- Lipase mediated enzymatic kinetic resolution of phenylethyl halohydrins acetates: A case of study and rationalization
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Racemic phenylethyl halohydrins acetates containing several groups attached to the aromatic ring were resolved via hydrolysis reaction in the presence of lipase B from Candida antarctica (Novozym 435). In all cases, the kinetic resolution was highly selective (E > 200) leading to the corresponding (S)-β-halohydrin with ee > 99 %. However, the time required for an ideal 50 % conversion ranged from 15 min for 2,4-dichlorophenyl chlorohydrin acetate to 216 h for 2-chlorophenyl bromohydrin acetate. Six chlorohydrins and five bromohydrins were evaluated, the latter being less reactive. For the β-brominated substrates, steric hindrance on the aromatic ring played a crucial role, which was not observed for the β-chlorinated derivatives. To shed light on the different reaction rates, docking studies were carried out with all the substrates using MD simulations. The computational data obtained for the β-brominated substrates, based on the parameters analysed such as NAC (near attack conformation), distance between Ser-O and carbonyl-C and oxyanion site stabilization were in agreement with the experimental results. On the other hand, the data obtained for β-chlorinated substrates suggested that physical aspects such as high hydrophobicity or induced change in the conformation of the enzymatic active site are more relevant aspects when compared to steric hindrance effects.
- Fonseca, Thiago de Sousa,Vega, Kimberly Benedetti,da Silva, Marcos Reinaldo,de Oliveira, Maria da Concei??o Ferreira,de Lemos, Telma Leda Gomes,Contente, Martina Letizia,Molinari, Francesco,Cespugli, Marco,Fortuna, Sara,Gardossi, Lucia,de Mattos, Marcos Carlos
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- Use of miconazole and derivatives thereof as TGR5 agonists (by machine translation)
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The invention belongs to the technical field of medicines, and relates to novel application TGR5 of miconazole and derivatives thereof in treatment, of diseases and conditions of a biological pathologic process involved in treatment, and. The miconazole and the analogues thereof can activate TGR5 active, for use TGR5 in the treatment or prevention of diseases associated with, activity modulation. (by machine translation)
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Paragraph 0031-0034
(2020/05/02)
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- Synthesis of Conformationally Locked and C-Linked Analogues of Imidazole-Based Ketene Dithioacetal Fungicides
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First examples with the unknown tricyclic 4,8 b -dihydro-3 aH -indeno[1,2- d ][1,3]dithiole ring system have been prepared. Also, imidazoles linked in ring position 5 to a ketene dithioacetal and 1,3-dithiane derivatives with an exocyclic cyano- and imidazole-substituted C-C double bond are completely new. All these compounds are either conformationally locked, C-linked or six-ring analogues of the antifungal agent luliconazole. Synthesis and fungicidal activity of these sterol biosynthesis inhibitors are reported.
- Gagnepain, Julien,Jeanmart, Stephane,Bonvalot, Damien,Jacob, Olivier,Lamberth, Clemens
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supporting information
p. 59 - 62
(2019/01/04)
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- Enantioselective Reduction of α,β-Unsaturated Ketones and Aryl Ketones by Perakine Reductase
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This report describes the enantioselective reduction of structurally diverse α,β-unsaturated ketones and aryl ketones by perakine reductase (PR) from Rauvolfia. This enzymatic reduction produces α-chiral allylic and aryl alcohols with excellent enantioselectivity and most of the products in satisfactory yields. Furthermore, the work demonstrates 1 mmol scale reactions for product delivery without any detrimental effect on yield and enantioselectivity. The catalytic mechanism, determined by 3D-structure-based modeling of PR and ligand complexes, is also described.
