- Design, synthesis of novel 4,5-dihydroisoxazole-containing benzamide derivatives as highly potent FtsZ inhibitors capable of killing a variety of MDR Staphylococcus aureus
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Antibiotic resistance among clinically significant bacterial pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. As a part of continuing effort to develop antibacterial agents, we rationally designed and synthesized two series of 4,5-dihydroisoxazol-5-yl and 4,5-dihydroisoxazol-3-yl-containing benzamide derivatives that targeted the bacterial cell division protein FtsZ. Evaluation of their activity against a panel of Gram-positive and -negative pathogens revealed that compound A16 possessing the 4,5-dihydroisoxazol-5-yl group showed outstanding antibacterial activity (MIC, ≤0.125–0.5 μg/mL) against various testing strains, including methicillin-resistant, penicillin-resistant and clinical isolated S. aureus strains. Besides, further mouse infection model revealed that A16 could be effective in vivo and non-toxic to Hela cells. Finally, a detailed discussion of structure-activity relationships was conducted, referring to the docking results. It is worth noting that substituting a 4,5-dihydroisoxazole ring for the isoxazole ring not only broadened the antibacterial spectrum but also resulted in a significant increase in antibacterial activity against S. aureus strains. Taken together, these results suggest a promising chemotype for the development of new FtsZ-targeting bactericidal agents.
- Song, Di,Bi, Fangchao,Zhang, Nan,Qin, Yinhui,Liu, Xingbang,Teng, Yuetai,Ma, Shutao
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supporting information
(2020/09/11)
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- Oxidative trifluoromethylation and fluoroolefination of unactivated olefins
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Fluorine-containing organic compounds are gaining increasing importance in medicinal chemistry. Described herein is a mild and efficient method for the radical addition of olefins with TMSCF3 and TMSCF2R (R = COOEt or CF3) to deliver various α-trifluoromethylated ketones and α-fluoroolefinated ketones.
- Wu, Ye-Bin,Lu, Guo-Ping,Yuan, Tao,Xu, Zhu-Bing,Wan, Li,Cai, Chun
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supporting information
p. 13668 - 13670
(2016/11/29)
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- Olefin-assisted iron-catalyzed alkylation of aryl chlorides
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A selective and operationally simple ironcatalyzed cross-coupling of aryl chlorides with alkylmagnesium halides has been developed. The reaction tolerates various functional groups and exhibits high chemoselectivity even in the presence of aryl bromides. Mechanistic studies indicate the essential role of the olefin substituent for substrate activation. Competing polymerization and reduction are effectively suppressed.
- Guelak, Samet,Gieshoff, Tim N.,Von Wangelin, Axel Jacobi
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supporting information
p. 2197 - 2202
(2013/10/01)
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- Highly selective Wacker reaction of styrene derivatives: A green and efficient aerobic oxidative process promoted by benzoquinone/NaNO 2/HClO4 under mild conditions
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A green and efficient catalytic redox system for the aerobic oxidative Wacker oxidation of styrene derivatives at room temperature using molecular oxygen as the terminal oxidant without copper chloride has been developed. The newly developed system exhibited excellent catalytic activity for the smooth transformation of terminal styrene derivatives to the desired methyl ketones with up to 96% yield and >99% selectivity. The Royal Society of Chemistry 2013.
- Zhang, Guofu,Xie, Xiaoqiang,Wang, Yong,Wen, Xin,Zhao, Yun,Ding, Chengrong
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supporting information
p. 2947 - 2950
(2013/07/25)
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- Chlorostyrenes in iron-catalyzed biaryl coupling reactions
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An effective protocol for iron-catalyzed biaryl syntheses by coupling chlorostyrenes with aryl Grignard reagents requires only mild reaction conditions and tolerates various functional groups. The underlying activation of deactivated aryl chlorides proceeds through a rate-determining coordination of the catalyst to the vinyl substituent and subsequent haptotropic migration along the conjugated πsystem to the site of C-Cl bond cleavage. Copyright
- Guelak, Samet,Jacobivonwangelin, Axel
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supporting information; experimental part
p. 1357 - 1361
(2012/03/26)
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- Selective 5-hydroxytryptamine 2c receptor agonists derived from the lead compound tranylcypromine: Identification of drugs with antidepressant-like action
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We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT2C agonist, a series of 1-aminomethyl-2- phenylcyclopropanes was investigated as 5-HT2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted be zene ring. Among the tested compounds, several were potent and efficacious 5-HT2C receptor agonists with selectivity over both 5-HT2A and 5-HT2B receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT 2A and 5-HT2B, respectively (EC50) 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.
- Sung, Jin Cho,Jensen, Niels H.,Kurome, Toru,Kadari, Sudhakar,Manzano, Michael L.,Malberg, Jessica E.,Caldarone, Barbara,Roth, Bryan L.,Kozikowski, Alan P.
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experimental part
p. 1885 - 1902
(2009/12/07)
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- Synthesis and olefination of carbonyl compounds using solid-supported reagents
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The development and application of three new solid-supported reagents for use in the synthesis or olefination of carbonyl compounds are described. The reagents include the Weinreb amide, Mukaiyama's S-2-pyridyl thioate and a Peterson methylenation reagent. As solid-supports p-benzyl alcohol resin, Wang resin and Merrifield resin (1-2% crosslinked polystyrene) have been used. The Royal Society of Chemistry.
- Hansen, Anne-Lene L.,Murray, Anthony,Tanner, David
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p. 4497 - 4505
(2008/09/18)
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- Pinacolboratamethyl-enetriphenylphosphonium iodide, a new methylene transfer reagent
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The title compound is easily prepared and reacts with various aldehydes and ketone. The reagent is compatible with free hydroxy groups. Yields with various aldehydes and ketones are in 50- > 99% range. Both aliphatic, aromatic and unsaturated carbonyls react.
- Al-Aziz Quntar, Abed,Srebnik, Morris
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p. 2575 - 2579
(2007/10/03)
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- Copper(I)-catalyzed intramolecular cyclization reaction of 2-(2'- chlorophenyl)ethanol to give 2,3-dihydrobenzofuran
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Functionalized 2,3-dihydrobenzofuran can be synthesized in good yield via an intramolecular cyclization of an aryl chloride and a primary alcohol under the catalysis of copper(I) chloride salt. (C) 2000 Elsevier Science Ltd.
- Zhu, Jingyang,Price, Benjamin A.,Zhao, Shannon X.,Skonezny, Paul M.
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p. 4011 - 4014
(2007/10/03)
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