- Diastereoselective intermolecular cobalt-catalyzed reductive aldol reactions of α,β-unsaturated amides with ketones
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Under cobalt catalysis, diethylzinc mediates the conjugate reduction of αβ-unsaturated amides to produce ethylzinc enolates that react with ketones in situ to produce tertiary alcohol-containing aldol products with up to >19:1 diastereoselectivity.
- Lumby, Ralph J. R.,Joensuu, Pekka M.,Lam, Hon Wai
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Read Online
- Photocoupling between Haloheterocyclic Derivatives and Arylalkenes and Arylalkynes: Intruments to Predict Reactivity
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Parameters useful to predict reactivity and regiochemical control of photocoupling reactions between haloheterocyclic derivatives and arylakenes or arylakynes have been studied.Electrochemical properties of arylakynes are shown to be useful to predict the reactivity of the substrates.However, oxidation potentials fail as reactivity indices if very fast photochemical processes are in competition with the observed complex formation between substrates and halogen atoms.The regiochemical behavior of the reaction can be estimated on the basis of dipoles of the reagents.In this case the assumptions that a reagent approaches the other on parallel planes and that the prevalent interaction is between the SOMO of the radical and the LUMO of the other reagent have been accepted.
- D'Auria, Maurizio,Ferri, Tomaso
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Read Online
- Design and synthesis novel amide derivatives containing an 1,3,4-oxadiazole moiety as potential antibacterial agents
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To find new antibacterial agents, 25 novel amide derivatives containing an 1,3,4-oxadiazole moiety were designed and synthesized, and their antibacterial activity against Xanthomonas oryzae pv. oryzicola (Xoc) and Xanthomonas oryzae pv. oryzae (Xoo) were tested. Interestingly, all target compounds showed excellent antibacterial activities against Xoc and Xoo. The EC50 values of compounds 1–25 against Xoc and Xoo were 1.2–4.0?mg/L and 0.5–2.3?mg/L, respectively, which were significantly superior to those of the thiodiazole copper (95.1 and 89.0?mg/L) and bismerthhibol (73.8 and 68.8?mg/L). For example, the EC50 values of compound 16 against Xoc and Xoo were 1.7 and 0.5?mg/L, respectively. Meanwhile, the curative and protection activity of compound 16 against rice bacterial leaf blight were 42.4% and 42.1%, respectively, which were superior to the control of jiahuangxianjunzuo (34.1% and 32.6%) and thiodiazole copper (33.0% and 27.1%). In addition, compound 16 might suppress the cell growth of Xoo by inhibiting the production of extracellular polysaccharide, the formation of biofilm, changes the cell membrane permeability, and cell surface morphology.
- Chen, Jixiang,Chen, Yifang,Luo, Xin,Wang, Yu,Xing, Zhifu
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supporting information
(2022/02/17)
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- Quinoline derivative containing furyl and preparation method and application thereof
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The invention belongs to the field of anti-cancer drugs, and particularly relates to a furyl-containing quinoline derivative and a preparation method and application thereof. The invention provides a compound as shown in the formula I, and a stereoisomer or pharmaceutically acceptable salt thereof. Compared with an existing antitumor drug, the compound disclosed by the invention has excellent antitumor activity on A431, SKOV3, SK-BR-3, BT474 and the like, and has a very good application prospect. In addition, the preparation method of the compound is low in cost, simple in step, mild in reaction condition, high in yield and easy for post-treatment.
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Paragraph 0098-0102
(2021/05/08)
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- Template-Directed Photochemical Homodimerization and Heterodimerization Reactions of Cinnamic Acids
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We developed a general method for the selective photochemical homo- and heterodimerization of cinnamic acid derivatives with the use of commercially available 1,8-dihydroxynaphthalene as a covalent template. A variety of symmetrical and unsymmetrical β-tr
- Yagci, Bilge Banu,Zorlu, Yunus,Türkmen, Yunus Emre
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p. 13118 - 13128
(2021/09/18)
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- Discovery and development of novel pyrimidine and pyrazolo/thieno-fused pyrimidine derivatives as potent and orally active inducible nitric oxide synthase dimerization inhibitor with efficacy for arthritis
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In order to discover and develop drug-like anti-inflammatory agents against arthritis, based on “Hit” we found earlier and to overcome drawbacks of toxicity, twelve series of total 89 novel pyrimidine, pyrazolo[4,3-d]pyrimidine and thieno[3,2-d]pyrimidine derivatives were designed, synthesized and screened for their anti-inflammatory activity against NO and toxicity for normal liver cells (LO2). Relationships of balance toxicity and activity have been summarized through multi-steps, and title compounds 22o, 22l were found to show lower toxicity (against LO2: IC50 = 2934, 2301 μM, respectively) and potent effect against NO release (IR = 98.3, 97.67%, at 10 μM, respectively). Furthermore, compound 22o showed potent iNOS inhibitory activity with value of IC50 is 0.96 μM and could interfere stability and formation of the active dimeric iNOS. It's anti-inflammatory activity in vivo was assessed by AIA rat model. Furthermore, the results of metabolic stability, CYP, PK study in vivo, acute toxicity study and subacute toxicity assessment indicated this compound had good drug-like properties for treatment.
