Ketones as building blocks for dynamic combinatorial libraries: Highly active neuraminidase inhibitors generated via selection pressure of the biological target

Journal of Medicinal Chemistry

Volumn 46, Issue 3, 2003, Pages 356-358

  Hochgürtel, Matthias ^a   Biesinger, Ralf ^a   Kroth, Heiko ^a   Piecha, Dorothea ^a   Hofmann, Michael W ^a   Krause, Sonja ^a   Schaaf, Otmar ^a   Nicolau, Claude ^a   Eliseev, Alexey V ^a  

^a Therascope AG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ENZYME INHIBITOR; KETONE; SIALIDASE INHIBITOR; VIRUS SIALIDASE; ZANAMIVIR;

ARTICLE; DRUG ACTIVITY; DRUG MECHANISM; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; ENZYME INHIBITION; INFLUENZA VIRUS; NONHUMAN; STRUCTURE ANALYSIS;

AMINES; COMBINATORIAL CHEMISTRY TECHNIQUES; DATABASES, FACTUAL; ENZYME INHIBITORS; KETONES; LIGANDS; NEURAMINIDASE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0037472768     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm025589m     Document Type: Article

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25. Scaffold 1 was synthesized as described previously (ref 13).
26. (a) The amounts of ketimines at equilibria were below detection limit of NMR.
27. (b) No reaction products with the less reactive second amino group could be detected (cf. ref 13).
28. Scaffold 1 (100μM) and a mixture of ketones (25 mM each) was incubated with neuraminidase (43 μM) in the presence of tetrabutylammonium cyanoborohydride (8 mM) for 12 h. The resulting reaction mixture was analyzed by LC/MS using ESI-MRM.
29. Colman, P. M. J Antimicrob. Chemother. 1999, 44 (Suppl B), 17-22.
30. In the case of neuraminidase, the ether forms of the DCC hits have higher inhibitory activity than the amino forms, probably, because they lack positive charge in neutral aqueous solutions and are therefore structurally closer to the imino forms selected by the target.