- Cai, Sheng,Shao, Nana,Chen, Yuanyuan,Li, Anbang,Pan, Jie,Zhu, Huajian,Zou, Hongbin,Zeng, Su,Sun, Lianli,Zhao, Jinhao
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supporting information
p. 4411 - 4414
(2019/05/22)
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- Chemoenzymatic Synthesis of Luliconazole Mediated by Lipases
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A straightforward chemoenzymatic synthesis of luliconazole has been developed. The key step involved the preparation of the enantiomerically pure β-halohydrin (1S)-2-chloro-1-(2,4-dichlorophenyl)-1-ethanol through kinetic resolution of the corresponding racemic acetate. This was achieved by a hydrolytic approach, mediated by the lipase from Thermomyces lanuginosus or Novozym 435. The latter enzyme proved to be a robust biocatalyst for the kinetic resolution, and the (S)-β-halohydrin was obtained with high selectivity (ee > 99 %, E > 200) after just 15 min, at 45 °C. It could be reused five times with maintenance of high values of both conversion and enantioselectivity. Subsequently, the (S)-β-halohydrin was subjected to a mesylation reaction; the mesylated derivative reacted with 1-cyanomethylimidazole in the presence of CS2 to give luliconazole in 43 % yield with >99 % ee.
- Fonseca, Thiago de S.,Lima, Lara D.,de Oliveira, Maria da C. F.,de Lemos, Telma L. G.,Zampieri, Davila,Molinari, Francesco,de Mattos, Marcos C.
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p. 2110 - 2116
(2018/05/31)
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- A cleaning preparation 2,4-di-chloro-α-chloro-methyl-phenyl-methanol method
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The invention discloses a clean preparation method for 2,4-dichloro-alpha-chloromethyl benzyl alcohol and belongs to the field of catalytic synthesis process of 2,4-dichloro-alpha-chloromethyl benzyl alcohol. 2,2',4'-trichloroacetophenone is taken as an initial raw material, aluminium isopropoxide serves as a catalyst, isopropyl alcohol serves as not only a solvent but also a reactant, and reduction reaction, reduced pressure distillation, acidation, water washing and curing are conducted to obtain the 2,4-dichloro-alpha-chloromethyl benzyl alcohol. An isopropyl alcohol and acetone mixed solution obtained through reduced pressure distillation is rectified, 80-84 DEG C fraction is collected for recycling, and the yield is basically kept unchanged. Acidized acid water is neutralized by ammonia water, then filtered to obtain aluminium hydroxide, and finally roasted to acquire aluminium oxide after being dried. The method is mild in reaction conditions, short in reaction time and convenient in after-treatment, and avoids environmental pollution. The conversion rate and the product yield of 2,2',4'-trichloroacetophenone are more than 99%, and the manufacturing cost is low. The method is an efficient and environmental-friendly method for synthesizing 2,4-dichloro-alpha-chloromethyl benzyl alcohol and facilitates large-scale industrial production.
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Paragraph 0022; 0024
(2017/02/09)
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- NOVEL MICROBIOCIDES
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Compounds of formula (I), wherein the other substituents X, Y, Z, A, Q, R1, R2, R3, R4, R6 and R7 are as defined in claim 1, and their use in compositions and methods for the control and/or prevention of microbial infection, particularly fungal infection, in plants and to processes for the preparation of these compounds.
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Page/Page column 41
(2015/02/02)
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- Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents
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Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure-activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg-1) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.
- Hameed P, Shahul,Chinnapattu, Murugan,Shanbag, Gajanan,Manjrekar, Praveena,Koushik, Krishna,Raichurkar, Anandkumar,Patil, Vikas,Jatheendranath, Sandesh,Rudrapatna, Suresh S.,Barde, Shubhada P.,Rautela, Nikhil,Awasthy, Disha,Morayya, Sapna,Narayan, Chandan,Kavanagh, Stefan,Saralaya, Ramanatha,Bharath, Sowmya,Viswanath, Pavithra,Mukherjee, Kakoli,Bandodkar, Balachandra,Srivastava, Abhishek,Panduga, Vijender,Reddy, Jitender,Prabhakar,Sinha, Achyut,Jiménez-Díaz, María Belén,Martínez, María Santos,Angulo-Barturen, I?igo,Ferrer, Santiago,Sanz, Laura María,Gamo, Francisco Javier,Duffy, Sandra,Avery, Vicky M.,Magistrado, Pamela A.,Lukens, Amanda K.,Wirth, Dyann F.,Waterson, David,Balasubramanian,Iyer, Pravin S.,Narayanan, Shridhar,Hosagrahara, Vinayak,Sambandamurthy, Vasan K.,Ramachandran, Sreekanth
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supporting information