- Chen, Liu Zeng,Shu, Hai Yang,Wu, Jing,Yu, Yun Long,Ma, Duo,Huang, Xin,Liu, Ming Ming,Liu, Xin Hua,Shi, Jing Bo
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- Multicomponent Enantioselective Synthesis of Tetrahydropyridazinones Employing Chiral α,β-Unsaturated Acylammonium Salts
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An enantioselective three-component reaction was developed for the synthesis of tetrahydropyridazinones employing chiral α,β-unsaturated acylammonium salts, malonates, and azodicarboxylates. An initial α-amination of a malonate with an azodicarboxylate an
- Kiledal, Sigrid A.,Jourdain, Roxane,Vellalath, Sreekumar,Romo, Daniel
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supporting information
p. 6622 - 6627
(2021/09/13)
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- Practical access to fluorescent 2,3-naphthalimide derivatives: Via didehydro-Diels-Alder reaction
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A practical and efficient approach for the synthesis of fluorescent 2,3-naphthalimide derivatives has been developed from readily available starting materials via an intramolecular didehydro-Diels-Alder reaction, which proceeded well under room temperature, exhibiting a wide substrate scope and good functional group tolerance. The practicability of this methodology has been verified by one-step synthesis of the environmentally sensitive fluorophore 6-DMN on a gram scale with a shorter time, fewer steps and less waste disposal, and without the utilization of toxic transition metals. The present experimental and computational studies support the crucial role of the propiolimide moiety in the transformation.
- Chen, Xia,Zhong, Cheng,Lu, Yuling,Yao, Meng,Guan, Zhenhua,Chen, Chunmei,Zhu, Hucheng,Luo, Zengwei,Zhang, Yonghui
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supporting information
p. 5155 - 5158
(2021/05/31)
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- Modular Cyclopentenone Synthesis through the Catalytic Molecular Shuffling of Unsaturated Acid Chlorides and Alkynes
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We describe a general strategy for the intermolecular synthesis of polysubstituted cyclopentenones using palladium catalysis. Overall, this reaction is achieved via a molecular shuffling process involving an alkyne, an α,β-unsaturated acid chloride, which serves as both the alkene and carbon monoxide source, and a hydrosilane to create three new C-C bonds. This new carbon monoxide-free pathway delivers the products with excellent yields. Furthermore, the regioselectivity is complementary to conventional methods for cyclopentenone synthesis. In addition, a set of regio- and chemodivergent reactions are presented to emphasize the synthetic potential of this novel strategy.
- Lee, Yong Ho,Denton, Elliott H.,Morandi, Bill
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supporting information
p. 20948 - 20955
(2020/12/21)
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- Enantioselective Synthesis of 3,4-Dihydropyran-2-ones via Phase-Transfer-Catalyzed Addition-Cyclization of Acetylacetone to Cinnamic Thioesters
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Herein, we present the first example of synthesis of 3,4-dihydropyran-2-ones from cinnamic thioesters via a stereoselective phase-transfer-catalyzed domino Michael-cyclization reaction with acetylacetone. The reaction proceeded under the catalysis of Cinchona-derived quaternary ammonium phenoxide that, in combination with inorganic bases, provided 3,4-dihydropyran-2-ones in yields of up to 93% and enantioselectivities of up to 88% enantiomeric excess.
- Destro, Dario,Bottinelli, Carlo,Ferrari, Ludovica,Albanese, Domenico C. M.,Bencivenni, Grazia,Gillick-Healy, Malachi W.,Kelly, Brian G.,Adamo, Mauro F. A.
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supporting information
p. 5183 - 5192
(2020/04/10)
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- Novel paeonol derivatives: Design, synthesis and anti-inflammatory activity in vitro and in vivo
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Paeonol has been proved to have potential anti-inflammatory activity, but its clinical application is not extensive due to the poor anti-inflammatory activity (14.74% inhibitory activity at 20 μM). In order to discover novel lead compound with high anti-inflammatory activity, series of paeonol derivatives were designed and synthesized, their anti-inflammatory activities were screened in vitro and in vivo. Structure-activity relationships (SARs) have been fully concluded, and finally (E)-N-(4-(2-acetyl-5-methoxyphenoxy)phenyl)-3-(3,4,5-trimet-hoxyphenyl)acrylamide (compound 11a) was found to be the best active compound with low toxicity, which showed 96.32% inhibitory activity at 20 μM and IC50 value of 6.96 μM against LPS-induced over expression of nitric oxide (NO) in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4, resulting in inhibiting of NF-κB and MAPK pathways. Further studies have shown that compound 11a has obvious therapeutic effect against the adjuvant-induced rat arthritis model.
- Hu, Yang Sheng,Han, Xu,Yu, Pei Jing,Jiao, Ming Ming,Liu, Xin Hua,Shi, Jing Bo
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- Visible Light-Mediated Synthesis of Enantiopure γ-Cyclobutane Amino and 3-(Aminomethyl)-5-phenylpentanoic Acids
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A visible light-mediated [2+2] photocycloaddition of amide-linked dienes using [Ir(dtb-bpy)(dF(CF3)ppy)2]PF6 as triplet sensitizer was applied to generate a variety of N-tert-butyl, N-benzyl- and N-tert-butoxycarbonyl-protected 3-azabicyclo[3.2.0]heptan-2-ones in good yields and with good diastereoselectivity. Density functional theory calculations shed light on the conformational prerequisites for the [2+2] photocycloaddition. The bicyclic key structures could be readily transformed into γ-cyclobutane amino acids. For the obtained racemic 3-phenyl-2-aminocyclobutane-1-carboxylic acid the resolution with chiral oxazolidin-2-one is demonstrated to allow access to both enantiomers. Alternatively, a chiral auxiliary approach led as well to the enantiomerically pure target compound. Finally, the synthesis of either enantiomer of 3-(aminomethyl)-5-phenylpentanoic acid, the racemate being described as an anticonvulsant, is described.
