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1.
Timothy Paulitz Brian Nowak-Thompson Pascale Gamard Evelyn Tsang Joyce Loper 《Journal of chemical ecology》2000,26(6):1515-1524
Pseudomonas aureofaciens (= P. chlororaphis) strain 63-28 is a biocontrol agent active against many soil-borne fungal plant pathogens and shows antifungal activity in culture assays. 3-(1-Hexenyl)-5-methyl-2-(5H)furanone was isolated from culture filtrates of this bacterium. The purified furanone showed antifungal activity against Pythium ultimum, Fusarium solani, Fusarium oxysporum, and Thielaviopsis basicola. The ED50S for spore germination of these fungi were 45, 54, 56, and 25 g/ml, respectively. The compound also inhibited the germ tube growth of Rhizoctonia solani growing from microsclerotia, with an ED50 of 61 g/ml. The compound is the reduced form of furanones previously described from this bacterium: 3-(1-hexenyl)-5-hydroxy-5-methyl-2-(5H)-furanone and 3-(1-hexenyl)-5-hydroxymethyl-2-(5H)-furanone. This volatile antifungal furanone has structural similarity to other antifungal furanones produced by actinomycetes (Streptomyces spp.), fungi (Trichoderma harzianum), and higher plants (Pulsatilla and Ranuculus spp.). This is the first report of 3-(1-hexenyl)-5-methyl-2-(5H)-furanone produced by a bacterium. 相似文献
2.
Akira Kaieda Dr. Masashi Takahashi Hiromi Fukuda Dr. Rei Okamoto Dr. Shinji Morimoto Masayuki Gotoh Takahiro Miyazaki Yuri Hori Satoko Unno Dr. Tomohiro Kawamoto Dr. Toshimasa Tanaka Dr. Sachiko Itono Terufumi Takagi Dr. Hiroshi Sugimoto Dr. Kengo Okada Dr. Weston Lane Dr. Bi-Ching Sang Dr. Kumar Saikatendu Dr. Shinichiro Matsunaga Dr. Seiji Miwatashi 《ChemMedChem》2019,14(24):2093-2101
We identified novel potent inhibitors of p38 mitogen-activated protein (MAP) kinase using a structure-based design strategy, beginning with lead compound, 3-(butan-2-yl)-6-(2,4-difluoroanilino)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one ( 1 ). To enhance the inhibitory activity of 1 against production of tumor necrosis factor-α (TNF-α) in human whole blood (hWB) cell assays, we designed and synthesized hybrid compounds in which the imidazo[4,5-b]pyridin-2-one core was successfully linked with the p-methylbenzamide fragment. Among the compounds evaluated, 3-(3-tert-butyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-4-methyl-N-(1-methyl-1H-pyrazol-3-yl)benzamide ( 25 ) exhibited potent p38 inhibition, superior suppression of TNF-α production in hWB cells, and also significant in vivo efficacy in a rat model of collagen-induced arthritis (CIA). In this paper, we report the discovery of potent, selective, and orally bioavailable imidazo[4,5-b]pyridin-2-one-based p38 MAP kinase inhibitors. 相似文献
3.
In presence of ammonia/ammonium acetate the 3,5-dimethyl-2-phenyl-1,1-dioxo-1,2-thiazine-4-carbaldehyde ( 1 ) reacts with ethyl cyanoacetate to the ethyl 2-cyano-4-[1-methyl-2-methylthio-2-(N-phenylsulfamoyl)vinyl)-hexa-2,4-dienoate] ( 3 ) and the Knoevenagel condensation product 4-(2-ethoxycarbonyl-2-cyanovinyl)-3,5-dimethyl-6-methylthio-1,1-dioxo-2-phenyl-2H-1,2-thiazine ( 2 a). The 4-(2,2-dicyanovinyl)-3,5-dimethyl-6-methylthio-1,1-dioxo-2-phenyl-2H-1,2-thiazine ( 2b ) is obtained from 1 and malononitril. The masked 1,5-dicarbonyl compound 2a undergoes ring transformation to the 3-cyano-1,6-dimethyl-5-[1-methylthio-2-(N-phenylsulfamoyl)vinyl]pyridin-2-one ( 5 ) with methylamine. With ethanolic ethoxide the condensation products 2a,b afford the 7-amino-6-ethoxycarbonyl-4-methylthio-2,2-dioxo-1-phenyl-benzo[c]1,2-thiazine ( 6a ), respectively the corresponding 6-cyano derivative 6b , while 3 cyclizises to furnish ethyl 2-amino-6-methyl-5-[1-methyl-2-methylthio-2-(N-phenyl-sulfamoyl)vinyl]nicotinate ( 4 ). 相似文献
4.
