- Discovery of Potent, Reversible, and Competitive Cruzain Inhibitors with Trypanocidal Activity: A Structure-Based Drug Design Approach
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A virtual screening conducted with nearly 4?000?000 compounds from lead-like and fragment-like subsets enabled the identification of a small-molecule inhibitor (1) of the Trypanosoma cruzi cruzain enzyme, a validated drug target for Chagas disease. Subsequent comprehensive structure-based drug design and structure-activity relationship studies led to the discovery of carbamoyl imidazoles as potent, reversible, and competitive cruzain inhibitors. The most potent carbamoyl imidazole inhibitor (45) exhibited high affinity with a Ki value of 20 nM, presenting both in vitro and in vivo activity against T. cruzi. Furthermore, the most promising compounds reduced parasite burden in vivo and showed no toxicity at a dose of 100 mg/kg. These carbamoyl imidazoles are structurally attractive, nonpeptidic, and easy to prepare and synthetically modify. Finally, these results further advance our understanding of the noncovalent mode of inhibition of this pharmaceutically relevant enzyme, building strong foundations for drug discovery efforts.
- De Souza, Mariana L.,De Oliveira Rezende Junior, Celso,Ferreira, Rafaela S.,Espinoza Chávez, Rocio Marisol,Ferreira, Leonardo L. G.,Slafer, Brian W.,Magalh?es, Luma G.,Krogh, Renata,Oliva, Glaucius,Cruz, Fabio Cardoso,Dias, Luiz Carlos,Andricopulo, Adriano D.
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p. 1028 - 1041
(2019/12/27)
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- Design and Synthesis of Novel 4-Hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one Derivatives for Use as Herbicides and Evaluation of Their Mode of Action
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In order to develop a novel herbicide containing the β-triketone motif, a series of 4-hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one derivatives were designed and synthesized. The bioassay results showed that compound II15 had good pre-emergent herbicidal activity even at a dosage of 187.5 g ha-1. Moreover, compound II15 showed a broader spectrum of weed control when compared with a commercial herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), and displayed good crop safety to Triticum aestivum L. and Zea mays Linn. when applied at 375 g ha-1 under pre-emergence conditions, which indicated its great potential as a herbicide. More importantly, studying the molecular mode of action of compound II15 revealed that the novel triketone structure is a proherbicide of its corresponding phenoxyacetic acid auxin herbicide, which has a herbicidal mechanism similar to that of 2,4-D. The present work indicates that the 4-hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one motif may be a potential lead structure for further development of novel auxin-type herbicides.
- Lei, Kang,Li, Pan,Yang, Xue-Fang,Wang, Shi-Ben,Wang, Xue-Kun,Hua, Xue-Wen,Sun, Bin,Ji, Lu-Sha,Xu, Xiao-Hua
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p. 10489 - 10497
(2019/10/02)
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- Ketoreductase catalyzed stereoselective bioreduction of α-nitro ketones
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We report here the stereoselective bioreduction of α-nitro ketones catalyzed by ketoreductases (KREDs) with publicly known sequences. YGL039w and RasADH/SyADH were able to reduce 23 class I substrates (1-aryl-2-nitro-1-ethanone (1)) and ten class II substrates (1-aryloxy-3-nitro-2-propanone (4)) to furnish both enantiomers of the corresponding β-nitro alcohols, with good-to-excellent conversions (up to >99%) and enantioselectivities (up to >99% ee) being achieved in most cases. To the best of our knowledge, KRED-mediated reduction of class II α-nitro ketones (1-aryloxy-3-nitro-2-propanone (4)) is unprecedented. Select β-nitro alcohols, including the synthetic intermediates of bioactive molecules (R)-tembamide, (S)-tembamide, (S)-moprolol, (S)-toliprolol and (S)-propanolol, were stereoselectively synthesized in preparative scale with 42% to 90% isolated yields, showcasing the practical potential of our developed system in organic synthesis. Finally, the advantage of using KREDs with known sequence was demonstrated by whole-cell catalysis, in which β-nitro alcohol (R)-2k, the key synthetic intermediate of hypoglycemic natural product (R)-tembamide, was produced in a space-time yield of 178 g L?1 d?1 as well as 95% ee by employing the whole cells of a recombinant E. coli strain coexpressing RasADH and glucose dehydrogenase as the biocatalyst.