- Kerres, Sabine,Plut, Eva,Malcherek, Simon,Rehbein, Julia,Reiser, Oliver
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supporting information
(2019/02/07)
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- Visible Light-Mediated Synthesis of Enantiopure g-Cyclobutane Amino and 3-(Aminomethyl)-5-phenylpentanoic Acids
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A visible light-mediated [2+2] photocycloaddition of amide-linked dienes using [Ir(dtb-bpy)(dF(CF3)ppy)2]PF6 as triplet sensitizer was applied to generate a variety of N-tert-butyl, N-benzyl- and N-tert-butoxycarbonyl-protected 3-aza-bicyclo[3.2.0]heptan-2-ones in good yields and with good diastereoselectivity. Density functional theory calculations shed light on the conformational prerequisites for the [2+2] photocycloaddition. The bicyclic key structures could be readily transformed into g-cyclobutane amino acids. For the obtained racemic 3-phenyl-2-aminocyclobu-tane-1-carboxylic acid the resolution with chiral oxazolidin-2-one is demonstrated to allow access to both enantiomers. Alternatively, a chiral auxiliary approach led as well to the enantiomerically pure target compound. Finally, the synthesis of either enantiomer of 3-(aminomethyl)-5-phenylpentanoic acid, the racemate being described as an anticonvulsant is described.
- Kerres, Sabine,Plut, Eva,Malcherek, Simon,Rehbein, Julia,Reiser, Oliver
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supporting information
p. 1400 - 1407
(2019/10/28)
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- Novel Pyrazolo[4,3- d]pyrimidine as Potent and Orally Active Inducible Nitric Oxide Synthase (iNOS) Dimerization Inhibitor with Efficacy in Rheumatoid Arthritis Mouse Model
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In order to discover novel anti-inflammatory agents for treatment of arthritis and based on preliminary structure-activity relationships, four series (A-D) of total 90 new pyrazolo[4,3-d]pyrimidine compounds were designed and synthesized. All the compounds have been tested for their anti-inflammatory activities by inhibiting of LPS-induced NO production. A clear structure-activity relationship has been concluded step by step, and finally 3,4,5-trimethoxystyryl-1H-pyrazolo[4,3-d]pyrimidine was found to be the most active scaffold. Among them, compound D27 was discovered as the most potent anti-inflammatory agent (IC50 = 3.17 μM) with low toxicity and strong inhibitory of NO release (IR = 90.4% at 10 μM). This compound also showed potent inhibition of iNOS with IC50 value of 1.12 μM. Preliminary mechanism studies indicated that it could interfere with the stability and formation of active dimeric iNOS. The anti-inflammatory effect of this compound was determined by adjuvant-induced arthritis in rat model. We believe these findings would further support the study of rational design of more efficient iNOS inhibitors in the future.
- Shi, Jing Bo,Chen, Liu Zeng,Wang, Bao Shi,Huang, Xin,Jiao, Ming Ming,Liu, Ming Ming,Tang, Wen Jian,Liu, Xin Hua
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p. 4013 - 4031
(2019/04/25)
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- Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors
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A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.
- Gao, Cheng-Zhi,Dong, Wei,Cui, Zhi-Wen,Yuan, Qiong,Hu, Xia-Min,Wu, Qing-Ming,Han, Xianlin,Xu, Yao,Min, Zhen-Li
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p. 150 - 162
(2018/11/30)
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- Pyridazinone derivative, and preparation method and medical application thereof
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The invention provides a pyridazinone derivative, and a preparation method and a medical application thereof. O-formylbenzoic acid used as a raw material reacts with dimethyl phosphite to obtain dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate, the dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate reacts with 3-cyano-4-fluorobenzaldehyde in the presence of triethylamine to prepare (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile, and the (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile is reduced by hydrazine hydrate to prepare 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid; and benzaldehyde or substituted aromatic formaldehyde or furfural used as a raw material and malonic acid undergo a Knoevenagel reaction to obtain cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid, the cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid and 1-tert-butoxycarbonylpiperazine undergo an amidation reaction, a tert-butoxycarbonyl group is removed from the obtained amidation product in the presence of trifluoroacetic acid, and the obtained product and the 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid undergo the amidation reaction to obtain a series of (E)-4-{3-[4-[(3-substituted aryl)acryloyl]piperazin-1-carbonyl]-4-fluorobenzyl}-2H-pyridazin-1-one derivatives. Results of preliminary pharmacological activity screening show that the compound represented by a general formula shown in the present invention has a certain in-vitro PARP-1 inhibition ability and a certain in-vitro tumor cell proliferation resisting activity. The structural general formula of compound is shown in the description; and in the general formula, Ar is selected from two formulas also shown in the description, and R1, R2, R3, R3, R4 and R5 can be the hydrogen atom, the fluorine atom, the chlorine atom, the bromine atom, a methyl group, a methoxy group, a tetrafluoromethyl group and a nitro group.