Dr. Zhongcheng Cao Tianlong Zhang Xianwu Fu Xingyue Wang Qian Xia Lei Zhong Dr. Jiang Zhu 《ChemMedChem》2023,18(6):e202200629
A series of 2-hydroxy-4-benzyloxylimine resveratrol derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of Parkinson's disease. The results revealed that most derivatives possessed good multifunctional activities. Among them, representative compound (E)-5-[(4-fluorobenzyl)oxy]-2-{[(4-hydroxyphenyl)imino]methyl}phenol ( 7 h ) exhibited excellent MAO-B inhibition (IC50=8.43×10−3 μM) and high antioxidant activity (ORAC=3.45 Trolox equivalent). Additionally, 7 h displayed good metal chelating ability, appropriate blood–brain barrier (BBB) permeability, significant neuroprotective effect, and great anti-neuroinflammatory activity. Furthermore, 7 h can also ameliorate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease symptoms in mice. Therefore, compound 7 h was found to be a promising candidate for further development against PD. 相似文献
5.
Dr. Christine Brotschi Dr. Martin H. Bolli Dr. John Gatfield Dr. Bibia Heidmann Dr. Francois Jenck Dr. Catherine Roch Dr. Thierry Sifferlen Dr. Alexander Treiber Dr. Jodi T. Williams Dr. Christoph Boss 《ChemMedChem》2020,15(5):430-448
The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone ( 6 ), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone ( 42 ), a DORA with improved in vivo efficacy compared to 6 . 相似文献
6.
Ibrahim M. A. Awad 《Journal of chemical technology and biotechnology (Oxford, Oxfordshire : 1986)》1993,56(4):339-345
5-Imino-3-methyl-l-phenyl-2-pyrazoline-4-dithiocarbamic acid (I) underwent simultaneous formylation and dimerization reactions with the Vilsmeier reagent giving 4-[5′-imino-3-(1″-formyl-2″-dimethylaminoethenyl)-3′-methyl-1′-phenyl-1′H-pyrazolo-4′-dithiocarbamyl-2,4-dihydro-3-imino-5-methyl-2-phenyl-1-pyrazoline]dithiocarbamate (II) which hydrolysed with sodium hydroxide to give 4-[3′-(1″-formyl-2″-hydroxyethenyl)-3′-methyl-1-phenyl-1′-H-pyrazolo-4′-dithiocarbamyl-1′-pyrazoline]dithiocarbamate-5,5′-dione (IV). Treatment of II and/or IV with morpholine, piperidine, piperazine, hydroxylamine, hydrazine hydrate or phenylhydrazine afforded the corresponding dipyrazolo-4,4′-dithiocarbamate derivatives with different heterocyclic systems at the 3-position. The structures of these compounds were confirmed by microanalysis data, IR and 1H-NMR spectrometry. All synthesized compounds have been screened in vitro against Gram-positive and Gram-negative bacteria, and fungi. 相似文献
7.
Metabolites of the Anaerobic Degradation of n-Hexane by Denitrifying Betaproteobacterium Strain HxN1
Dr. Julian Küppers Nico Mitschke Simone Heyen Prof. Dr. Ralf Rabus Prof. Dr. Heinz Wilkes Prof. Dr. Jens Christoffers 《Chembiochem : a European journal of chemical biology》2020,21(3):373-380
The constitutions of seven metabolites formed during anaerobic degradation of n-hexane by the denitrifying betaproteobacterium strain HxN1 were elucidated by comparison of their GC and MS data with those of synthetic reference standards. The synthesis of 4-methyloctanoic acid derivatives was accomplished by the conversion of 2-methylhexanoyl chloride with Meldrum's acid. The β-oxoester was reduced with NaBH4, the hydroxy group was eliminated, and the double bond was displaced to yield the methyl esters of 4-methyl-3-oxooctanoate, 3-hydroxy-4-methyloctanoate, (E)-4-methyl-2-octenoate, and (E)- and (Z)-4-methyl-3-octenoate. The methyl esters of 2-methyl-3-oxohexanoate and 3-hydroxy-2-methylhexanoate were similarly prepared from butanoyl chloride and Meldrum's acid. However, methyl (E)-2-methyl-2-hexenoate was prepared by Horner–Wadsworth–Emmons reaction, followed by isomerization to methyl (E)-2-methyl-3-hexenoate. This investigation, with the exception of 4-methyl-3-oxooctanoate, which was not detectable in the cultures, completes the unambiguous identification of all intermediates of the anaerobic biodegradation of n-hexane to 2-methyl-3-oxohexanoyl coenzyme A (CoA), which is then thiolytically cleaved to butanoyl-CoA and propionyl-CoA; these two metabolites are further transformed according to established pathways. 相似文献
8.
