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Preparation and bioactive conformations of quinuclidine ketoximes

Bioactive chemical scaffolds such as nitrogen bicyclic bridged-rings as quinuclidines are recognized as compounds with a broad spectrum of biological activities not only in the fields of central nervous system disorders (Alzheimer’s disease, AD) but also in infectious diseases. In this work syntheses of series of novel N-alkyl derivatives of quinucline-3-oximes are described. The possibility of mechanochemical oxime synthesis with hydroxylamine hydrochloride, without any base and with or without catalytic amount of solvent was investigated. Furthermore, quaternization of quinuclidine nitrogen atom which was carried out with methyl, ethyl, allyl and differently substituted benzyl halides resulted in a set of compounds with different conformational space and and electronic structure. All compounds were prepared in very good yields and characterized by standard analytical spectroscopy methods (1D and 2D NMR, IR, MS). pKa values were measured and compared to that of neutral oxime. For all compounds, antimicrobial activity was estimated and efficacy toward multidrug-resistant Gram- negative bacteria will be discussed. To combine experimental and theoretical data molecular modeling, docking studies and a newly developed method for application of multi-way analysis was performed.

quinuclidine oximes, mechanochemical synthesis

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