27656-21-9Relevant academic research and scientific papers
Structural basis for rational design of inhibitors targeting Trypanosoma cruzi Sterol 14α-demethylase: Two regions of the enzyme molecule potentiate its inhibition
Friggeri, Laura,Hargrove, Tatiana Y.,Rachakonda, Girish,Williams, Amanda D.,Wawrzak, Zdzislaw,Di Santo, Roberto,De Vita, Daniela,Waterman, Michael R.,Tortorella, Silvano,Villalta, Fernando,Lepesheva, Galina I.
, p. 6704 - 6717 (2014/09/29)
Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14α-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of β-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50 = 1.2 nM, vs (S)-2/(S)-3, EC50 = 1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs.
Asymmetric chemoenzymatic synthesis of miconazole and econazole enantiomers. the importance of chirality in their biological evaluation
Mangas-Sanchez, Juan,Busto, Eduardo,Gotor-Fernandez, Vicente,Malpartida, Francisco,Gotor, Vicente
, p. 2115 - 2122 (2011/05/19)
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.
Synthesis of dendrimer-type chiral stationary phases based on the selector of (1S,2R)-(+)-2-amino-1,2-diphenylethanol derivate and their enantioseparation evaluation by HPLC
He, Bao-Jiang,Yin, Chuan-Qi,Li, Shi-Rong,Bai, Zheng-Wu
experimental part, p. 69 - 76 (2010/09/09)
In our recent work, a series of dendritic chiral stationary phases (CSPs) were synthesized, in which the chiral selector was L-2-(p-toluenesulfonamido)-3- phenylpropionyl chloride (selector I), and the CSP derived from three-generation dendrimer showed the best separation ability. To further investigate the influence of the structures of dendrimer and chiral selector on enantioseparation ability, in this work, another series CSPs (CSPs 1-4) were prepared by immobilizing (1S,2R)-1,2-diphenyl-2-(3-phenylureido)ethyl 4-isocyanatophenylcarbamate (selector II) on one- to four-generation dendrimers that were prepared in previous work. CSPs 1 and 4 demonstrated the equivalent enantioseparation ability. CSPs 2 and 3 showed the best and poorest enantioseparation ability respectively. Basically, these two series of CSPs exhibited the equivalent enantioseparation ability although the chiral selectors were different. Considering the enantioseparation ability of the CSP derived from aminated silica gel and selector II is much better than that of the one derived from aminated silica gel and selector I, it is believed that the dendrimer conformation essentially impacts enantioseparation.
Asymmetric synthesis and stereochemical structure-activity relationship of (R)- and (S)-8-[1-(2,4-dichlorophenyl)-2-imidazol-1-yl-ethoxy] octanoic acid heptyl ester, a potent inhibitor of allene oxide synthase
Oh, Keimei,Shimura, Yoichiro,Ishikawa, Kyoko,Ito, Yudai,Asami, Tadao,Murofushi, Noboru,Yoshizawa, Yuko
, p. 1090 - 1095 (2008/09/19)
The preparation of both enantiomers of 8-[1-(2,4-dichlorophenyl)-2-imidazol-1-yl-ethoxy] octanoic acid heptyl ester (JM-8686), a potent inhibitor of allene oxide synthase, has been achieved using 2,4-dichlorophenacyl bromide as a starting material. The key step was the asymmetric reduction of 1-(2,4-dichlorophenyl)-2-imidazol-1-yl-ethanone with chiral BINAL-H. The products were purified by chiral high-performance liquid chromatography (HPLC) to afford pure (R)-JM-8686 and (S)-JM-8686. The inhibitory activities and binding affinities of these enantiomers toward allene oxide synthase were determined. We found that the inhibition potency of (R)-JM-8686 is approximately 200 times greater than that of (S)-JM-8686, with IC50 values of approximately 5 ± 0.2 nM and 950 ± 18 nM, respectively. The dissociation constants of (R)-JM-8686 and (S)-JM-8686 with respect to the recombinant allene oxide synthase were approximately 1.4 ± 0.3 μM and 4.8 ± 0.6 μM, respectively.
The "reverse-tethered" ruthenium (II) catalyst for asymmetric transfer hydrogenation: Further applications
Morris, David J.,Hayes, Aidan M.,Wills, Martin
, p. 7035 - 7044 (2007/10/03)
The attachment of a tethering group from the basic nitrogen atom to the arene ligand of a ruthenium(II) catalyst greatly improves its ability to catalyze asymmetric transfer hydrogenation (ATH) reactions. In this paper, we describe further applications of this versatile system to an extended substrate range.
Applications of asymmetric hydrosilylations mediated by catalytic (DTBM-SEGPHOS)CuH
Lipshutz, Bruce H.,Lower, Asher,Kucejko, Robert J.,Noson, Kevin
, p. 2969 - 2972 (2007/10/03)
Several aryl ketone precursors useful in the synthesis of known physiologically active compounds have been reduced to the corresponding nonracemic alcohols. The previously reported combination of a catalytic quantity of (R)-(-)-DTBM-SEGPHOS-ligated CuH an
METHOD FOR MANUFACTURING ENANTIOMERIC IMIDAZOLE COMPOUNDS
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Page/Page column 9, (2008/06/13)
The invention relates to a method for manufacturing R- (-) - sertaconazole mononitrate. The invention also relates to R- - (-)-sertaconazole mononitrate hemiacetonate.
An efficient catalytic asymmetric route to 1-aryl-2-imidazol-1-yl-ethanols
Lennon, Ian C.,Ramsden, James A.
, p. 110 - 112 (2012/12/24)
The asymmetric hydrogenation of 1-aryl-2-imidazol-1-yl-ethanones offers a concise route to homochiral 1-aryl-2-imidazol-1-yl-ethanols. Catalytic asymmetric transfer hydrogenation with formic acid using [(R,R)-TsDPEN] Ru(Cymene)Cl as precatalyst was shown to be effective in this transformation. Preliminary process development showed that the hydrogenation could be carried out under mild conditions at a molar substrate-to-catalyst (S/C) ratio of 1000-2000.
A switch in enantiomer preference between mitochondrial F1F 0-ATPase chemotypes
Bisaha, Sharon N.,Malley, Mary F.,Pudzianowski, Andrew,Monshizadegan, Hossain,Wang, Paulina,Madsen, Cort S.,Gougoutas, Jack Z.,Stein, Philip D.
, p. 2749 - 2751 (2007/10/03)
The preferred absolute configuration of two series of F1F 0-ATP synthase inhibitors was determined. Although the configuration of the active enantiomer in each series is different, each series presents the same 'triaryl' pharmacophor
