- Design, synthesis and evaluation of pyrazole derivatives as non-nucleoside hepatitis B virus inhibitors
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In continuation of our efforts toward the discovery of potent non-nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have employed bioisosterism and hybrid pharmacophore-based strategy to explore the chemically diverse space of bioactive compounds. In this article, the original thiazole platform was replaced with pyrazole scaffold to yield the optimal pharmacophore moieties in order to generate novel non-nucleoside HBV inhibitors with desirable potency. Some of the new compounds were able to inhibit HBV activity in the low micromolar range. In particular, compound 6a3 displayed the most potent activity against the secretion of HBsAg and HBeAg with IC50of 24.33?μM and 2.22?μM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was investigated, which may help designing more potent molecules.
- Jia, Haiyong,Bai, Fuxiang,Liu, Na,Liang, Xiaohong,Zhan, Peng,Ma, Chunhong,Jiang, Xuemei,Liu, Xinyong
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Read Online
- Synthetic Scope of Br?nsted Acid-Catalyzed Reactions of Carbonyl Compounds and Ethyl Diazoacetate
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The comprehensive study of the reactions of carbonyl compounds and ethyl diazoacetate in the presence of a Br?nsted acid catalyst is described. In result, a broad range of 3-oxo-esters were synthesized from a variety of ketones and aliphatic aldehydes by 1,2-aryl/alkyl/hydride shift. Aryl-methyl ketones produced only aryl-migrated products, whereas other ketones yielded a mixture of products. For diaryl ketones, the identity of two inseparable migrated products was confirmed by two-dimensional NMR spectroscopy.
- Rahaman, Mizzanoor,Ali, M. Shahnawaz,Jahan, Khorshada,Hinz, Damon,Belayet, Jawad Bin,Majinski, Ryan,Hossain, M. Mahmun
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p. 6138 - 6147
(2021/05/06)
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- Fungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate-Directed Formation of Quinolones versus Quinazolinones
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Previous studies showed that the FeII/α-ketoglutarate dependent dioxygenase AsqJ induces a skeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans, generating a quinolone scaffold from benzo[1,4]diazepine-2,5-dione substrates. We report that AsqJ catalyzes an additional, entirely different reaction, simply by a change in substituent in the benzodiazepinedione substrate. This new mechanism is established by substrate screening, application of functional probes, and computational analysis. AsqJ excises H2CO from the heterocyclic ring structure of suitable benzo[1,4]diazepine-2,5-dione substrates to generate quinazolinones. This novel AsqJ catalysis pathway is governed by a single substituent within the complex substrate. This unique substrate-directed reactivity of AsqJ enables the targeted biocatalytic generation of either quinolones or quinazolinones, two alkaloid frameworks of exceptional biomedical relevance.
- Einsiedler, Manuel,Jamieson, Cooper S.,Maskeri, Mark A.,Houk, Kendall N.,Gulder, Tobias A. M.
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supporting information
p. 8297 - 8302
(2021/03/01)
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- Design, diversity-oriented synthesis and biological evaluation of novel heterocycle derivatives as non-nucleoside HBV capsid protein inhibitors
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The capsid assembly is a significant phase for the hepatitis B virus (HBV) lifespan and is an essential target for anti-HBV drug discovery and development. Herein, we used scaffold hopping, bioisosterism, and pharmacophore hybrid-based strategies to design and synthesize six series of various heterocycle derivatives (pyrazole, thiazole, pyrazine, pyrimidine, and pyridine) and screened for in vitro anti-HBV non-nucleoside activity. Drug candidate NZ-4 and AT-130 were used as lead compounds. Several compounds exhibited prominent anti-HBV activity compared to lead compound NZ-4 and positive drug Lamivudine, especially compound II-8b, showed the most prominent anti-HBV DNA replication activity (IC50 = 2.2 ± 1.1 μM). Also compounds IV-8e and VII-5b showed the best in vitro anti-HBsAg secretion (IC50 = 3.8 ± 0.7 μM, CC50 > 100 μM) and anti-HBeAg secretion (IC50 = 9.7 ± 2.8 μM, CC50 > 100 μM) respectively. Besides, II-8b can interact HBV capsid protein with good affinity constants (KD = 60.0 μM), which is equivalent to lead compound NZ-4 ((KD = 50.6 μM). The preliminary structure-activity relationships (SARs) of the newly synthesized compounds were summarized, which may help researchers to discover more potent anti-HBV agents.