p. 5702 - 5713
(2014/08/05)
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- New copper(II) complexes with isoconazole: Synthesis, structures and biological properties
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There is an increasing demand for novel metal-based complexes with biologically relevant molecules in technology and medicine. Three new Cu(II) coordination compounds with antifungal agent isoconazole (L), namely mononuclear complexes [CuCl2(L)2] (1), and [Cu(O2CMe) 2(L)2]·2H2O (2) and coordination polymer [Cu(pht)(L)2]n (3) (where H2pht-o-phthalic acid) were synthesized and characterized by IR spectroscopy, thermogravimetric analysis and X-ray crystallography. X-ray analysis showed that in all complexes, the isoconazole is coordinated to Cu(II) centres by a N atom of the imidazole fragment. In complex 1, the square-planar environment of Cu(II) atoms is completed by two N atoms of isoconazole and two chloride ligands, whereas the Cu(II) atoms are coordinated by two N atoms from two isoconazole ligands and two O atoms from the different carboxylate residues: acetate in 2 and phthalate in 3. The formation of an infinite chain through the bridging phthalate ligand is observed in 3. The biosynthetic ability of micromycetes Aspergillus niger CNMN FD 10 in the presence of the prepared complexes 1-3 as well as the antifungal drug isoconazole were studied. Complexes 2 and 3 accelerate the biosynthesis of enzymes (β-glucosidase, xylanase and endoglucanase) by this fungus. Moreover, a simplified and improved method for the preparation of isoconazole nitrate was developed.
- Dulcevscaia, Galina M.,Kravtsov, Victor Ch.,Macaev, Fliur Z.,Duca, Gheorghe G.,Stingachi, Eugenia P.,Pogrebnoi, Serghei I.,Boldescu, Veaceslav V.,Clapco, Steliana F.,Tiurina, Janeta P.,Deseatnic-Ciloci, Alexandra A.,Lipkowski, Janusz,Liu, Shi-Xia,Decurtins, Silvio,Baca, Svetlana G.
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p. 106 - 114
(2013/06/05)
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- Asymmetric chemoenzymatic synthesis of miconazole and econazole enantiomers. the importance of chirality in their biological evaluation
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A simple and novel chemoenzymatic route has been applied for the first time in the synthesis of miconazole and econazole single enantiomers. Lipases and oxidoreductases have been tested in stereoselective processes; the best results were attained with oxidoreductases for the introduction of chirality in an adequate intermediate. The behaviors of a series of ketones and racemic alcohols in bioreductions and acetylation procedures, respectively, have been investigated; the best results were found with alcohol dehydrogenases A and T, which allowed the production of (R)-2-chloro-1-(2,4-dichlorophenyl)ethanol in enantiopure form under very mild reaction conditions. Final chemical modifications have been performed in order to isolate the target fungicides miconazole and econazole both as racemates and as single enantiomers. Biological evaluation of the racemates and single enantiomers has shown remarkable differences against the growth of several microorganisms; while (R)-miconazole seemed to account for most of the biological activity of racemic miconazole on all the strains tested, both enantiomers of econazole showed considerable biological activities. In this manner, (R)-econazole showed higher values against Candida krusei, while higher values were observed for (S)-econazole against Cryptococcus neoformans, Penicillium chrysogenum, and Aspergillus niger.
- Mangas-Sanchez, Juan,Busto, Eduardo,Gotor-Fernandez, Vicente,Malpartida, Francisco,Gotor, Vicente
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supporting information; experimental part
p. 2115 - 2122
(2011/05/19)
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- Reduction processes biocatalyzed by Vigna unguiculata
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Whole cells from the Brazilian beans feijao de corda (Vigna unguiculata) have been employed as biocatalysts in different bioreduction processes. Good to excellent selectivities can be obtained in the reduction of aromatic and aliphatic ketones, as well as β-ketoesters, depending on the conversions and the chemoselectivity on the substrate structure. This biocatalyst was also able to reduce the nitro moiety of different aromatic nitro compounds, showing as well enoate reductase activity, and chemoselectively catalyzing the double bond reduction of 4-phenyl-3-buten-2-one with moderate conversion.
- Bizerra, Ayla M.C.,Gonzalo, Gonzalo de,Lavandera, Ivan,Gotor-Fernandez, Vicente,de Mattos, Marcos Carlos,de Oliveira, Maria da Conceicao F.,Lemos, Telma L.G.,Gotor, Vicente
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experimental part
p. 566 - 570
(2010/08/06)
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