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- Novel inhibitors of Staphylococcus aureus RnpA that synergize with mupirocin
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We recently discovered RnpA as a promising new drug discovery target for methicillin-resistant S. aureus (MRSA). RnpA is an essential protein that is thought to perform two required cellular processes. As part of the RNA degrasome Rnpa mediates RNA degradation. In combination with rnpB it forms RNase P haloenzymes which are required for tRNA maturation. A high throughput screen identified RNPA2000 as an inhibitor of both RnpA-associated activities that displayed antibacterial activity against clinically relevant strains of S. aureus, including MRSA. Structure-activity studies aimed at improving potency and replacing the potentially metabotoxic furan moiety led to the identification of a number of more potent analogs. Many of these new analogs possessed overt cellular toxicity that precluded their use as antibiotics but two derivatives, including compound 5o, displayed an impressive synergy with mupirocin, an antibiotic used for decolonizing MSRA whose effectiveness has recently been jeopardized by bacterial resistance. Based on our results, compounds like 5o may ultimately find use in resensitizing mupirocin-resistant bacteria to mupirocin.
- Lounsbury, Nicole,Eidem, Tess,Colquhoun, Jennifer,Mateo, George,Abou-Gharbia, Magid,Dunman, Paul M.,Childers, Wayne E.
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supporting information
p. 1127 - 1131
(2018/02/21)
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- Asymmetric synthesis of Rauhut-Currier-type esters via Mukaiyama-Michael reaction to acylphosphonates under bifunctional catalysis
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A highly enantioselective organocatalytic Mukaiyama-Michael reaction of silyloxy dienes and α,β-unsaturated acyl phosphonates under bifunctional organocatalysis is presented. The new reactivity triggered by the catalyst conducted to Rauhut-Currier type es
- Laina-Martín, Víctor,Del Río-Rodríguez, Roberto,Díaz-Tendero, Sergio,Fernández-Salas, Jose A.,Alemán, José
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supporting information
p. 13941 - 13944
(2019/01/03)
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- Novel non-trimethoxylphenyl piperlongumine derivatives selectively kill cancer cells
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Piperlongumine (PL) is a natural alkaloid with broad biological activities. Twelve analogues have been designed and synthesized with non-substituted benzyl rings or heterocycles in this work. Most of the compounds showed better anticancer activities than the parent PL without apparent toxicity in normal cells. Elevation of cellular ROS levels was one of the main anticancer mechanisms of these compounds. Cell apoptosis and cell cycle arrest for the best compound ZM90 were evaluated and similar mechanism of action with PL was demonstrated. The SAR was also characterized, providing worthy directions for further optimization of PL compounds.
- Zhang, Youjun,Ma, Hao,Wu, Yuelin,Wu, Zhongli,Yao, Zhengguang,Zhang, Wannian,Zhuang, Chunlin,Miao, Zhenyuan
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supporting information
p. 2308 - 2312
(2017/05/10)
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- All trans 1-(3-arylacryloyl)-3,5-bis (pyridin-4-ylmethylene)piperidin-4-ones as curcumin-inspired antineoplastics
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A series of eleven N-acryloyl/N-cinnamoyl 3,5-bis(pyridin-4-yl)methylene-4-piperidones were synthesized as curcumin-based candidate antineoplastic agents. The cytostatic potency of these compounds was evaluated against three representative cell lines and all compounds were found to exhibit significant anti-cancer cell activity in vitro. QSAR studies using several physicochemical parameters and 50% inhibitory concentration (IC50) values resulted in certain important correlations which will aid design of more potent analogs. Representative test compounds were investigated in the NCI 60-cell line panel where they were found to display a profound cytotoxicity. These compounds were also potent anti-oxidants and inhibitors of human topoisomerase II±. Representative compounds were well-tolerated by human fibroblasts and by mice during the survival/toxicity studies.
- Paul, Nawal K.,Jha, Mamta,Bhullar, Khushwant S.,Rupasinghe, H.P. Vasantha,Balzarini, Jan,Jha, Amitabh
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p. 461 - 470
(2015/03/05)
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- Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives: Synthesis and anticancer activity
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A series of novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives were designed and synthesized. All compounds have been screened for their antiproliferative activity against MGC-803, SGC-7901 and Bcap-37 cell lines in vitro. The results revealed that compounds 8a, 8c and 8e exhibited strong inhibitory activity against MGC-803 cell line. The flow cytometric analysis result showed that compound 8e could inhibit MGC-803 proliferation. Some title compounds were tested against telomerase, and compound 8e showed the most potent inhibitory activity with IC50 value at 1.02 ± 0.08 μM. The docking simulation of compound 8e was performed to get the probable binding model, among them, LYS 189, LYS 372, LYS 249 and ASP 254 may be the key residues for the telomerase activity.
- Shi, Jing Bo,Tang, Wen Jian,Qi, Xing Bao,Li, Rong,Liu, Xin Hua
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p. 889 - 896
(2015/06/02)
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- Synthesis and antibacterial activity of 4'3-O-(trans-β-arylacrylamido)carbamoyl azithromycin analogs
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Novel 4'3-O-(trans-β-arylacrylamido)carbamoyl azithromycin analogs were designed, synthesized and evaluated for their antibacterial activity against nine significant pathogens using broth microdilution method. A majority of these derivatives maintained the activity of azithromycin against susceptible Streptococcus pyogenes and all the compounds demonstrated remarkably improved activity compared with the references against all the three phenotypes of resistant Streptococcus pneumoniae. In particular, compound 24 exhibited the most potent activity against susceptible Staphylococcus aureus (MIC = 0.5 μg/mL), S. pneumoniae (MIC = 0.06 μg/mL) and S. pyogenes (MIC = 0.25 μg/mL). The most active compound 7 (MIC = 0.015 μg/mL) against resistant S. pneumoniae expressing the mefA gene, exhibited 512 and 256-fold more potent activity than erythromycin and azithromycin, respectively. Compounds 28 (MIC = 0.5 μg/mL), 29 (MIC = 0.25 μg/mL) and 30 (MIC = 0.5 μg/mL) demonstrated potent activity against resistant S. pneumoniae expressing the ermB gene, which were 256, 512 and 256-fold better than the references, respectively.