- Jia, Haiyong,Yu, Ji,Du, Xianhong,Cherukupalli, Srinivasulu,Zhan, Peng,Liu, Xinyong
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- Five Roads That Converge at the Cyclic Peroxy-Criegee Intermediates: BF3-Catalyzed Synthesis of β-Hydroperoxy-β-peroxylactones
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We have discovered synthetic access to β-hydroperoxy-β-peroxylactones via BF3-catalyzed cyclizations of a variety of acyclic precursors, β-ketoesters and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals, with H2O2. Strikingly, independent of the choice of starting material, these reactions converge at the same β-hydroperoxy-β-peroxylactone products, i.e., the peroxy analogues of the previously elusive cyclic Criegee intermediate of the Baeyer-Villiger reaction. Computed thermodynamic parameters for the formation of the β-hydroperoxy-β-peroxylactones from silyl enol ethers, enol acetates, and cyclic acetals confirm that the β-peroxylactones indeed correspond to a deep energy minimum that connects a variety of the interconverting oxygen-rich species at this combined potential energy surface. The target β-hydroperoxy-β-peroxylactones were synthesized from β-ketoesters, and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals were obtained in 30-96% yields. These reactions proceed under mild conditions and open synthetic access to a broad selection of β-hydroperoxy-β-peroxylactones that are formed selectively even in those cases when alternative oxidation pathways can be expected. These β-peroxylactones are stable and can be useful for further synthetic transformations.
- Vil, Vera A.,Gomes, Gabriel Dos Passos,Ekimova, Maria V.,Lyssenko, Konstantin A.,Syroeshkin, Mikhail A.,Nikishin, Gennady I.,Alabugin, Igor V.,Terent'Ev, Alexander O.
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p. 13427 - 13445
(2018/11/02)
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- GPR40 AGONISTS FOR THE TREATMENT OF TYPE II DIABETES
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Disclosed are compounds, compositions and methods for treating of disorders that are affected by the modulation of the GPR40 receptor. Such compounds are represented by Formula II.
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Page/Page column 87
(2017/03/17)
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- GPR40 AGONISTS FOR THE TREATMENT OF TYPE II DIABETES
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Disclosed are compounds, compositions and methods for treating of disorders that are affected by the modulation of the GPR40 receptor. Such compounds are represented by Formula (I), as follows: wherein R1, R2, R4, W, X, Y, and G, are defined herein.
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Page/Page column 102
(2017/03/08)
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- GPR40 AGONISTS FOR THE TREATMENT OF TYPE II DIABETES
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Disclosed are compounds, compositions and methods for treating of disorders that are affected by the modulation of the GPR40 receptor. Such compounds are represented by Formula (III); wherein R1c, R2C, R4C, Wc, Yc, Zc and Gc, are defined herein.
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Page/Page column 98
(2017/03/08)
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- Total synthesis and biological evaluation of the antibiotic lysocin E and its enantiomeric, epimeric, and N-demethylated analogues
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Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solidphase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N-demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action.
- Murai, Motoki,Kaji, Takuya,Kuranaga, Takefumi,Hamamoto, Hiroshi,Sekimizu, Kazuhisa,Inoue, Masayuki
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supporting information
p. 1556 - 1560
(2015/01/30)
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- Evaluation of several routes to advanced pregabalin intermediates: Synthesis and enantioselective enzymatic reduction using ene-reductases
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This publication describes the evaluation of four synthetic routes to the advanced pregabalin (Lyrica) intermediate 7. Asymmetric reduction of (E)-7 with an ene-reductase (OPR1 from Lycopersicon esculentum) gave a saturated cyanoester intermediate 5 with the desired S stereocenter in ≥99% ee. OPR1 also catalyzed the reduction of (Z)-7 to (S)-5, but with lower conversion and selectivity.
