is one of the major strategies for finding new antibiotics at present. Hence, we here performed a phenotypic screening against MRSA and identified NPS-2143 exhibiting activity against MRSA with an MIC value of 16 μg ml?1. In order to discover more potent anti-MRSA agents, a series of derivatives of NPS-2143 were designed and synthesized. The most promising compounds 48 and 49 exhibited favorable antimicrobial activity with an MIC value of 2 μg ml?1.
- Chen, Yao,Ju, Yuan,Li, Chungen,Yang, Tao,Deng, Yong,Luo, Youfu
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p. 545 - 554
(2019/04/10)
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- An unusual (R)-selective epoxide hydrolase with high activity for facile preparation of enantiopure glycidyl ethers
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A novel epoxide hydrolase (BMEH) with unusual (R)-enantioselectivity and very high activity was cloned from Bacillus megaterium ECU1001. Highest enantioselectivities (E>200) were achieved in the bioresolution of ortho-substituted phenyl glycidyl ethers and para-nitrostyrene oxide. Worthy of note is that the substrate structure remarkably affected the enantioselectivities of the enzyme, as a reversed (S)-enantiopreference was unexpectedly observed for the ortho-nitrophenyl glycidyl ether. As a proof-of-concept, five enantiopure epoxides (>99% ee) were obtained in high yields, and a gram-scale preparation of (S)-ortho-methylphenyl glycidyl ether was then successfully performed within a few hours, indicating that BMEH is an attractive biocatalyst for the efficient preparation of optically active epoxides. Copyright
- Zhao, Jing,Chu, Yan-Yan,Li, Ai-Tao,Ju, Xin,Kong, Xu-Dong,Pan, Jiang,Tang, Yun,Xu, Jian-He
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experimental part
p. 1510 - 1518
(2011/08/03)
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- Bacillus alcalophilus MTCC10234 catalyzed enantioselective kinetic resolution of aryl glycidyl ethers
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The phenyl glycidyl ether derivatives have been kinetically resolved with the growing cells of Bacillus alcalophilus MTCC10234 yielding (S)-epoxides with up to >99% ee and (R)-diols with up to 89% ee. The enantiomeric ratio (E) of up to 67 has been obtained for biohydrolysis process. The effect of different substituents of phenyl glycidyl ether on the biocatalytic efficiency of B. alcalophilus MTCC10234 showed preference for methyl- and chloro-substituted aryl glycidyl ether derivatives whereas nitro-derivatives were transformed at a slower rate. 2,6-Dimethylphenyl glycidyl ether which contains a bulky aryl group having methyl group on both the ortho positions was resolved with an E=39.
- Bala, Neeraj,Chimni, Swapandeep Singh,Saini, Harvinder Singh,Chadha, Bhupinder Singh
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experimental part
p. 128 - 134
(2010/10/04)
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- Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists
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Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11-64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC50 values between 30-100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.
- Tahirovic, Yesim A.,Geballe, Matthew,Gruszecka-Kowalik, Ewa,Myers, Scott J.,Lyuboslavsky, Polina,Le, Phuong,French, Adam,Irier, Hasan,Choi, Woo-Baeg,Easterling, Keith,Yuan, Hongjie,Wilson, Lawrence J.,Kotloski, Robert,McNamara, James O.,Dingledine, Raymond,Liotta, Dennis C.,Traynelis, Stephen F.,Snyder, James P.
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supporting information; experimental part
p. 5506 - 5521
(2009/08/07)
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- Nitrite-mediated hydrolysis of epoxides catalyzed by halohydrin dehalogenase from Agrobacterium radiobacter AD1: A new tool for the kinetic resolution of epoxides
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Halohydrin dehalogenase obtained from Agrobacterium radiobacter AD1, has been tested for the nitrite-mediated ring opening of epoxides. This reaction mainly leads to the formation of unstable hydroxynitrite ester intermediates, which can be further hydrolyzed to the corresponding diols. This conversion proceeds with high enantioselectivity and high regioselectivity towards styrene oxide derivatives. It has been concluded that halohydrin dehalogenase can serve as an attractive alternative to epoxide hydrolases in the preparation of enantiopure epoxides by kinetic resolution.
- Hasnaoui, Ghannia,Lutje Spelberg, Jeffrey H.,De Vries, Erik,Tang, Lixia,Hauer, Bernhard,Janssen, Dick B.
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p. 1685 - 1692
(2007/10/03)
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- CsF in organic synthesis. Regioselective nucleophilic reactions of phenols with oxiranes leading to enantiopure β-blockers
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The two modes of the paths in the reaction of oxiranes with phenols are completely controlled by CsF. Glycidyl nosylate undergoes exclusive substitution at the C1 position whereas the ring-opening (C-3 attack) occurs with epichlorohydrin, glycidol, and 1,2-epoxyalkanes. These reactions provide convenient access to enantiopure β-blockers.
- Kitaori, Kazuhiro,Furukawa, Yoshiro,Yoshimoto, Hiroshi,Otera, Junzo
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p. 14381 - 14390
(2007/10/03)
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- N-quinolinyl alkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing class III antiarrhythmic activity
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This invention relates to N-heteroalkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing anti-arrhythmic activity, to pharmaceutical compositions and to methods for production thereof.
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- Synthesis and Selective Class III Antiarrhythmic Activity of Novel N-Heteroaralkyl-Substituted 1-(Aryloxy)-2-propanolamine and Related Propylamine Derivatives
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The synthesis and biological evaluation of a series of novel 1-(aryloxy)-2-propanolamines and several related deshydroxy analogues are described.Compounds 4-29 were prepared and investigated for their class III electrophysiological activity in isolated canine Purkinje fibers and in anesthetized open-chest dogs.None of these compounds showed any class I activity.On the basis of the in vitro data, structure-activity relationships for the series are discussed.Two compounds, N-propoxy>phenyl>methanesulfonamide (12, WAY-123,223) and N-phenoxy>propyl>amino>methyl>-6-quinolinyl>methanesulfonamide (24, WAY-125,971) were identified and characterized as potent and specific class III antiarrhythmic agents in vitro and in vivo.Compound 12 was found to be orally bioavailable, to produce large increases of ventricular fibrillation threshold (VFT), and, in some instances, to restore sinus rhythm from ventricular fibrillation in anesthetized open-chest dogs at a dose of 5 mg/kg (iv).The enantiomers of 12 (i.e., 13 and 14) were synthesized and were found to exhibit similar electrophysiological effects in the Purkinje fiber screen.Compound 24, a propylamine analogue with potency and efficacy comparable to those of UK-68798 (2) and E-4031 (3), was studied in voltage-clamp experiments (isolated cat myocytes) and was found to be a potent and specific blocker of the delayed rectifier potassium current (IK).
- Butera, John A.,Spinelli, Walter,Anantharaman, Viji,Marcopulos, Nicholas,Parsons, Roderick W.,et al.
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p. 3212 - 3228
(2007/10/02)
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