- Novel fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety: Design, synthesis, crystal structure and biological evaluation
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A series of fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety have been designed, synthesized and evaluated for their antifungal activity. All the target compounds were determined by1H-NMR,13C-NMR, FTIR and HR-MS spectra. The single-crystal structures of compounds 4e, 4h, 5h and 6c were further confirmed using X-ray diffraction. The antifungal activities against Botrytis cinerea (B. cinerea), Alternaria solani (A. solani), Gibberella zeae (G. zeae), Rhizoctorzia solani (R. solani), Colletotrichum orbiculare (C. orbiculare) and Alternaria alternata (A. alternata) were evaluated in vitro. The preliminary bioassays showed that some of the designed compounds displayed the promising antifungal activities against the above tested fungi. Strikingly, the target compounds 5f and 6h exhibited outstanding antifungal activity against B. cinerea at 100 μg/mL, with the corresponding inhibition rates reached 90.1 and 85.0%, which were better than the positive control Osthole (83.6%) and Azoxystrobin (46.5%). The compound 5f was identified as the promising fungicide candidate against B. cinerea with the EC50 values of 5.75 μg/mL, which was obviously better than Osthole (33.20 μg/mL) and Azoxystrobin (64.95 μg/mL). Meanwhile, the compound 5f showed remarkable antifungal activities against R. solani with the EC50 values of 28.96 μg/mL, which was better than Osthole (67.18 μg/mL) and equivalent to Azoxystrobin (21.34 μg/mL). The results provide a significant foundation for the search of novel fluorinated 7-hydroxycoumarin derivatives with good antifungal activity.
- Dai, Peng,Jiao, Jian,Wang, Qing-Qing,Zhang, Shu-Guang,Zhang, Wei-Hua
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- The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901
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A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzam ide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modification of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-b enzamide PD 0325901.
- Barrett, Stephen D.,Bridges, Alexander J.,Dudley, David T.,Saltiel, Alan R.,Fergus, James H.,Flamme, Cathlin M.,Delaney, Amy M.,Kaufman, Michael,LePage, Sophie,Leopold, Wilbur R.,Przybranowski, Sally A.,Sebolt-Leopold, Judith,Van Becelaere, Keri,Doherty, Annette M.,Kennedy, Robert M.,Marston, Dan,Howard Jr., W. Allen,Smith, Yvonne,Warmus, Joseph S.,Tecle, Haile
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supporting information; experimental part
p. 6501 - 6504
(2009/10/01)
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- Synthesis and fungicidal activity of macrolactams and macrolactones with an oxime ether side chain
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Three series of novel macrolactams and macrolactones - 12-alkoxyimino- tetradecanlactam, 12-alkoxyiminopentadecanlactam, and 12-alkoxyiminodecanlactone derivatives (7A, 7B, and 7C) - were synthesized from corresponding 12-oxomacrolactams and 12-oxomacrolactone. Their structures were confirmed by 1H NMR and elemental analysis. The Z and E isomers of 7A and 7B were separated, and their configurations were determined by 1H NMR. These compounds showed fair to excellent fungicidal activities against Rhizoctonia solani Kuehn. It is interesting that the Z and E isomers of most of the compounds have quite different fungicidal activities. The fact that the compounds have a gradual increase of fungicidal activity in the order of 7A, 7C, and 7B indicated that the macrocyclic derivatives with a hydrogen-bonding acceptor (=N-O-) and a hydrogen-bonding donor (-CONH-) on the ring, and a three methylenes distance (CH2CH2CH2) between these two functional groups, exhibited the best fungicidal activity. The bioassay also showed that 7B not only has good fungicidal activity but also may have a broad spectrum of fungicidal activities.
- Huang, Jia-Xing,Jia, Yue-Mei,Liang, Xiao-Mei,Zhu, Wei-Juan,Zhang, Jian-Jun,Dong, Yan-Hong,Yuan, Hui-Zu,Qi, Shu-Hua,Wu, Jin-Ping,Chen, Fu-Heng,Wang, Dao-Quan
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experimental part
p. 10857 - 10863
(2009/11/30)
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- Stereoselective synthesis of multiply substituted [1,2]oxazinan-3-ones via ring-closing metathesis
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The title compounds are α-amino acids whose nitrogen atoms are enclosed within 4,5-disubstituted, six-membered cyclic hydroxamates and they are of interest as potential β-lactam surrogates. The compounds have been synthesized in the present work by functionalization of the double bonds of N-substituted 6H-[1,2]oxazin-3-ones, which are obtained upon successive reaction of the inflates of 5-α-hydroxy esters with O-allylhydroxylamine and acryloyl chloride, followed by cyclization of the resulting A-α-TV- acryloyl-N-allyloxyamino esters in the presence of the ring-closing metathesis (RCM) catalyst bis(tricyclohexylphosphine)benzylideneruthenium dichloride. The olefins are also accessible, but less efficiently so, by a Wittig sequence that employs bromoacetyl bromide in place of acryloyl chloride, followed successively by triphenylphosphine, silver triflate, ozonolysis, and cyclization. Asymmetric dihydroxylation of these chiral olefins affords a single diastereomer in high yield having either the αR,4S,5S- or the αR,4R,5R configuration, depending on the auxiliary. The configuration of the αR,4R,5R isomer has been confirmed by its conversion to (αR,4S,5R)-2-(α-carboxyethyl)-4- phenylacetylamino-5-hydroxy-1,2-oxazinan-3-one, whose αR,4K,5S diastereomer was previously prepared from L-ascorbic acid. With N-bromosuccinimide in aqueous dimethylformamide, a 6H-[1,2]oxazin-3-one afforded a separable 1:1 mixture of bromohydrins, which could be cyclized to epoxides or hydrogenolyzed to 5-hydroxy-1,2-oxazinan-3-ones.
- Shustov, Gennady V.,Chandler, Melanie K.,Wolfe, Saul
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- Nodulisporic acid derivatives
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The present invention relates to novel nodulosporic acid derivatives, which are acaricidal, antiparasitic, insecticidal and anthelmintic agents.
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- Thermolysis of Oxime O-Allyl Ethers: A New Method for Pyridine Synthesis
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Thermolysis of cycloalkanone oxime O-allyl ethers in air gave the corresponding cycloalkenopyridines, providing a new method for the synthesis of cycloalkenopyridine derivatives.Keywords - cycloalkanone oxime O-allyl ether; cycloalkenopyridine; thermolysis; O-allylhydroxylamine; cyclohexanone; tetrahydroquinoline
- Koyama, Junko,Sugita, Teruyo,Suzuta, Yukio,Irie, Hiroshi
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p. 2601 - 2606
(2007/10/02)
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