- Debarge, Sebastien,McDaid, Paul,O'Neill, Pat,Frahill, James,Wong, John W.,Carr, Donncha,Burrell, Adam,Davies, Simon,Karmilowicz, Mike,Steflik, Jeremy
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p. 109 - 121
(2014/05/20)
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- Chemoenzymatic asymmetric synthesis of pregabalin precursors via asymmetric bioreduction of β-cyanoacrylate esters using ene-reductases
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The asymmetric bioreduction of a library of β-cyanoacrylate esters using ene-reductases was studied with the aim to provide a biocatalytic route to precursors for GABA analogues, such as pregabalin. The stereochemical outcome could be controlled by substrate-engineering through size-variation of the ester moiety and by employing stereochemically pure (E)- or (Z)-isomers, which allowed to access both enantiomers of each product in up to quantitative conversion in enantiomerically pure form. In addition, stereoselectivities and conversions could be improved by mutant variants of OPR1, and the utility of the system was demonstrated by preparative-scale applications.
- Winkler, Christoph K.,Clay, Dorina,Davies, Simon,O'Neill, Pat,McDaid, Paul,Debarge, Sebastien,Steflik, Jeremy,Karmilowicz, Mike,Wong, John W.,Faber, Kurt
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p. 1525 - 1533
(2013/04/10)
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- Synthesis and tautomerism of substituted pyrazolo[4,3-c]pyrazoles
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Fused five-membered nitrogen heterocycles comprise a very important group of compounds frequently utilized in pharmaceutical applications. In this study, we report the first systematic synthesis of substituted pyrazolo[4,3-c]pyrazoles and three regioisomers of their N-methyl derivatives. All compounds were fully characterized by NMR spectroscopy in solution and selected compounds also were studied by X-ray diffraction in the solid state. 1H, 13C, and 15N NMR spectroscopic data for all isomers were interpreted by DFT calculations of nuclear shielding constants and indirect spin-spin coupling constants. The N-methyl isomers were used in the following steps as model compounds to investigate a potential N1-H/N4-H, N2-H/N4-H, and N1-H/N5-H tautomerism of 3,6-substituted pyrazolo[4,3-c]pyrazoles by using low-temperature NMR spectroscopy. All bases were shown to occur predominantly in the N1-H/N4-H tautomeric form and the structure of minor form was governed by the substituents at positions 3 and 6. Stabilities of individual tautomeric forms are calculated by DFT methods and discussed. A relationship between the tautomeric populations and the ratios among N-methyl isomers obtained upon methylation of selected bases in solution are investigated. The stability of various tautomeric forms of substituted pyrazolo[4,3-c]pyrazoles characterized by low-temperature NMR spectroscopy can be qualitatively explained by electronic and steric effects of substituents in positions 3 and 6 in individual tautomers, as revealed by the DFT calculations. Copyright
- Kadam, Shivaji S.,Maier, Lukas,Kostakis, Ioannis,Pouli, Nicole,Tousek, Jaromir,Necas, Marek,Marakos, Panagiotis,Marek, Radek
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supporting information
p. 6811 - 6822
(2013/11/06)
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- PROCESS FOR THE PREPARATION OF ( S ) - 3 - CYANO - 5 - METHYLHEXANOIC ACID DERIVATIVES ADN OF PREGABALIN
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The invention provides a process for the manufacture of a compound of formula (I) using an enzyme catalysed reduction of a compound of formula (lla) or llb). Compounds of formula (I) are useful for preparing pregabalin.
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Page/Page column 15-16
(2012/03/26)
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- CHEMICAL COMPOUNDS
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The invention is directed to to substituted indazole derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R1 - R6 and X are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of disorders characterized by constitutively activated ACG kinases such as cancer and more specifically leukemia and cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 134
(2010/11/04)
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- PROCESS TO PREGABALIN
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The present invention relates to a novel method for the preparation of racemic pregabalin (1) or a single enantiomer thereof, (S)-(+)-3-(aminomethyl)-5-methyl-hexanoic acid (2).
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Page/Page column 11
(2010/12/31)
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- PROCESSES TO PREGABALIN
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The present invention relates to a novel method for the preparation of racemic pregabalin (1) or a single enantiomer thereof, (S)-(+)-3-(aminomethyl)-5-methyl-hexanoic acid (2).