- Wang, Zexu,Wu, Xiaofan,Li, Zhining,Huang, Zedu,Chen, Fener
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supporting information
p. 3575 - 3580
(2019/04/14)
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- Isoflavone amide derivatives, their preparation method and medical use
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The invention belongs to the field of medicinal chemistry, and relates to derivatives of isoflavones amides, as well as a preparation method and medical application of derivatives, in particular to the derivatives of the isoflavones amides with the general formula of (I) shown as the specification, the preparation method and the medical application of the derivatives, particularly the application of the derivatives of the isoflavones amides serving as medicaments for preventing or treating hyperlipemia, adiposis or type-II diabetes.
- -
-
Paragraph 0077
(2017/08/31)
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- An Efficient One-Pot Synthesis of 2-(Aryloxyacetyl)cyclohexane-1,3-diones as Herbicidal 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors
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4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is an important target for new bleaching herbicides discovery. As a continuous work to discover novel crop selective HPPD inhibitor, a series of 2-(aryloxyacetyl)cyclohexane-1,3-diones were rationally designed and synthesized by an efficient one-pot procedure using N,N′-carbonyldiimidazole (CDI), triethylamine, and acetone cyanohydrin in CH2Cl2. A total of 58 triketone compounds were synthesized in good to excellent yields. Some of the triketones displayed potent in vitro Arabidopsis thaliana HPPD (AtHPPD) inhibitory activity. 2-(2-((1-Bromonaphthalen-2-yl)oxy)acetyl)-3-hydroxycyclohex-2-en-1-one, II-13, displayed high, broad-spectrum, and postemergent herbicidal activity at the dosage of 37.5-150 g ai/ha, nearly as potent as mesotrione against some weeds. Furthermore, II-13 showed good crop safety against maize and canola at the rate of 150 g ai/ha, indicating that II-13 might have potential as a herbicide for weed control in maize and canola fields. II-13 is the first HPPD inhibitor showing good crop safety toward canola.
- Wang, Da-Wei,Lin, Hong-Yan,He, Bo,Wu, Feng-Xu,Chen, Tao,Chen, Qiong,Yang, Wen-Chao,Yang, Guang-Fu
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p. 8986 - 8993
(2016/12/09)
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- Finding new elicitors that induce resistance in rice to the white-backed planthopper Sogatella furcifera
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Herein we report a new way to identify chemical elicitors that induce resistance in rice to herbivores. Using this method, by quantifying the induction of chemicals for GUS activity in a specific screening system that we established previously, 5 candidate elicitors were selected from the 29 designed and synthesized phenoxyalkanoic acid derivatives. Bioassays confirmed that these candidate elicitors could induce plant defense and then repel feeding of white-backed planthopper Sogatella furcifera.
- He, Xingrui,Yu, Zhaonan,Jiang, Shaojie,Zhang, Peizhi,Shang, Zhicai,Lou, Yonggen,Wu, Jun
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supporting information
p. 5601 - 5603
(2015/11/17)
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- Total synthesis of the 2-arylbenzo[b]furan-containing natural products from Artocarpus
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In this study, 2-arylbenzo[b]furan-containing derivatives moracin C (1) and moracin M (4), the natural products from Artocarpus, have been synthesized in highest overall yield to date (1, 7 steps with an overall yield of 41.9%; 4, 6 steps with an overall yield of 56.3%), and we also report the first total synthesis of artoindonesianin B-1 (2), another member of this family, in the same route (8 steps with an overall yield of 11.3%). This discovery provides a concise route for preparing enough amounts of 1, 2, and 4 as well as 2-arylbenzo[b]furan-containing natural product-like analogs (71-74) to explore the biological potential.