A novel series of sulfur-containing dihydrochromeno[8,7-e][1,3]oxazine-2(8H)-thiones has been synthesized through an eco-friendly Mannich-type condensation cyclization reaction of 7-hydroxy-4-methyl-2-thiocoumarin or 6-chloro-7-hydroxy-4-methyl-2-thiocoumarin with formaldehyde and primary amines in water at 80–90°C for 2 h. All the synthesized compounds were screened for their in vitro anti-bacterial efficacy against two Gram-positive and three Gram-negative bacterial strains by using the disc diffusion method. The compound (8c) was found to be most potent with the zone of inhibition of 16 and 15 mm against Staphylococcus aureus ATCC 2937 and Klebsiella pneumoniae ATCC 31488, respectively. 相似文献
9.
A variety of oxidation products (4–29) of α-tocopherol, 1 and of its model compound, 2,2,5,7,8-pentamethyl-6-chromanol (2)
has been tested for antioxidant activity against autoxidizing safflower oil (ASO) and autoxidizing methyl linoleate (AML).
The following compounds showed good antioxidant activity against both substrates: 5-hydroxymethyl-2,2,7,8-tetramethyl-6-chromanol
(4), 5-(2,2,5,7,8-pentamethyl-6-chromanoxy)methyl-2,2,7,8-tetramethyl-6-chromanol (15), 1,2-bis(2,2,7,8-tetramethyl-6-chromanol-5-)ethane (16), 5-ethoxymethyl-7,8-dimethyltocol (19), 5-mthoxymethyl-2,2,7,8-tetramethyl-6-chromanol
(21), 5-ethoxymethyl-2,2,7,8-tetramethyl-6-chromanol (20), 5-propoxymethyl-2,2,7,8-tetramethyl-6-chromanol (22), 5-butoxymethyl-2,2,7,8-tetramethyl-6-chromanol
(23), 5-(2-methyl-1-propoxy)methyl-2,2,7,8-tetramethyl-6-chromanol (24), 5-(2-methyl-2-propoxy)methyl-2,2,7,8-tetramethyl-6-chromanol
(25), 5-heptoxymethyl-2,2,7,8-tetramethyl-6-chromanol (26), 5-undecoxymethyl-2,2,7,8-tetramethyl-6-chromanol (27), 5-phytoxymethyl-2,2,7,8-tetramethyl-6-chromanol
(28) and 5-cholesteroxymethyl-2,2,7,8-tetramethyl-6-chromanol (29). 2,2,7,8-Tetramethylchroman-5,6-dione (17) and 1,2-bis(2,2,7-trimethylchroman-5,6-dione-8-)ethane (18) showed significant antioxidant activity against ASO but not against AML.
If the corresponding oxidation products of 1 are formedin vivo it means that the antioxidant activity of 1 is not lost on oxidation. This may help to explain the outstanding capacity of
1 to protect cell membranes. 相似文献
10.
Kosuke Anan Dr. Yasuyoshi Iso Dr. Takuya Oguma Dr. Kenji Nakahara Shinji Suzuki Dr. Takahiko Yamamoto Eriko Matsuoka Dr. Hisanori Ito Dr. Gaku Sakaguchi Shigeru Ando Dr. Kenji Morimoto Dr. Naoki Kanegawa Dr. Yasuto Kido Tomoyuki Kawachi Dr. Tamio Fukushima Dr. Ard Teisman Dr. Vijay Urmaliya Dr. Deborah Dhuyvetter Dr. Herman Borghys Dr. Nigel Austin Dr. An Van Den Bergh Peter Verboven Dr. Francois Bischoff Dr. Harrie J. M. Gijsen Dr. Yoshinori Yamano Dr. Ken-ichi Kusakabe 《ChemMedChem》2019,14(22):1894-1910
The β-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as β-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aβ reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [14C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound. 相似文献
11.