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Page/Page column 23
(2009/07/25)
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- PENEM PRODRUG
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The invention relates to prodrugs of sulopenem of formula (I): wherein R1 is —(C2-C8)alkyl, or a solvate or hydrate thereof. The invention also relates to the preparation, formulation, and use of the prodrugs of sulopenem to treat a disorder such as an infection in a patient in need thereof.
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Page/Page column 8; 9
(2008/12/05)
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- Modulators of calcitonin and amylin receptor activity
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In various aspects, the present invention relates to non-peptidic compounds, which modulate calcitonin and amylin receptor activity; to processes for the preparation of some such compounds; and to pharmaceutical compositions including such compounds. Compounds of the invention are useful as calcitonin and/or amylin agonists and in the treatment of bone diseases and metabolic diseases.
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Page/Page column 25
(2008/12/06)
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- A novel synthetic method for β-keto esters
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A novel synthetic method for the preparation of β-keto esters has been developed. α-Phenylseleno acetate was treated with LDA to produce a selenium-stabilised carbanion, which reacted with aldehydes, followed by selenoxide syn-elimination, to give β-keto esters.
- Qian, Hao,Ge, Chunrong,Huang, Xian
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p. 160 - 161
(2008/02/03)
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- CuSO4-catalyzed diazo decomposition in water: a practical synthesis of β-keto esters
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CuSO4 was found to be an efficient catalyst for the diazo decomposition of β-hydroxy α-diazoesters in water. 1,2-H shift occurred efficiently to give β-keto esters in high yields. No O-H bond insertion products were identified.
- Liao, Mingyi,Wang, Jianbo
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p. 8859 - 8861
(2007/10/03)
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- Preparation of polystyrene-supported α-seleno acetate and application to solid-phase synthesis of β-keto esters
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A novel polystyrene-supported α-seleno acetate has been developed. This novel resin was treated with LDA to produce a selenium-stabilized carbanion, which reacted with aldehydes, followed by selenoxide syn-elimination to give β-keto esters. Georg Thieme Verlag Stuttgart.
- Qian, Hao,Huang, Xian
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p. 1547 - 1548
(2007/10/03)
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- Synthesis of a 2,3′;6′,3″-terpyridine scaffold as an α-helix mimetic
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(Chemical Equation Presented) A terpyridine scaffold has been designed as an α-helix mimetic. A facile synthesis of the ortho-functionalized 2,3′-oligopyridine has been accomplished using sequential Bohlmann-Rahtz heteroannulation reactions.
- Davis, Jessica M.,Truong, Anh,Hamilton, Andrew D.
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p. 5405 - 5408
(2007/10/03)
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- Expeditious solid-phase synthesis of pyrazoledicarboxylic acid derivatives by functionalization of resin-bound cyanoformate
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Esterification of the Wang resin 5 with the monoamide of oxalic acid (oxamic acid, 7) followed by dehydration of the amide function furnishes the resin-bound cyanoformate 9, which can be elaborated by zinc-catalyzed reaction with β-keto esters. The obtained enamino keto diesters 10a-d react with hydrazines affording, after removal from the solid support, fully substituted pyrazoledicarboxylic acids 12a-n. Optimization of the above sequence and the solid-phase synthesis of a small test-library of 1,5-disubstituted pyrazole-3,4-dicarboxylic acid derivatives are described. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.
- Morelli, Carlo F.,Saladino, Alberto,Speranza, Giovanna,Manitto, Paolo
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p. 4621 - 4627
(2007/10/03)
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- Microwave-assisted solution-phase synthesis of 1,4,5-trisubstituted pyrazoles
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A small parallel library of 1,4,5-trisubstituted pyrazoles was prepared in solution using a three-step procedure starting from Meldrum acid. The Meldrum acid was acylated with different acyl chlorides and the products opened with different alcohols and amines to give substituted β-keto esters and β-keto amines. Further reaction with N,N-dimethylformamide dimethylacetal and the final cyclisation were effectively carried out under microwave irradiation. Scavenger resins were employed exclusively in the first step, whereas use of microwaves allowed complete conversion of the starting materials in the other two steps. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Giacomelli, Giampaolo,Porcheddu, Andrea,Salaris, Margherita,Taddei, Maurizio
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p. 537 - 541
(2007/10/03)
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- Enantioselective synthesis of (R)- and (S)-2-methyl-4-octanol, the male-produced aggregation pheromone of Curculionidae species
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This work describes an enantioselective synthesis of (R)- and (S)-2-methyl-4-octanol, a compound that has been identified as the aggregation pheromone of some sugarcane weevils. (S)-2-Methyl-4-octanol was efficiently prepared in five steps and 20% overall yield, and its (R)-enantiomer, in six steps and 14% overall yield, both from commercial isovaleryl chloride. The key step of our synthetic route is the asymmetric reduction of ethyl 5-methyl-3-oxohexanoate with Saccharomyces cerevisiae to its corresponding (S)-alcohol in good yield and high enantiomeric excess.