- Wu, Deyan,Mei, Hanbing,Tan, Ping,Lu, Weiqiang,Zhu, Jin,Wang, Wei,Huang, Jin,Li, Jian
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supporting information
p. 4383 - 4387
(2015/06/22)
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- Synthesis and biological evaluation of isoflavone amide derivatives with antihyperlipidemic and preadipocyte antiproliferative activities
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A series of isoflavone amides were designed with isoflavone in place of the scaffold of 2-arylbenzoxazole as cholesterol ester transfer protein (CETP) inhibitors. Twelve new compounds were synthesized, and their inhibitory activities of CETP and preadipocyte proliferation were assayed. The hypolipidemic potency of the most effective compound HY-2c was further tested in vivo by hamster. The results indicate that HY-2c exhibited favorable antihyperlipidemic and preadipocyte antiproliferative activities.
- Wang, Wenbin,He, Yi,Xu, Pei,You, Qidong,Xiao, Hong,Xiang, Hua
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p. 4428 - 4433
(2015/08/03)
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- Synthesis, evaluation and in silico molecular modeling of pyrroyl-1,3,4-thiadiazole inhibitors of InhA
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Enoyl acyl carrier protein reductase (ENR) is an essential type II fatty acid synthase (FAS-II) pathway enzyme that is an attractive target for designing novel antitubercular agents. Herein, we report sixty-eight novel pyrrolyl substituted aryloxy-1,3,4-thiadiazoles synthesized by three-step optimization processes. Three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for pyrrolyl substituted aryloxy-1,3,4-thiadiazole series of InhA inhibitors using the comparative molecular field analysis (CoMFA). Docking analysis of the crystal structure of ENR performed by using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of pyrrolyl substituted aryloxy 1,3,4-thiadiazole into hydrophobic pocket of InhA enzyme. Based on docking and database alignment rules, two computational models were established to compare their statistical results. The analysis of 3D contour plots allowed us to investigate the effect of different substituent groups at different positions of the common scaffold. In vitro testing of ligands using biological assays substantiated the efficacy of ligands that were screened through in silico methods.
- Joshi, Shrinivas D.,More, Uttam A.,Koli, Deepshikha,Kulkarni, Manoj S.,Nadagouda, Mallikarjuna N.,Aminabhavi, Tejraj M.
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p. 151 - 167
(2015/03/30)
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- In silico and pharmacological screenings identify novel serine racemase inhibitors
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d-Serine is a coagonist of the N-methyl-d-aspartate (NMDA)-type glutamate receptor and its biosynthesis is catalyzed by serine racemase (SR). The overactivation of the NMDA receptor has been implicated in the development of neurodegenerative diseases, strokes, and epileptic seizures, thus, the inhibitors of SR have potential against these pathological states. Here, we have developed novel inhibitors of SR by in silico screening and in vitro enzyme assay. The newly developed inhibitors have lower IC50 value comparing with that of malonate, one of the standard SR inhibitor. The structural features of novel inhibitors suggest the importance of central amide structure having a phenoxy substituent in their structure for the SR inhibitory activity. The present findings suggest the importance and rational development of new drugs for diseases of NMDAR overactivation.
- Mori, Hisashi,Wada, Ryogo,Li, Jie,Ishimoto, Tetsuya,Mizuguchi, Mineyuki,Obita, Takayuki,Gouda, Hiroaki,Hirono, Shuichi,Toyooka, Naoki
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supporting information
p. 3732 - 3735
(2014/09/03)
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- Design, synthesis and PASS assisted evaluation of novel 2-substituted benzimidazole derivatives as potent anthelimintics
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Two series of compounds (AB and APB) bearing substituted phenoxy groups at 2-position of benzimidazole nucleus through amino or phenyleneamino were synthesized and evaluated through PASS software for predicting the activity spectrum of each compound. All compounds of both the series were predicted to have potent anthelmintic activity. The activity of each compound was evaluated experimentally at the concentrations of 0.1, 0.2 and 0.5% in terms of mortality time and paralysis time of the helminthes and was found to comply with the PASS predicted activity. In general, all compounds of APB series were more potent than those of AB series probably due to the additional hydrophobic interactions of the spacer phenyl ring in the APB series. The activity of all compounds was found to increase with increasing concentration. The compound with p-chlorophenoxy moiety was the most active from the APB series (mortality time 5.7±0.4 min and paralysis time 3.1±0.3 min) and equipotent to albendazole (mortality time 5.4±0.1 min and paralysis time 2.8±0.2 min) at concentration of 0.2%. The o-chlorophenoxy analogs in both the series were found to be the least active of all. Based on these results, a substituent capable of binding with the receptor through van der Waals and/or electronic interactions at 4-position of the phenoxy ring in the compound is suggested to increase binding interaction leading to potent anthelmintic activity.