Twelve compounds produced by the metasternal glands (MGs) of the triatomine bug Rhodnius prolixus were identified by solid phase microextraction (SPME) combined with coupled gas chromatography-mass spectrometry (GC-MS)
using achiral and chiral columns. All substances were ketones or alcohols, and the same compound profile was found in the
secretions produced by either sex. The most abundant compounds were 2-methyl-3-buten-2-ol, (2S)-pentanol, (3E)-2-methyl-3-penten-2-ol, and (2R/2S)-4-methyl-3-penten-2-ol. Emission of these compounds was detected more frequently from females than males, and females released
them more frequently during the early hours of the scotophase, the period when sexual activity in this species is at its peak.
These compounds were also detected in the headspace above mating pairs. Finally, the occlusion of the MG orifices of male
or female bugs with paraffin resulted in a significant decrease in copulation frequency compared to sham-operated insects.
Together, these data suggest that the MG secretions of R. prolixus may be involved in sexual communication. 相似文献
12.
T. Corrales F. Catalina C. Peinado E. L. Madruga N. S. Allen 《Polymer International》1997,42(4):397-403
Two new monomers based on thioxanthone, 2-(3′-acryloxy)propoxythioxanthone (M-2) and 1-methyl-4-(3′-acryloxy)propoxythioxanthone (M-4), were prepared and their radical copolymerization at 70°C with methyl methacrylate (MMA) was studied. By varying the conversion reached for a fixed feed composition, fMMA=0·983, and using Jaacks method, the reactivity ratios were determined. Identical values of reactivity ratios were found for both systems, with values of rMMA=2·46 and rM-2=rM-4=0·4. The homopolymerization of MMA in the presence of a model compound, 1-methyl-4-propoxythioxanthone, was also examined and confirmed that the thioxanthone chromophore does not have any influence on the free radical polymerization of MMA. © of SCI. 相似文献
13.
Satoshi Kubo Koh Hashida Shojiro Hishiyama Tatsuhiko Yamada Shuji Hosoya 《木材化学与工艺学杂志》2015,35(1):62-72
In the alkaline decomposition of a β-O-4 type lignin model compound (erythro-guaiacylglycerol-β-guaiacyl ether, compound 1), an isomeric pair of C6C2 enol-ether (2-methoxy-4-[2-(2-methoxyphenoxy)-vinyl]-phenol, compound 2) was detected as the main decomposition product with no trace of C6C3 enol-ether (4-[3-hydroxy-1-(2-methoxyphenoxy)-propenyl]-2-methoxy-phenol, compound 3) or other dimers. In contrast, compound 2 was not detected in the alkaline decomposition products of compound 3. Under alkaline conditions, the γ-hydroxymethyl group of compound 3 was reduced to form 2-methoxy-4-[1-(2-methoxyphenoxy)-propenyl]-phenol (compound 4). In the HSQC analysis of soda lignin, the formation of substructures of C6C2 type enol-ether (related to compound 2) was confirmed. However, no substructures related to compound 4, which could be formed if a substructure of C6C3 type enol-ether was formed under alkaline conditions, were detected. Therefore, it could be concluded that C6C3 type enol-ethers could not be intermediates of alkaline decomposition products of lignin. 相似文献
14.
Highly selective asymmetric synthesis of 2-hydroxy fatty acid methyl esters has been accomplioshed through chiral imide enolates.
