- Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine Fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β Fibrils
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A BF3·OEt2 catalyzed intramolecular Povarov reaction was used to synthesize 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with several O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogues substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.
- Adolfsson, Dan E.,Tyagi, Mohit,Singh, Pardeep,Deuschmann, Adrian,?dén, J?rgen,Gharibyan, Anna L.,Jayaweera, Sanduni Wasana,Lindgren, Anders E. G.,Olofsson, Anders,Almqvist, Fredrik
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p. 14174 - 14189
(2020/11/13)
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- Novel Staphyloxanthin Inhibitors with Improved Potency against Multidrug Resistant Staphylococcus aureus
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Diapophytoene desaturase (CrtN) is a potential novel target for intervening in the biosynthesis of the virulence factor staphyloxanthin. In this study, 38 1,4-benzodioxan-derived CrtN inhibitors were designed and synthesized to overwhelm the defects of leading compound 4a. Derivative 47 displayed superior pigment inhibitory activity, better hERG inhibitory properties and water solubility, and significantly sensitized MRSA strains to immune clearance in vitro. Notably, 47 displayed excellent efficacy against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate MRSA, VISA), and NRS271 (linezolid-resistant MRSA, LRSA) comparable to that of linezolid and vancomycin in vivo.
- Ni, Shuaishuai,Li, Baoli,Chen, Feifei,Wei, Hanwen,Mao, Fei,Liu, Yifu,Xu, Yixiang,Qiu, Xiaoxi,Li, Xiaokang,Liu, Wenwen,Hu, Linghao,Ling, Dazheng,Wang, Manjiong,Zheng, Xinyu,Zhu, Jin,Lan, Lefu,Li, Jian
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p. 233 - 237
(2018/03/21)
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- Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections
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Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H2O2 killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271.
- Wei, Hanwen,Mao, Fei,Ni, Shuaishuai,Chen, Feifei,Li, Baoli,Qiu, Xiaoxia,Hu, Linghao,Wang, Manjiong,Zheng, Xinyu,Zhu, Jin,Lan, Lefu,Li, Jian
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p. 235 - 251
(2018/01/17)
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- Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti-MRSA/VISR/LRSA Agents with Reduced hERG Activity
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CrtN has been identified as an attractive and druggable target for treating pigmented Staphylococcus aureus infections. More than 100 new compounds were synthesized, which target the overwhelming the defects of the CrtN inhibitor 1. Analogues 23a and 23b demonstrated a significant activity against pigmented S. aureus Newman and 13 MRSA strains (IC50 = 0.02-10.5 nM), along with lower hERG inhibition (IC50 > 30 μM, ~10-fold decrease in comparison with 1). Furthermore, 23a and 23b were confirmed to reduce the staphylococcal load in the kidney and heart in a mouse model with normal treatment deeper than pretreatment ones, comparable even with vancomycin and linezolid. Remarkably, 23a could strongly block the pigment biosynthesis of these nine multidrug-resistant MRSA strains, including excellent activity against LRSA strains and VISA strains in vivo, and all of which demonstrated that 23a has a huge potential against intractable MRSA, VISA, and LRSA issues as a therapeutic drug.
- Li, Baoli,Ni, Shuaishuai,Mao, Fei,Chen, Feifei,Liu, Yifu,Wei, Hanwen,Chen, Wenhua,Zhu, Jin,Lan, Lefu,Li, Jian
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p. 224 - 250
(2018/02/10)
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- Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate Staphylococcus aureus Infections in Vivo
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Our previous work (Wang et al. J. Med. Chem. 2016, 59, 4831-4848) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.
- Ni, Shuaishuai,Wei, Hanwen,Li, Baoli,Chen, Feifei,Liu, Yifu,Chen, Wenhua,Xu, Yixiang,Qiu, Xiaoxia,Li, Xiaokang,Lu, Yanli,Liu, Wenwen,Hu, Linhao,Lin, Dazheng,Wang, Manjiong,Zheng, Xinyu,Mao, Fei,Zhu, Jin,Lan, Lefu,Li, Jian
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supporting information
p. 8145 - 8159
(2017/10/18)
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- Rapid assembly of the polyhydroxylated β-amino acid constituents of microsclerodermins C, D, and e
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A very short and efficient synthesis of protected derivatives of APTO and AETD, the complex polyhydroxylated β-amino acid residues present in microsclerodermins C, D, and E, is described. The targets are obtained in only five steps, in 23% and 16% overall yields, respectively. The key transformation involves the completely diastereoselective two-carbon homologation of appropriately selected intermediate chiral sulfinimines.
- Hjelmgaard, Thomas,Faure, Sophie,Lemoine, Pascale,Viossat, Bernard,Aitken, David J.
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supporting information; experimental part
p. 841 - 844
(2009/04/07)
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