- Singh, Gurmeet,Bansal, Yogita,Bansal, Gulshan,Goel, Rajesh Kumar
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p. 418 - 425
(2014/05/20)
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- Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors
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Screening of the 50 000 ChemBridge compound library led to the identification of the oxadiazole-isopropylamide 1 (PI-1833) which inhibited chymotrypsin-like (CT-L) activity (IC50 = 0.60 μM) with little effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and postglutamyl-peptide-hydrolysis-like (PGPH-L). LC-MS/MS and dialysis show that 1 is a noncovalent and rapidly reversible CT-L inhibitor. Focused library synthesis provided 11ad (PI-1840) with CT-L activity (IC50 = 27 nM). Detailed SAR studies indicate that the amide moiety and the two phenyl rings are sensitive toward modifications. Hydrophobic residues, such as propyl or butyl in the para position (not ortho or meta) of the A-ring and a m-pyridyl group as B-ring, significantly improve activity. Compound 11ad (IC50 = 0.37 μM) is more potent than 1 (IC50 = 3.5 μM) at inhibiting CT-L activity in intact MDA-MB-468 human breast cancer cells and inhibiting their survival. The activity of 11ad warrants further preclinical investigation of this class as noncovalent proteasome inhibitors.
- Ozcan, Sevil,Kazi, Aslamuzzaman,Marsilio, Frank,Fang, Bin,Guida, Wayne C.,Koomen, John,Lawrence, Harshani R.,Sebti, Sa?d M.
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p. 3783 - 3805
(2013/06/27)
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- Synthesis and biological activity of 2-Aryloxyacetylamino-2-Deoxy-D- Glucoses
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D-Glucosamine possesses extensive bioactivities including antibacterial, insecticidal and plant growth-regulating activities. A series of 2-aryloxyacetylamino-2-deoxy-D-glucoses have been synthesized by acylation of D-glucosamine with aryloxyacetyl chlorides and their plant growth-regulating activities were tested. The results show that these compounds bearing chlorine atom at para position of benzene ring have notable inhibiting activities against cotyledon rootage of cucumber which are comparable with that of 2,4-dichlorophenoxyacetic acid.
- Han, Liang,Zhu, Qiong-Yan,Jia, Jian-Hong,Li, Yu-Jin,Gao, Jian-Rong
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experimental part
p. 1223 - 1226
(2012/09/07)
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- PROTEASOME CHYMOTRYPSIN-LIKE INHIBITION USING PI-1833 ANALOGS
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Focused library synthesis and medicinal chemistry on an oxadiazole- isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring?s para-position and meta-pyridyl group at the B- ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer)
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Page/Page column 58
(2012/10/08)
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- The synthesis of ethacrynic acid thiazole derivatives as glutathione S-transferase pi inhibitors
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Glutathione S-transferase pi (GSTpi) is a phase II enzyme which protects cells from death and detoxifies chemotherapeutic agents in cancer cells. Ethacrynic acid (EA) is a weak GSTpi inhibitor. Structure modifications were done to improve the ability of EA to inhibit GSTpi activity. Eighteen EA thiazole derivatives were designed and synthesized. Compounds 9a, 9b and 9c with a replacement of carboxyl group of EA by a heterocyclic thiazole exhibited improvement over EA to inhibit GSTpi activity.
