Synthesis of 3‐aminorhodanine derivatives as aldose reductase inhibitors

Hanefeld, Wolfgang; Schlitzer, Martin

doi:10.1002/jhet.5570320358

Cited by 17 publications

(11 citation statements)

References 8 publications

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“…Thus, inhibition of AR provides a possible strategy to prevent the complications of chronic diabetes 10. Accordingly, considerable research effort has resulted in the detailed structural characterization of AR11–18 and in the discovery of a large number of structurally distinct AR inhibitors (ARIs) 19–28. Even though a remarkable number of different inhibitors are known, they all fall into mainly two classes of compounds (spirohydantoins and carbonic acids) and only one compound (Epalrestat) is presently available on the market in Japan.…”

Section: Introductionmentioning

confidence: 99%

Virtual screening for inhibitors of human aldose reductase

et al. 2004

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The inhibition of aldose reductase (AR) provides an interesting strategy to prevent the complications of chronic diabetes. Although a large number of different AR inhibitors are known, very few of these compounds exhibit sufficient efficacy in clinical trials. We performed a virtual screening based on the ultrahigh resolution crystal structure of the inhibitor IDD594 in complex with human AR. AR operates on a large scale of structurally different substrates. To achieve this pronounced promiscuity, the enzyme can adapt rather flexibly to its substrates. Likewise, it has a similar adaptability for the binding of inhibitors. We applied a protocol of consecutive hierarchical filters to search the Available Chemicals Directory. In the first selection step, putative ligands were chosen that exhibit functional groups to anchor the anion-binding pocket of AR. Subsequently, a pharmacophore model based on the binding geometry of IDD594 and the mapping of the binding pocket in terms of putative "hot spots" of binding was applied as a second consecutive filter. In a third and final filtering step, the remaining candidate molecules were flexibly docked into the binding pocket of IDD594 with FlexX and ranked according to their estimated DrugScore values. Out of 206 compounds selected by this search and complemented by a cluster analysis and visual inspection, 9 compounds were selected and subjected to biological testing. Of these, 6 compounds showed IC50 values in the micromolar range. According to the proposed binding mode, the two inhibitors BTB02809 (IC50 = 2.4 +/- 0.5 microM) and JFD00882 (IC50 = 4.1 +/- 1.0 microM) both place a nitro group into the hydrophobic specificity pocket of human AR in an orientation coinciding with the position of the bromine atom of IDD594. The interaction of this Br with Thr113 has been identified as a key feature that is responsible for selectivity enhancement.

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Section: Introductionmentioning

confidence: 99%

Virtual screening for inhibitors of human aldose reductase

et al. 2004

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“…An analytically pure sample of aldehyde mixture was recrystallized from a mixture of ethanol and DMF. 5-(3-Nitrophenyl)-2-thiophenecarbaldehyde (3b) was obtained in 28% yield; mp 144-145ºC ( [22], mp 147ºC) and 5-(4-chlorophenyl)-2-thiophenecarbaldehyde (3c) in 27% yield; mp 88-89ºC ( [23], mp 89-90ºC).…”

Section: -Arylthiophene-2-carbaldehydes 3a-f (General Method)mentioning

confidence: 99%

Synthesis and reactions of 5-aryl-2-thiophenecarbaldehydes

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Matiychuk

Lytvyn

2008

Chem Heterocycl Comp

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“…Da die Aldehydfunktion von 2 auch die Möglichkeit bot, mit CH-aciden Verbindungen über Aldolkondensationen verbunden zu werden, haben wir einige methylenaktive 3-Aminorhodanine, die sich als wertvolle Bausteine für Aldose-Reduktase-Hemmstoffe erwiesen hatten [15,16], unter Basenkatalyse mit 2 zu den Produkten 12 kondensiert.…”

Section: Abb 5 Vergleich Der Charakteristischen Nmr-daten Der O-unsuunclassified

Synthese potentieller Pflanzenschutzwirkstoffe auf 2,3-Dihydrothiazol-2-thion-Basis II [1] Strukturvariationen ausgehend von einer C4 -Carbaldehydfunktion

Hanefeld

Wurtz

2000

J. prakt. Chem.

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445In Teil 1 unserer Mitteilungen über die Synthese potentieller Pflanzenschutzwirkstoffe auf 2,3-Dihydrothiazol-2-thion-Basis hatten wir eine Leitstruktur mit diesem Heterocyclus als Kernstruktur vorgestellt sowie über Strukturvariationen am N 3 und C 4 berichtet [1], die zum Ziel hatten, auf dem Gebiet von Pflanzenschutzmitteln relevante Substituenten in das Kernmolekül enzufügen. Da aber zum Aufbau des 2,3-Dihydrothiazol-2-thionsystems nur Aminkomponenten ausreichender Nucleophile zur Reaktion mit Schwefelkohlenstoff eingesetzt werden können, können viele interessante Stickstoffnucleophile auf diese Weise nicht eingeführt werden. Dieses sollte nun auf anderem Wege ermöglicht werden, indem zunächst 2-Thioxo-3-(3-trifluormethylphenyl)-2,3-dihydrothiazol-4-carbaldehyd (2) darzustellen war, dessen Aldehydfunktion zahlreiche Derivatisierungsreaktionen ermöglicht. Ergebnisse und DiskussionDa eine Aldehydfunktion eine Vielzahl von Umwandlungsmöglichkeiten bietet, wurde nach einem mit guter Ausbeute verlaufenden Syntheseweg für den 2-Thioxo-3-(3-trifluormethyl-phenyl)-2,3-dihydrothiazol-4carbaldehyd (2) gesucht, damit ausreichendes Material für zahlreiche Umwandlungsreaktionen bereit gestellt werden konnte. Als Edukt wurde 4-Chlormethyl-3-(3trifluormethylphenyl)-2,3-dihydrothiazol-2-thion (1) [1] gewählt und zunächst analog zu einer von Silberg et al. für andere 4-Chlormethylthiazole gegebenen Vorschrift [2] umgesetzt, wobei allerdings in unserem Falle schon die erste Reaktionsstufe, die Finkelstein-Reaktion zum Synthese potentieller Pflanzenschutzwirkstoffe auf 2,3-Dihydrothiazol-2-thion-Basis II [1]Abstract. 2-Thioxo-3-(3-trifluormethylphenyl)-2,3-dihydrothiazol-4-carbaldehyde (2) has been prepared from the corresponding chloromethyl compound 1 by a modified Kornblum oxidation. The aldehyde function has been reacted with aromatic and heterocyclic primary amines to yield the imino compounds 3, with hydrazino compounds to yield hydrazones 4 and with hydroxylamine or O-substituted hydroxylamines to form the oximes 7 -10, which could be separated into pure E and Z-isomers. The unsubstituted oxime 7 could be transformed to the carbonitrile 11 with 3,5-dinitrobenzoylchloride. 2 could be condensed in presence of a base with the CHacidic 5-position of 3-aminorhodanine derivatives to yield 12.

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Synthesis of 3‐aminorhodanine derivatives as aldose reductase inhibitors

Cited by 17 publications

References 8 publications

Virtual screening for inhibitors of human aldose reductase

Virtual screening for inhibitors of human aldose reductase

Synthesis and reactions of 5-aryl-2-thiophenecarbaldehydes

Synthese potentieller Pflanzenschutzwirkstoffe auf 2,3-Dihydrothiazol-2-thion-Basis II [1] Strukturvariationen ausgehend von einer C4 -Carbaldehydfunktion

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