Five chiral oleic acid imides were prepared by reaction of oleioc acid with pivaloyl chloride followed by reaction with five
different lithiated chiral oxazolidinones including (R)-(+)-4-benzyl-2-, (S)-(-)-4-benzyl-2-, (4R,5S)-(+)-4-methyl-5-phenyl-2-, (4S,5R)-(-)-4-methyl-5-phenyl-2-, and (R)-(+)-4-isopropyl-2-oxazolidinones in 88–92% yileds. The chiral imides were reacted with NaN(Me3Si)2 at −78°C to give enolates, which subsequently reacted with 2-(phenylsulfonyl)-3-phenyloxaziridine to give hydroxylated products
in 78–83% yields. Methanolysis of the hydroxylated products with magnesium methoxide gave methyl 2-hydroxyoleate. Enantiomeric
excesses (ee) of the products were determined to be very high (98–99% ee) by 1H nuclear magnetic resonance study after esterification of the hydroxy group with (S)-(+)-O-acetylmandelic acid. Enantioselective hydroxylation of other fatty acids including elaidic, petroselinic, vaccenic, and linoleic
was evaluated under the similar conditions using (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary to give 98% ee values for all cases. 相似文献
15.
Ei-ichi Negishi Tomas Tobrman Honghua Rao Shiqing Xu Ching-Tien Lee 《Israel journal of chemistry》2010,50(5-6):696-701
(Z)-β-bromo-1-propenyl(pinacol)borane ( 4 ), recently made available in 85 % yield as a ≥98 % isomerically pure compound via bromoboration of 1-propyne, has been converted to β-alkyl-, aryl-, and alkenyl-substituted (Z)-2-methyl-1-alkenyl(pinacol)boranes ( 2a ) in ca. 75 % yield based on propyne via Pd-catalyzed Negishi alkenylation with suitable organozinc bromide. The previously sluggish and modest-yielding Suzuki alkenylation of β,β-disubstituted alkenylboranes has been significantly promoted by fluorides, especially nBu4NF(TBAF) or CsF, to give trisubstituted alkenes, i.e., (Z)-β-Me-substituted 3 - i – 3-xi and (E)-β-Ph-substituted 2b–i and 2b–ii . In all cases, each alkene product was formed in a ≥98 % stereoselectivity. The propyne-based protocol nicely complements the widely used Zr-catalyzed alkyne methylalumination–Pd-catalyzed alkenylation by providing a highly stereoselective(≥98 %) route to (Z)-Me-substituted alkenes. 相似文献
16.
Alice L. Perez Rebecca H. Hallett Regine Gries Gerhard Gries A. Cameron Oehlschlager John H. Borden 《Journal of chemical ecology》1996,22(2):357-368
Production of 4-methyl-5-nonanol, and 4-methyl-5-nonanone by two sympatric Asian palm weevils,Rhynchophorus ferrugineus (Oliv.) andR. vulneratus (Panz.) suggested that enantiospecificity of either compound could impart species specificity of pheromone communication. Weevil-produced, racemic 4-methyl-5-nonanol and 4-methyl-5-nonanone and their stereoselectively synthesized optical isomers were subjected to gas chromatographic-electroantennographic detection (GC-EAD) and GC-mass spectrometry (MS) on a chiral Cyclodex-B column. Only theS,S stereoisomer of 4-methyl-5-nonanol was EAD active and was produced by bothR. ferrugineus andR. vulneratus. Production and EAD activity of (S)-4-methyl-5-nonanone exceeded that of its antipode in both weevils. In field experiments in Java. (4S, 5S)-4-methyl-5-nonanol and the stereoisomeric mixture were equally attractive. The 4R,5R stereoisomer was inactive. The corresponding ketone enantiomers neither enhanced nor reduced attraction to (4S,5S)-4-methyl-5-nonanol. Lack of apparent differences betweenR. ferrugineus andR. vulneratus pheromones suggests that synonomy of both weevils should be considered unless other pre- or postzygotic reproductive isolating mechanisms are disclosed in future studies. 相似文献
17.