- Li, Ting,Liu, Guyue,Li, Hongcai,Yang, Xinmei,Jing, Yongkui,Zhao, Guisen
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scheme or table
p. 2316 - 2322
(2012/05/07)
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- Inhibition of monoamine oxidase by 8-phenoxymethylcaffeine derivatives
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A recent study has reported that a series of 8-benzyloxycaffeines are potent and reversible inhibitors of both human monoamine oxidase (MAO) isoforms, MAO-A and -B. In an attempt to discover additional caffeine derivatives with potent MAO inhibitory activities, and to contribute to the known structure-activity relationships of MAO inhibition by caffeine derived compounds, the present study investigates the MAO inhibitory potencies of series of 8-phenoxymethylcaffeine and 8-[(phenylsulfanyl)methyl]caffeine derivatives. The results document that the 8-phenoxymethylcaffeine derivatives act as potent reversible inhibitors of MAO-B, with IC50 values ranging from 0.148 to 5.78 μM. In contrast, the 8-[(phenylsulfanyl)methyl]caffeine derivatives were found to be weak inhibitors of MAO-B, with IC50 values ranging from 4.05 to 124 μM. Neither the 8-phenoxymethylcaffeine nor the 8-[(phenylsulfanyl)methyl]caffeine derivatives exhibited high binding affinities for MAO-A. While less potent than the 8-benzyloxycaffeines as MAO-B inhibitors, this study concludes that 8-phenoxymethylcaffeines may act as useful leads for the design of MAO-B selective inhibitors. Such compounds may find application in the therapy of neurodegenerative disorders such as Parkinson's disease. Using molecular docking experiments, this study also proposes possible binding orientations of selected caffeine derivatives in the active sites of MAO-A and -B.
- Okaecwe, Thokozile,Swanepoel, Abraham J.,Petzer, Anél,Bergh, Jacobus J.,Petzer, Jacobus P.
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experimental part
p. 4336 - 4347
(2012/08/28)
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- Studies of O,O-Dimethyl α-(2,4-Dichlorophenoxyacetoxy) ethylphosphonate (HW02) as a new herbicide. 1. Synthesis and herbicidal activity of HW02 and analogues as novel inhibitors of pyruvate dehydrogenase complex
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On the basis of the previous work for optimization of O,O-diethyl α-(substituted phenoxyacetoxy)alkylphosphonates, further extensive syntheticmodifications were made to the substituents in alkylphosphonate and phenoxymoieties of the title compounds. New O,O-dimethyl α-(substituted phenoxyacetoxy)alkylphosphonates were synthesized as potential inhibitors of pyruvate dehydorogenase complex (PDHc). Their herbicidal activity and efficacy in vitro against PDHc were examined. Some of these compounds exhibited significant herbicidal activity and were demonstrated to be effective inhibitors of PDHc from three different plants. The structure-activity relationships of these compounds including previously reported analogous compoundswere studied by examining their herbicidal activities. Both inhibitory potency against PDHc and herbicidal activity of title compounds could be increased greatly by optimizing substituent groups of the title compounds. O,O-Dimethyl α-(2,4- dichlorophenoxyacetoxy)ethylphosphonate (I-5), which acted as a competitive inhibitor of PDHc with much higher inhibitory potency against PDHc from Pisum sativum and Phaseolus radiatus than from Oryza sativa, was found to be themost effective compound against broadleaf weeds and showed potential utility as herbicide.
- He, Hong-Wu,Yuan, Jun-Lin,Peng, Hao,Chen, Ting,Shen, Ping,Wan, Shu-Qing,Lee, Yanjun,Tan, Hong-Liang,He, Ya-Hui,He, Jun-Bo,Li, Yan
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scheme or table
p. 4801 - 4813
(2011/12/04)
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- Aza-Michael addition of acrylonitrile with 2-aryloxymethylbenzimidazole derivatives under microwave irradiation
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A simple, rapid, and highly efficient method has been developed for the aza-Michael addition of acrylonitrile to 2-aryl-oxymethylbenzimidazole derivatives in the presence of anhydrous potassium carbonate under microwave irradiation. A series novel of 1-cyanoethyl-2-aryloxymethylbenzimidazole derivatives have been prepared and characterised by 1H NMR, 13C NMR, IR spectra and elemental analysis.