- Baraldi, Patricia T.,Zarbin, Paulo H.G.,Vieira, Paulo C.,Correa, Arlene G.
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p. 621 - 624
(2007/10/03)
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- Structure-Activity Relations. Part 12. Antibacterial Activity of a Series of 2,4-Diamino-6-substituted 5-(4-pyridylmethylamino)pyrimidines and 2,4-Diamino-5-(4-substituted benzylamino)pyrimidines.
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A series of 6-substituted 2,4-diamino-5-(4-pyridylamino)pyrimidines and of 2,4-diamino-5-(4-substituted benzylamino)pyrimidines has been prepared.Their antibacterial activity towards L. casei, S. aureus and E. coli has been investigated.These activities have been successfully correlated by Hansch-type relations.Dependence on both lipophilicity and electronic (polar) factors has been found.The results are related to the structure and interactions with the receptor.
- Bowden, Keith,Bright, Andrew C.
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p. 514 - 539
(2007/10/02)
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- Preparation of γ-Substituted β-Oxoesters with a New Heterocyclic Synthon
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Ethyl 2,5-dihydro-2,3-dimethyl-5-oxoisoxazole-4-carboxylate was alkylated and acylated via its potassium-salt generated by potassium t-butoxide under convenient conditions.Hydrolysis of the enamines obtained by the catalytic hydrogenation of the 3-alkylated/acetylated derivatives affords β-oxo and β,δ-dioxoesters, respectively.Hydrogenolysis of the 3-acyl derivatives allows the regiospecific synthesis of β-enamino-δ-oxoesters.
- Doleschall, Gabor,Seres, Peter,Kovacs, Attila
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p. 324 - 346
(2007/10/02)
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- A NEW ENAMINE-SALT FOR THE SYNTHESIS OF γ-ALKYLATED ETHYL ACETOACETATE DERIVATIVES
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A convenient method for the preparation of γ-alkylated ethyl acetoacetate from alkyl halides via a new isoxazole enamine-salts is reported.
- Doleschall, G.
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p. 6339 - 6340
(2007/10/02)
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- Process for the producton of 4-substituted acetoacetic acid derivatives
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Process for the production of 4-substituted acetoacetic acid derivatives. An acetoacetic acid derivative having the formula: STR1 wherein R is alkoxy having 1 to 6 C atoms, phenoxy, --NR'2, wherein R' is alkyl having 1 to 6 C atoms or aryl, or NR'2, which is azetidine, pyrrolidine or piperidine, is treated with a secondary amine at an elevated temperature and in the presence of an organic solvent. The water formed is separated. The intermediate is converted into the corresponding 3-enamine carboxylic acid derivative. The derivative is converted by treatment with sodium amide in liquid ammonia into the corresponding sodium salt. The sodium salt is converted by treatment with a halogen compound having the formula R1 CH2 X or R1 R2 CHX, wherein R1 and R2 each are alkyl, alkenyl, alkinyl or aryl and X is chlorine, bromine or iodide, into the corresponding 4-substituted enamino derivative. The derivative is hydrolyzed into the 4-substituted acetoacetic acid derivative.
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- Synthesis of dihydrotagetone (2,6-dimethyloct-7-en-4-one)
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The acyclic monoterpene dihydrotagetone (2,6-dimethyloct-7-en-4-one) has been prepared from isobutyl methyl ketone in two stages. The key step involves a simple extension of the Carroll reaction.
- McAndrew,Riezebos
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p. 367 - 369
(2007/10/12)
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