A switch in enantiomer preference between mitochondrial F1F0-ATPase chemotypes

Bisaha, Sharon N.; Malley, Mary F.; Pudzianowski, Andrew T.; Monshizadegan, Hossain; Wang, Paulina; Madsen, Cort S.; Gougoutas, Jack Z.; Stein, Philip D.

doi:10.1016/j.bmcl.2005.03.115

Cited by 9 publications

(17 citation statements)

References 8 publications

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“…1), the imidazole ring is almost parallel to the benzene ring, the dihedral angle between them being 7.3 (2)°. All bond lengths and bond angles are normal and comparable to those observed in similar crystal structures (Bisaha et al 2005).…”

Section: Data Collectionsupporting

confidence: 82%

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Imazalil: 1-[2-(2,4-dichlorophenyl)-2-(prop-2-enyloxy)ethyl]-1H-imidazole

et al. 2011

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In the title compound, C14H14Cl2N2O, the imidazole ring is almost parallel to the benzene ring, the dihedral angle between them being 7.3 (2)°. In the crystal, there is an intermolecular C—Cl⋯π interaction (Cl⋯centroid = 3.36 Å and C—Cl⋯centroid = 89.2°). In addition, a Cl⋯Cl contact of 3.411 (1) Å and an intermolecular C—H⋯N hydrogen bond are observed. These interactions contribute to the stabilization of the crystal packing.

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Section: Data Collectionsupporting

confidence: 82%

“…For information on the toxicity of the title compound, see: Sisman & Tü rkez (2010). For related structures, see: Bisaha et al (2005).…”

Section: Related Literaturementioning

confidence: 99%

Imazalil: 1-[2-(2,4-dichlorophenyl)-2-(prop-2-enyloxy)ethyl]-1H-imidazole

et al. 2011

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“…Experimental data for this series of compounds shows a pattern of stereo‐specific inhibition of Mycobacterium tuberculosis and M. smegmatis that may provide insight into the binding mode of the compounds 1. Stereo‐specific inhibition of ATPases is probably not uncommon, for it has for instance also been observed for another series of inhibitors of mitochondrial ATPases 36…”

Section: Discussionmentioning

confidence: 85%

A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910

et al. 2007

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Diarylquinolines (DARQs) are a new class of potent inhibitors of the ATPase of Mycobacterium tuberculosis. We have created a homology model of a binding site for this class of compounds located on the contact area of the a-subunit (gene atpB) and c-subunits (gene atpE) of Mycobacterium tuberculosis ATPase. The binding pocket that was identified from the analysis of the homology model is formed by 4 helices of three c-subunits and 2 helices of the a-subunit. The lead compound of the DARQ series, R207910, was docked into the pocket using a simulated annealing, multiple conformer, docking algorithm. Different stereoisomers were treated separately. The best docking pose for each stereoisomer was optimized by molecular dynamics simulation on the 5300 atoms of the binding region and ligand. The interaction energies in the computed complexes enable us to rank the different stereoisomers in order of interaction strength with the ATPase binding pockets. We propose that the activity of R207910 against Mycobacterium tuberculosis is based on interference of the compound with the escapement geometry of the proton transfer chain. Upon binding the compound mimics the conserved Arg-186 residue of the a-subunit and interacts in its place with the conserved acidic residue Glu-61 of the c-subunit. This mode of action is corroborated by the good agreement between the computed interaction energies and the observed pattern of stereo-specificity in the model of the binding region.

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“…[28] (S)-1-(2,4- The imidazole ring was synthesized from 13, glyoxal, formal-dehyde, and ammonium acetate, [29] to give 14 in a yield of 70 %. [30] Finally alkylation of the hydroxyl group with 2,4-dichloro-1-(chloromethyl)benzene [31] afforded (S)-miconazole (15) in a yield of 76 % with an ee value of 98 %, without loss of optical purity in any of the steps of the synthetic sequence.…”

Section: Resultsmentioning

confidence: 99%

New Highly Asymmetric Henry Reaction Catalyzed by Cu^II and a C₁‐Symmetric Aminopyridine Ligand, and Its Application to the Synthesis of Miconazole

Blay

Domingo

Hernández‐Olmos

et al. 2008

Chemistry A European J

179

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A new catalytic asymmetric Henry reaction has been developed that uses a C(1)-symmetric chiral aminopyridine ligand derived from camphor and picolylamine. A variety of aromatic, heteroaromatic, aliphatic, and unsaturated aldehydes react with nitromethane and other nitroalkanes in the presence of DIPEA (1.0 equiv), Cu(OAc)(2)*H(2)O (5 mol %), and an aminopyridine ligand (5 mol %) to give the expected products in high yields (up to 99 %), moderate-to-good diastereoselectivites (up to 82:18), and excellent enantioselectivities (up to 98 %). The reaction is air-tolerant and has been used in the synthesis of the antifungal agent miconazole.

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A switch in enantiomer preference between mitochondrial F1F0-ATPase chemotypes

Cited by 9 publications

References 8 publications

Imazalil: 1-[2-(2,4-dichlorophenyl)-2-(prop-2-enyloxy)ethyl]-1H-imidazole

Imazalil: 1-[2-(2,4-dichlorophenyl)-2-(prop-2-enyloxy)ethyl]-1H-imidazole

A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910

New Highly Asymmetric Henry Reaction Catalyzed by Cu^II and a C₁‐Symmetric Aminopyridine Ligand, and Its Application to the Synthesis of Miconazole

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A switch in enantiomer preference between mitochondrial F1F0-ATPase chemotypes

Cited by 9 publications

References 8 publications

Imazalil: 1-[2-(2,4-dichlorophenyl)-2-(prop-2-enyloxy)ethyl]-1H-imidazole

Imazalil: 1-[2-(2,4-dichlorophenyl)-2-(prop-2-enyloxy)ethyl]-1H-imidazole

A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910

New Highly Asymmetric Henry Reaction Catalyzed by CuII and a C1‐Symmetric Aminopyridine Ligand, and Its Application to the Synthesis of Miconazole

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Product

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New Highly Asymmetric Henry Reaction Catalyzed by Cu^II and a C₁‐Symmetric Aminopyridine Ligand, and Its Application to the Synthesis of Miconazole