- Wei, Tai-Bao,Hua, Mao-Tang,Shi, Hai-Xiong,Liu, Yong,Zhang, You-Ming
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scheme or table
p. 452 - 454
(2010/12/24)
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- Synthesis and biological evaluation of some novel 2-mercaptobenzothiazoles carrying 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole moieties
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Several 2-mercaptobenzothiazole derivatives containing 1,3,4-oxadiazoles, 1,2,4-triazoles and 1,3,4-thiadiazoles at the second position were synthesized. Some of these synthesized compounds were evaluated for their in vivo analgesic, anti-inflammatory, acute toxicity and ulcerogenic actions. Some of the tested compounds showed significant analgesic and anti-inflammatory activities. Two of the compounds showed significant gastrointestinal protection compared to the standard drug diclofenac sodium. The compounds were also tested for their in vitro antimicrobial activity with most displaying selective activity against the Gram-negative bacteria Pseudomonas aeruginosa. In the present investigation the tested compounds did not possess antifungal activity.
- Azam, M. Afzal,Suresh, Bhojraj,Kalsi, Sandip S.,Antony, A. Shinesh
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scheme or table
p. 114 - 122
(2011/06/09)
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- Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin
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Plasmepsin (Plm) is a potential target for new antimalarial drugs, but most reported Plm inhibitors have relatively low antimalarial activities. We synthesized a series of dipeptide-type HIV protease inhibitors, which contain an allophenylnorstatine-dimethylthioproline scaffold to exhibit potent inhibitory activities against Plm II. Their activities against Plasmodium falciparum in the infected erythrocyte assay were largely different from those against the target enzyme. To improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity. These results suggest that auxiliary substituents on a specific basic group contribute to deliver the inhibitors to the target Plm.
- Hidaka, Koushi,Kimura, Tooru,Ruben, Adam J.,Uemura, Tsuyoshi,Kamiya, Mami,Kiso, Aiko,Okamoto, Tetsuya,Tsuchiya, Yumi,Hayashi, Yoshio,Freire, Ernesto,Kiso, Yoshiaki
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scheme or table
p. 10049 - 10060
(2009/04/07)
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- Synthesis and anti-inflammatory activity of 2-aryloxy methyl oxazolines
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A series of potential biologically active 2-aryloxy methyl oxazolines 3a-n have been synthesized from substituted hydroxybenzenes 1a-n with good chemical yield. The compounds 3a-n were screened for their anti-inflammatory, ulcerogenic, cyclooxygenase activities and also for their acute toxicity. The potency of the compounds was compared with that of the standard drugs, aspirin and phenyl butazone. The outcome indicates that compounds 3b (48.2%), 3h (48.5%) and 3l (46.5%) offered significant anti-inflammatory activity with low ulcerogenic activity than the standard drugs.
- Khanum, Shaukath Ara,Khanum, Noor Fatima,Shashikanth
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body text
p. 4597 - 4601
(2009/04/06)
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- The synthesis of α,β-unsaturated carbonyl derivatives with the ability to inhibit both glutathione S-transferase P1-1 activity and the proliferation of leukemia cells
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Ethacrynic acid (EA), an α,β-unsaturated carbonyl compound, is a glutathione S-transferase P1-1 (GSTP1-1) inhibitor. Twenty-one novel EA derivatives have been synthesized. The effects of these compounds on GSTP1-1 activity and on the proliferation of human leukemia HL-60 cells have been determined. Compounds with a halogen substitution at the 3′-position of the aromatic ring have greater inhibitory effects on GSTP1-1 activity than those of compounds with a methyl substitution there. Compounds with substitutions at both the 2′- and 3′-positions of the aromatic ring have more antiproliferative ability than those with one substitution at 3′-position. Esterification of the carboxyl group appears to increase the antiproliferative ability.
- Zhao, Guisen,Liu, Chuan,Wang, Rui,Song, Dandan,Wang, Xiaobing,Lou, Hongxiang,Jing, Yongkui
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p. 2701 - 2707
(2008/02/07)
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- An efficient synthesis of benzofurans and their application in the preparation of natural products of the genus Calea
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The intramolecular cyclization of the β-substituted olefins methyl 2-aryloxy-3-dimethylaminopropenoates 3a-3f catalyzed by Lewis acids leads to a short and novel synthesis of benzofurans 2a-2f. When the olefins 4-dimethylamino-3-aryloxy-3-buten-2-ones 4a-4f were used, the cyclization process was faster and provided the corresponding substituted 2-acetylbenzofurans 1a-1f. Among the latter, naturally occurring compounds calebertin (1a), caleprunin A (1b), and caleprunin B (1c) were prepared in good overall yields. These benzofurans were also obtained by direct treatment under MW irradiation of the precursors 1-aryloxypropan-2-ones 7a-7c with DMFDMA, followed by addition of the catalyst, resulting in a route that was one step shorter.