- Yan, Mi,Ma, Xiaodong,Dong, Ruiqian,Li, Xin,Zhao, Can,Guo, Zhenzhen,Shen, Yan,Liu, Fang,Ma, Ruixin,Ma, Shutao
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p. 506 - 515
(2015/10/06)
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- βUnsaturated acyl cyanides as new bis-electrophiles for enantioselective organocatalyzed formal [3+3]spiroannulation
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α,β-Unsaturated acyl cyanides are key bis-electrophile substrates for successful domino enantioselective organocatalyzed Michael-intramolecular acylation domino sequences. This new reactivity has been applied to the synthesis of enantioenriched azaspiro[4
- Goudedranche, Sebastien,Bugaut, Xavier,Constantieux, Thierry,Bonne, Damien,Rodriguez, Jean
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supporting information
p. 410 - 415
(2014/04/03)
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- All trans 1-(3-arylacryloyl)-3,5-bis (pyridin-4-ylmethylene)piperidin-4-ones as curcumin-inspired antineoplastics
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A series of eleven N-acryloyl/N-cinnamoyl 3,5-bis(pyridin-4-yl)methylene-4-piperidones were synthesized as curcumin-based candidate antineoplastic agents. The cytostatic potency of these compounds was evaluated against three representative cell lines and all compounds were found to exhibit significant anti-cancer cell activity in vitro. QSAR studies using several physicochemical parameters and 50% inhibitory concentration (IC50) values resulted in certain important correlations which will aid design of more potent analogs. Representative test compounds were investigated in the NCI 60-cell line panel where they were found to display a profound cytotoxicity. These compounds were also potent anti-oxidants and inhibitors of human topoisomerase III±. Representative compounds were well-tolerated by human fibroblasts and by mice during the survival/toxicity studies.
- Paul, Nawal K.,Jha, Mamta,Bhullar, Khushwant S.,Rupasinghe, H.P. Vasantha,Balzarini, Jan,Jha, Amitabh
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p. 461 - 470
(2015/01/09)
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- Discovery of a series of novel compounds with moderate anti-avian H5N1 influenza virus activity in chick embryo
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Enlightened by some flavonoid compounds, which had been found as influenza neuraminidase inhibitors, we designed and synthesized a series of novel compounds containing different amino acid fragments. We also reported a simple synthetic route from oseltamivir to prepare its active form which was used as the positive control. The result of enzyme inhibition assay indicated that all the designed compounds displayed weak inhibitory activity against neuraminidase. However, they showed moderate anti-avian H5N1 influenza virus activity in chick embryo. Besides interfering with the function of neuraminidase, these compounds seemed to inhibit the replication of influenza virus by some other mechanism which deserved deep study.
- Xie, Yuanchao,Huang, Bing,Yu, Kexiang,Shi, Fangyuan,Xu, Wenfang
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p. 3485 - 3496
(2013/07/19)
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- Synthesis of some amino acid and peptide conjugates and their evaluation as potential anti-allergic and anti-inflammatory agents
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ANEW series of N-3-(2-furanyl) acryloyl, N-3-(5-methyl)-2-(furanyl)-acryoyl amino acids, peptide and piprazines amids, were structurally designed and synthesized. About 23 compounds (5a-w) were synthesized and their anti-allergic and anti-inflamatory acti
- Shalaby,Abd Al-Salam,Kalmouch,El-Shihaby,Abdullah
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p. 401 - 415
(2015/10/20)
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- The design, synthesis and in vitro immunosuppressive evaluation of novel isobenzofuran derivatives
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The synthesis and biological evaluation of a series of novel isobenzofuran-based compounds are described. The compounds were evaluated for their immunosuppressive effects of T-cell proliferation and IMPDH type II inhibitor activity in vitro, as well as their structure-activity relationships were assessed. Several compounds demonstrated highly efficacious immunosuppressive properties, especially compounds 2d, 2e, 2h and 2j, which were superior to MPA, while compounds 2k, 2m, 2n, 4c and 5d exhibited an equipotent inhibitory activity compared to MPA. Generally, it was obviously demonstrated that α,β-unsaturated amides proved more potent than the diamide and urea series. The present study provides a guide for further research on development of safe and effective immunosuppressive agents.
- Yang, Na,Wang, Qing-He,Wang, Wen-Qian,Wang, Jian,Li, Feng,Tan, Shen-Peng,Cheng, Mao-Sheng
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- Synthesis, characterization, antibacterial and antifungal evaluation of novel monosaccharide esters
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A novel series of 3-(2-furyl)acrylate monosaccharide esters Ia-f and menthyloxycarbonyl monosaccharide esters IIa-f were designed and synthesized. The chemical structures of the target compounds were confirmed by IR, 1H- and 13C-NMR and ESI-MS, and the target compounds were investigated for their in vitro antibacterial and antifungal activities. The antibacterial screening results showed that the 3-(2-furyl)acrylate monosaccharide ester derivatives Ia-f were either inactive or only weakly active against the three Gram-positive bacterial strains tested, whereas the menthyloxycarbonyl monosaccharide ester derivatives IIa-f exhibited higher levels of activity, with compound IIe being especially potent. The results of the antifungal screening revealed that compounds Ib, Ie, IIb and IIc displayed potent in vitro activities, whereas If and IIf showed promising activities against all of the microorganisms tested, with If exhibiting levels of activity deserving of further investigation.