A C18 1-pyrroline fatty ester, methyl 8-(5-hexyl-2-pyrrolin-1-yl)octanoate (1), was prepared from methyliso-ricinoleate. The C=N bond of the pyrroline ring was oxidized bym-chloroperoxy-benzoic acid to yield a mixture of oxaziridine isomers 2a,2b, which decomposed during gas chromatographic analysis
to a 2,5-disubstituted pyrrole derivative, methyl 8-(5-hexyl-1H-pyrrole-2-)octanoate (3). Compound 3 was also obtained by reaction of 2a,2b with dilute HCl in methanol. Reaction of compound
1 with iodo-methane formed anN-methyl iminium iodide intermediate 4, which on reduction with sodium borohydride furnished a mixture ofcis/trans-N-methyl-2,5-disubstituted pyrrolidine derivatives, methyl 8-(cis/trans-5-hexyl-N-methyl-pyrrolidine-2-)octanoates 5a,5b. Reduction of compound 1 with NaBH4 gave a mixture ofcis/trans-isomers of 2,5-disubstituted pyrrolidine derivatives, methyl 8-(5-hexyl-pyrrolidine-2-)octanoates 6a,6b. Acetylation of compounds
6a,6b with acetic anhydride furnished the correspondingN-acetyl pyrrolidines 7a,7b. When compound 1 was treated with perchloric acid, the corresponding iminium perchlorate derivative,
methyl 8-(5-hexyl-1-pyrrolinium perchlorate-2-)octanoate 8 was obtained. The structures of the various derivatives were characterized
by a combination of chromatographic, mass spectral and spectroscopic techniques. 相似文献
18.
Marcel K. W. Mackwitz Eva Hesping Dr. Yevgeniya Antonova-Koch Dr. Daniela Diedrich Dr. Tamirat Gebru Woldearegai Assoc. Prof. Dr. Tina Skinner-Adams Mary Clarke Andrea Schöler Laura Limbach Prof. Dr. Thomas Kurz Prof. Dr. Elizabeth A. Winzeler Dr. Jana Held Prof. Dr. Katherine T. Andrews Prof. Dr. Finn K. Hansen 《ChemMedChem》2019,14(9):912-926
Novel malaria intervention strategies are of great importance, given the development of drug resistance in malaria-endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis, and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, we modified all regions of the peptoid scaffold by using a one-pot multicomponent pathway and submonomer routes to gain a deeper understanding of the structure–activity and structure–toxicity relationships. Most compounds displayed potent activity against asexual blood-stage P. falciparum parasites, with IC50 values in the range of 0.0052–0.25 μm and promising selectivity over mammalian cells (SIPf3D7/HepG2: 170–1483). In addition, several compounds showed encouraging sub-micromolar activity against P. berghei exo-erythrocytic forms (PbEEF). Our study led to the discovery of the hit compound N-(2-(benzylamino)-2-oxoethyl)-N-(4-(hydroxycarbamoyl)benzyl)-4-isopropylbenzamide ( 2 h ) as a potent and parasite-specific dual-stage antiplasmodial HDAC inhibitor (IC50 Pf3D7=0.0052 μm , IC50 PbEEF=0.016 μm ). 相似文献
19.
Guo Li Xiang-Hong He He-Ping Li Qian Zhao Dong-Ai Li Hong-Ping Zhu Yue-Hua Zhang Prof. Gu Zhan Prof. Wei Huang 《ChemMedChem》2022,17(11):e202200104
A series of densely functionalized THαCs were designed and synthesized as Akt1 inhibitors. Organocatalytic [3+3] annulation between indolin-2-imines 1 and nitroallylic acetates 2 provided rapid access to this pharmacologically interesting framework. In vitro kinase inhibitory abilities and cytotoxicity assays revealed that compound 3 af [(3S*,4S*)-4-(4-bromo-2-fluorophenyl)-9-methyl-3-nitro-1-tosyl-2,3,4,9-tetrahydro-1H-pyrido[2,3-b]indole] was the most potent Akt1 inhibitor, and mechanistic study indicated that compound 3 af suppressed the proliferation of colorectal cancer cells via inducing apoptosis and autophagy. Molecular docking suggested that the indole fragment of 3 af was inserted into the hydrophobic pocket of Akt1 protein, and the H-bond between 3 af and residue Lys179 also contributed to the stable binding. This article provides an efficient strategy to design and synthesize biologically important compounds as novel Akt1 inhibitors. 相似文献
20.
《Journal of Sulfur Chemistry》2013,34(4):427-438
A new synthetic strategy for the synthesis of novel 6-methyl-3′-aryl spiro[isoxazolo[2,3-b][1,2,4]thiadiazole-2,2′-thiazolidin]-4′-ones (9a–9e) and 6-methyl-3′-aryl spiro[isoxazolo[2,3-b][1,2,4]oxadiazole- 2,2′-thiazolidin]-4′-ones (12a–12e) analogs is described. These compounds showed significant antimicrobial activity against all the standard strains. 相似文献