- A switch in enantiomer preference between mitochondrial F1F 0-ATPase chemotypes
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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
- Bisaha, Sharon N.,Malley, Mary F.,Pudzianowski, Andrew,Monshizadegan, Hossain,Wang, Paulina,Madsen, Cort S.,Gougoutas, Jack Z.,Stein, Philip D.
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- A convergent, scalable and stereoselective synthesis of azole CYP51 inhibitors
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The study and development of azole-based CYP51 inhibitors is an active area of research across disciplines of biochemistry, pharmacology and infectious disease. Support of in vitro and in vivo studies require the development of robust asymmetric routes to single enantiomer products of this class of compounds. Herein, we describe a scalable and enantioselective synthesis to VNI and VFV, the two potent inhibitors of protozoan sterol 14α-demethylase (CYP51) that are currently under consideration for clinical trials for Chagas disease. A key transformation is the Jacobsen Hydrolytic Kinetic Resolution (HKR) reaction. The utility of the synthetic route is illustrated by the preparation of >25 g quantities of single enantiomers of VNI and VFV.
- Lepesheva, Galina,Christov, Plamen,Sulikowski, Gary A.,Kim, Kwangho
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supporting information
p. 4248 - 4250
(2017/10/12)
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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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p. 2115 - 2122
(2011/05/19)
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