- Shen, Yi,Sun, Yufeng,Sang, Zhipei,Sun, Chengjun,Dai, Ya,Deng, Yong
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experimental part
p. 8661 - 8673
(2012/10/08)
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- Design, synthesis, and insecticidal activity of 1,5-diphenyl-1-pentanone analogues
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Three series of novel 1,5-diphenyl-1-pentanone derivatives were designed and synthesized. Their structures were characterized by IR, 1H NMR techniques, and elemental analysis. The insecticidal activities of the new compounds were preliminarily evaluated. The bioassay results indicated that the compounds X11-X30 displayed better aphicidal activity against Aphis gossypii than compounds X1-X10 and the lead compound (E)-1,5-diphenyl-1-penten-1-one (A). The inhibitory rates of compounds X6 and X29 were 100% against Plutella xylostella (L.) at 600 mg·L-1. Compounds X12, X13, X19, X24, X25, X26 and X27 showed higher insecticidal activity against Tetranychus cinnabarinus (Boisduval) at 600 mg·L-1 than the lead compound (A).
- Yang, Shaoxiang,Kang, Tieniu,Rui, Changhui,Yang, Xinling,Sun, Yufeng,Cui, Zining,Ling, Yun
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experimental part
p. 2394 - 2400
(2012/02/04)
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- Role of terminal heterocyclic ring on mesomorphic properties of homologous series
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Two new homologous series of compounds with a heterocyclic ring having sulfur and oxygen as a hetero atom derived from p-hydroxy acetophenone and alkoxy aniline containing cinnamate-azomethine as central linkages have been synthesized. viz. 4(furalacryloxy) α-methyl benzylidine-4′-alkoxy aniline and 4(thianylacryloxy) α-methyl benzylidine-4′-alkoxy aniline. The compound of both the series have been characterized by elemental analysis, FT-IR, 1H-NMR, and mass spectrometry method. Their liquid crystalline properties have been investigated by optical polarizing microscopy and differential scanning calorimetry (DSC) studies. All the derivatives are mesomorphic in nature showing the nemetic phase. The mesomorphic properties of the present two series are compared with other structurally related series to evaluate the effect of thiophene and furan on mesomorphism. Copyright Taylor & Francis Group, LLC.
- Thaker,Patel,Solanki,Dhimmer,Dave
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experimental part
p. 63 - 80
(2010/09/05)
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- (+)-6-Hydroxy-Morphinan or (+)-6-Amino-Morphinan Derivatives
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The present invention provides (+)-morphinanium compounds comprising substituted 6-hydroxy or 6-amine groups. The invention also provides methods for inhibiting microglial activation by administering the compounds of the invention.
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Page/Page column 5
(2010/09/05)
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- Skeletally diverse small molecules using a build/couple/pair strategy
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Intermolecular couplings of simple building blocks using catalytic, stereoselective cross-Mannich reactions followed by intramolecular functional group-pairing reactions of easily accessed variants of the Mannich products are explored as a route to skelet
- Uchida, Takuya,Rodriquez, Manuela,Schreiber, Stuart L.
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supporting information; experimental part
p. 1559 - 1562
(2009/09/06)
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- Nitrile Ylides: Diastereoselective cycloadditions using chiral oxzolidinones without Lewis acid
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"Chemical Equation Presented" Lewis acid complexation Is generally required for chiral-auxiliary-controlled stereoselectivity, and chiral Lewis acid catalysis Is frequently optimal for Introducing asymmetry. In this work, we show that nitrlle ylide cycloadditions to electron-poor acceptors attached to chiral auxiliaries proceed In high yield and stereoselectivity in the absence of Lewis acids. In contrast, chiral Lewis acids are Inferior In these cycloadditions.
- Mukund P, Sibi,Soeta, Takahlro,Jasperse, Craig P.
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supporting information; experimental part
p. 5366 - 5369
(2010/02/28)
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- Design, synthesis and in vitro antibacterial/antifungal evaluation of novel 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid derivatives
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A series of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid (norfloxacin) derivatives were prepared according to the principle of combinating bioactive substructures and tested for their activities against five plant pathogenic bacteria and three fungi in vitro. The preliminary bioassays indicated that almost all synthesized target compounds retained the antibacterial activities of norfloxacin and had some antifungal activities as carboxylic acid amide compounds. The activities of compounds 1 and 22 against Xanthomonas oryzae were better than norfloxacin and all tested compounds had better antibacterial activities as compared to the agricultural streptomycin sulfate (a commercial bactericide) against X. oryzae, Xanthomonas axonopodis and Erwinia aroideae. Additionally, compounds 2 and 20 displayed good antifungal activities against Rhizoctonia solani and their inhibition of growth reached 83% and 94% respectively at the concentration of 200 mg/L.