- Del Carmen Cruz, María,Tamariz, Joaquín
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p. 10061 - 10072
(2007/10/03)
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- One-pot synthesis of fluorine containing 3-cyano/ethoxycarbonyl-2-methyl- benzo[b]furans
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Fluoro-substituted 3-cyano-2-methyl-benzo[b]furans and ethyl 2-methyl-benzo[b]furan-3-carboxylates are conveniently prepared in a single step in good yield by the microwave induced tandem intramolecular Wittig and Claisen rearrangement reactions of the corresponding [(aryloxyacetyl) (cyano) methylene] triphenylphosphorane and [(aryloxyacetyl) (ethoxycarbonyl) methylene] triphenylphosphoranes, respectively. Graphical Abstract
- RamaRao,Venkat Reddy,Maitraie,Ravikanth,Yadla,Narsaiah,Shanthan Rao
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p. 12231 - 12237
(2007/10/03)
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- Captodative olefins: Methyl 2-aryloxy-3-dimethyl-aminopropenoates and their application in a new synthesis of benzofurans
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The β-substituted captodative olefins methyl 2-aryloxy-3- dimethylaminopropenoates 4a-h were synthesized, via aminomethylenation of the corresponding 2-phenoxyacetic esters 9a-h. Lewis acid promoted intramolecular cyclization of alkenes 4 led to benzofurans 7a-h, in an efficient synthetic approach to the benzofuran frame.
- Cruz, María Del Carmen,Tamariz, Joaquín
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p. 2377 - 2380
(2007/10/03)
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- Design, synthesis and antihistaminic (H1) activity of some condensed 3- aminopyrimidin-4(3H)-ones
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A novel series of condensed 3-amino-2-(substituted)methylpyrimidin- 4(3H)-ones is reported with potential H1 receptor antagonistic activity. The IC50 values for 23 compounds were found to be in the micromolar range. Five lead compounds (10c, e, g, r and t), when evaluated by the in vivo method were found to protect guinea-pigs from the histamine induced asphyxia and antagonized histamine in a competitive and reversible manner. With a pA2 value of 8.7 and protection time of 9.5 min (in vivo test), compound 10g was the most active amongst these five compounds. The isosteric replacement of the side chain -NH- in series 1, by oxygen and -NHSO2- functions, was undertaken to investigate the role of two amino functions in the receptor binding. This isosteric replacement with -O- does not affect the antihistaminic activity and the sedative potential of the series. Preliminary molecular modelling, studies indicate that the compounds with -NHSO2- in the side chain exhibit a closer fit with temelastine than their -O- isosteres. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Shishoo, Chamanlal J.,Shirsath, Vikas S.,Rathod, Ishwarsinh S.,Yande, Vikas D.
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p. 351 - 358
(2007/10/03)
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- Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine
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We designed and synthesized a new class of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy- 4-phenylbutyric acid], with a hydroxymethylcarbonyl (HMC) isostere as the active moiety. A systematic evaluation of structure - activity relationships for HIV protease inhibition, anti-HIV activities, and pharmacokinetic profiles has led to the delineation of a set of structural characteristics that appear to afford an orally available HIV protease inhibitor. Optimum structures, exemplified by 21f (JE-2147), incorporated 3-hydroxy-2- methylbenzoyl groups as the P2 ligand, (R)-5,5-dimethyl-1,3-thiazolidine-4- carbonyl (Dmt) residue at the P1' site, and 2-methylbenzylcarboxamide group as the P2' ligand. The present study demonstrated that JE-2147 has potent antiviral activities in vitro and exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals.