- Yu, Zhiyi,Shi, Guanying,Sun, Qiu,Jin, Hong,Teng, Yun,Tao, Ke,Zhou, Guoping,Liu, Wei,Wen, Fang,Hou, Taiping
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experimental part
p. 4726 - 4733
(2010/01/06)
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- 5-Nitrofuranes and 5-nitrothiophenes with anti-trypanosoma cruzi activity and ability to accumulate squalene
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Chagas disease represents a serious public health problem in South America. The first line of treatment is Nifurtimox and Benznidazole which generate toxic effects in treated patients. We have recently shown that a number of 5-nitrofuranes possess activity against Trypanosoma cruzi through oxidative stress and inhibition of parasite ergosterol biosynthesis, specifically at the level of squalene epoxidase. Here, we identify new 5-nitrofuranes and the thia-analogues with excellent effects on the viability of T. cruzi and adequate parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated, during 120 h, with the compounds showed that some of them accumulated squalene suggesting the squalene epoxidase activity inhibition of the parasite. Nifurtimox was able to accumulate squalene only at lower incubation times. Due to this fact some derivatives were also tested as antifungal agents. Quantitative structure-activity relationship studies were also performed showing relevant features for further new derivatives design. Taken together, the results obtained in the present work point to a more general effect of 5-nitrofuranes and 5-nitrothiophenes in trypanosomatids, opening potential therapeutic possibilities of them for these infectious diseases.
- Gerpe, Alejandra,álvarez, Guzmán,Benítez, Diego,Boiani, Lucía,Quiroga, Martín,Hernández, Paola,Sortino, Maximiliano,Zacchino, Susana,González, Mercedes,Cerecetto, Hugo
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experimental part
p. 7500 - 7509
(2011/02/24)
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- Diastereoselective nickel-catalyzed reductive Aldol cyclizations using diethylzinc as the stoichiometric reductant: Scope and mechanistic insight
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In the presence of diethylzinc as a stoichiometric reductant, Ni(acac) 2 functions as an efficient precatalyst for the reductive aldol cyclization of α,β-unsaturated carbonyl compounds tethered to a ketone electrophile through an amide or an ester linkage. The reactions are tolerant of a wide range of substitution at both α,β-unsaturated carbonyl and ketone components and proceed smoothly to furnish β-hydroxylactams and β-hydroxylactones with generally high diastereoselectivities. A series of experiments, including deuterium-labeling studies, was carried out in an attempt to gain some insight into the possible reaction mechanisms that might be operative.
- Joensuu, Pekka M.,Murray, Gordon J.,Fordyce, Euan A. F.,Luebbers, Thomas,Hon, Wai Lam
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p. 7328 - 7338
(2008/12/22)
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- Structure-activity relationship of ortho- and meta-phenol based LFA-1 ICAM inhibitors
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LFA-1 ICAM inhibitors based on ortho- and meta-phenol templates were designed and synthesized by Mitsunobu chemistry. The selection of targets was guided by X-ray co-crystal data, and led to compounds which showed an up to 30-fold increase in potency over reference compound 1 in the LFA-1/ICAM1-Ig assay. The most active compound exploited a new hydrogen bond to the I-domain and exhibited subnanomolar potency.
- Lin, Edward Yin-Shiang,Guckian, Kevin M.,Silvian, Laura,Chin, Donovan,Ann Boriack-Sjodin,van Vlijmen, Herman,Friedman, Jessica E.,Scott, Daniel M.
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scheme or table
p. 5245 - 5248
(2009/05/08)
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- Diastereoselective cobalt-catalyzed reductive aldol cyclizations using diethylzinc as the stoichiometric reductant
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Cobalt catalysis enables a new method for the generation of zinc enolates using diethylzinc to reduce α,β-unsaturated amides. This method has been applied to a high-yielding diastereoselective reductive aldol cyclization.
- Lam, Hon Wai,Joensuu, Pekka M.,Murray, Gordon J.,Fordyce, Euan A. F.,Prieto, Oscar,Luebbers, Thomas
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p. 3729 - 3732
(2007/10/03)
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- Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues
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Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3- methylthiomorpholine-1,1-dioxide, containing alfa-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four der
- Pozas, Rocio,Carballo, Javier,Castro, Clementina,Rubio, Julieta
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p. 1417 - 1421
(2007/10/03)
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- Cu(I)-catalyzed reductive aldol cyclizations: Diastereo- and enantioselective synthesis of β-hydroxylactones
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(Chemical Equation Presented) Copper bisphosphine complexes catalyze the intramolecular reductive aldol reaction of α,β-unsaturated esters with ketones, affording five-and six-membered β-hydroxylactones in high stereoselectivities. Utilization of chiral nonracemic bisphosphines render the cyclizations enantioselective.
- Lam, Hon Wai,Joensuu, Pekka M.
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p. 4225 - 4228
(2007/10/03)
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- An entry to a chiral dihydropyrazole scaffold: Enantioselective [3 + 2] cycloaddition of nitrile imines
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We have developed a versatile strategy to access dihydropyrazoles in highly enantioenriched form. Dipolar cycloaddition of electron-deficient acceptors and in situ-generated nitrile imines proceeds with high regio- and enantioselectivity using 10 mol % chiral Lewis acid catalyst. A variety of dihydropyrazoles that incorporate functionality for further manipulation have been prepared. Copyright
- Sibi, Mukund P.,Stanley, Levi M.,Jasperse, Craig P.
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p. 8276 - 8277
(2007/10/03)
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- ARYLPHENYLAMINO-AND ARYLPHENYLETHER-SULFIDE DERIVATIVES
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The present invention relates in part to compounds of formulas (I) and (III): and pharmaceutically-acceptable salts and prodrugs thereof. These compounds can be useful for treating diseases such as inflammatory and immune diseases. The present invention also relates to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation or suppressing immune response in a subject.
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Page/Page column 50
(2010/02/14)
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- ARYLPHENYLAMINO-, ARYLPHENYLAMIDE-, AND ARYLPHENYLETHER-SULFIDE DERIVATIVES
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The present invention relates in part to compounds of formulas I and III: and pharmaceutically-acceptable salts and prodrugs thereof. These compounds can be useful for treating diseases such as inflammatory and immune diseases. The present invention also relates to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation or suppressing immune response in a subject.
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Page/Page column 64
(2010/02/14)
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- De novo design and synthesis of HIV-1 integrase inhibitors
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Existing AIDS therapies are out of reach for most HIV-infected people in developing countries and, where available, they are limited by their toxicity and their cost. New anti-HIV agents are needed urgently to combat emerging viral resistance and reduce the side effects associated with currently available drugs. Toward this end, LeapFrog, a de novo drug design program was used to design novel, potent, and selective inhibitors of HIV-1 integrase. The designed compounds were synthesized and tested for in vitro inhibition of HIV-1 integrase. Out of the 25 compounds that were designed, and synthesized, four molecules (compounds 23, 26, 43, and 59) showed moderate to low inhibition of HIV-1 integrase for 3′-processing and 3′- strand transfer activities. Nonetheless, these compounds possess structural features not seen in known HIV-1 integrase inhibitors and thus can serve as excellent leads for further optimization of anti-HIV-1 integrase activity.
- Makhija, Mahindra T.,Kasliwal, Rajesh T.,Kulkarni, Vithal M.,Neamati, Nouri
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p. 2317 - 2333
(2007/10/03)
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- N-phenacylpyridinium bromides as acid corrosion inhibitors
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The inhibiting effect of N-phenacylpyridinium bromides with the amide group in the pyridine ring on corrosion of carbon steel in 3 M sulfuric acid is studied. A relationship between the nature of substituents at the amide group and the corrosion-protectiv
- Yurchenko,Pogrebova,Pilipenko,Shubina
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p. 1117 - 1120
(2007/10/03)
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- Synthesis of naturally occurring acetylenes via an alkylidene carbenoid rearrangement
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Naturally occurring mosquito larvicidal acetylenes 1 and 2, and analogues 3 and 4, each containing either a 1,3-butadiynyl or a 1,3,5-hexatriynyl moiety, are synthesized via a Fritsch - Buttenberg - Wiechell rearrangement. The alkylidene carbenoid interme
- Shi Shun, Annabelle L. K.,Tykwinski, Rik R.
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p. 6810 - 6813
(2007/10/03)
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- N-benzylhydroxylamine addition to β-aryl enoates. Enantioselective synthesis of β-aryl-β-amino acid precursors
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(matrix presented) Chiral Lewis acid catalyzed N-benzylhydroxylamine addition to pyrrolidinone-derived enoates afforded β-aryl-β-amino acid derivatives in high enantiomeric purity with moderate to very good chemical efficiency.
- Sibi, Mukund P.,Liu, Mei
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p. 3393 - 3396
(2007/10/03)
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- Stereoselectivity and Generality of the Palladium-Catalysed Cyclopropanation of α,β-Unsaturated Carboxylic Acids Derivatized with Oppolzer's Sultam
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A series of α,β-unsaturated carboxylic acids derivatized with camphorsultam 1 a s a chiral auxiliary has been stereoselectively cyclopropanated. the selectivity of the reaction produces cyclopropanated products with the 1R,2R absolute configuration as indicated by the optical rotations as well as by an X-ray structure determineation.The temperature dependence of the reaction was studied with three substrates. the highest stereoselectivity was obtained at temperatures above 25 deg C.Branching at the α- or β-carbons disfavours complete conversion, and electron-withdrawing substituents at these positions seem to prevent the reaction.The auxiliary was removed by using titanium(IV) isopropoxide in benzyl alcohol followed by alkaline hydrolysis of the intermediate ester. the potent 5-HT1A receptor agonist (1R,2S)-2-(2-hydroxyphenyl)-N,N-dipropylcyclopropylamine 13 was synthesized by this method
- Vallaerda, Jerk,Appelberg, Ulf,Csoeregh, Ingeborg,Hacksell, Uli
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p. 461 - 470
(2007/10/02)
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- Flash Vacuum Pyrolysis of Stabilised Phosphorous Ylides. Part 6. Pyrolysis of Substituted Cinnamoyl Ylides as a Route to Conjugated Enynes
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The substituted cinnamoyl ylides 6 and 7, readily prepared in one step from the quaternary phosphonium salts 8 and cinnamoyl chlorides 9, undergo extrusion of Ph3PO upon FVP to give the 1,3-enynes 12 and 13 in moderate yield.At 500 deg C there is little double bond isomerisation, but at 700 deg C this does occur to give almost 1:1 mixtures of E and Z isomers.In a few cases, including those with a nitrophenyl group present, the yields are poor or the reactions fail stabilised ylide was only partly successful since the severe conditions required for loss of the ester group resulted in significant isomerisation to naphthalene.The fully assigned 13C NMR spectra for 20 enynes are reported.One examples of the isomeric β,γ-unsaturated-δ-oxo ylides, 14 has been prepared and is found to undergo loss of Ph3P on FVP at 700 deg C to give indene and benzene in low yield.
- Aitken, R. Alan,Boeters, Christine,Morrison, John J.
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p. 2473 - 2480
(2007/10/02)
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