- Mimoto, Tsutomu,Kato, Ryohei,Takaku, Haruo,Nojima, Satoshi,Terashima, Keisuke,Misawa, Satoru,Fukazawa, Tominaga,Ueno, Takamasa,Sato, Hideharu,Shintani, Makoto,Kiso, Yoshiaki,Hayashi, Hideya
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p. 1789 - 1802
(2007/10/03)
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- Synthesis of 1,1,1-trichloro-2,2-bis-(carboxymethoxyaryl)ethanes as potential antimicrobial and insecticidal agents
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Some new 1,1,1-trichloro-2,2-bis-(carboxymethoxyaryl)-ethanes 2a-t have been synthesised by the treating aryloxyacetic acid (two moles) with chloral hydrate (1 mole) in the presence of catalytic amount of conc. sulphuric acid. The aryloxyacetic acid are prepared by the reaction of substituted phenols with chloroacetic acid in the presence of aq. sodium hydroxide. The antimicrobial activity of these compounds have been assayed against various Gram+ve, Gram-ve bacteria and fungi. The constitution of the products have been elucidated by IR, 1H NMR and mass spectral data and elemental analyses.
- Purohit,Shah
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p. 618 - 622
(2007/10/03)
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- Skeletal Rearrangements Preceding CO Loss from Metastable Phenoxymethylene Ions Derived from Phenoxyacetic Acid and Anisole
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The loss of CHO2(.) from the molecular ion of phenoxyacetic acid and the expulsion of an H(.) atom from ionized anisole lead to phenoxymethylene ions, which fragment predominantly by CO loss on the microsecond time-scale.Carbon-13 labelling reveals that ca. 90percent of the CO molecules expelled from the metastable ions derived from phenoxyacetic acid incorporate the carbon atom from the 1-position of the phenyl group of the parent compound, whereas the residual CO molecules contain one of the other carbon atoms of the aromatic ring.The 2-fluoro- and 2-methylphenoxymethylene ions derived from the appropriate aryloxyacetic acids behave similarly, i.e. the carbon atom of the methylene group of the parent compound is not incorporated in the expelled CO molecules.In contrast, ca. 45percent of the CO molecules eliminated from the metastable phenoxymethylene ions formed from ionized anisole contain the carbon atom of the methyl group, while the remaining part contains the carbon atom from the 1-position of the phenyl ring of the parent compound.This result is taken as evidence for the occurrence of a skeletal rearrangement of the anisole molecular ion leading to an interchange between the carbon atom of the methyl group and the carbon atom at the 1-position of the ring.The elimination of CO from the metastable ions generated from either phenoxyacetic acid or anisole gives rise to a composite metastable peak.Conclusive evidence as to the formation of (+) isomers other than the phenoxymethylene ion is not obtained, indicating that the composite metastable peak is a result of two competing reactions both leading to CO loss.Possible mechanisms of these reactions are discussed together with the mechanism of the skeletal rearrangement of the molecular ion of anisole prior to H(.) loss.
- Molenaar-Langeveld, Tineke A.,Ingemann, Steen,Nibbering, Nico M. M.
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p. 1167 - 1178
(2007/10/02)
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- Synthesis and Biological Activity of 3-Pentadecylaryloxyacetic Acids, Their Hydrazides and Cyclic Derivatives: Oxadiazoles and Pyrroles
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Several 3-pentadecylaryloxyacetic acids (III), their hydrazides (IV), 2-amino-5-(3'-pentadecylaryloxymethyl)-1,3,4-oxadiazoles (V) and 1-(3'-pentadecylaryloxyacetamido)-2,5-dimethylpyrroles (VI) have been synthesised and evaluated for their biological activity.Some of the compounds exhibit strong antiinflammatory action in experimental animals.Presence of a long alkyl chain (C13H31) renders the compounds to be less toxic.
- Ramalingam, T.,Sattur, P. B.
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p. 1204 - 1207
(2007/10/02)
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- POLYMER SUPPORTED REAGENTS: USE OF ANION EXCHANGE RESIN IN THE SYNTHESIS OF ARYLOXY ACETIC ACIDS
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Phenoxides supported on Amberlite IRA 400 on reaction with sodium salt of chloroacetic acid gave corresponding aryloxy acetic acid in high yields.Interestingly nitrophenols, 4-hydroxy coumarin and p-hydroxy ethylbenzoate gave excellent yields of the product.
- Deshmukh, J. G.,Jagdale, M. H.,Mane, R. B.,Salunkhe, M. M.
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p. 479 - 484
(2007/10/02)
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