Synthesis, stereochemistry, and antimicrobial evaluation of substituted piperidin-4-one oxime ethers

In a wide search program toward new and efficient antimicrobial agents, a series of substituted piperidin-4-one oxime ethers (5a-5k) was synthesized and tested for their in vitro antibacterial and antifungal activities. Also, the structures of these oxime ethers and their relative stereochemistries have been investigated by nuclear magnetic resonance spectroscopy. In all the oxime ethers synthesized, the orientation of the N-O bond of the oxime ether moiety syn to C-5 (E-isomer) was deduced based on H-1 NMR and C-13 NMR spectra. It was found that the sterically less hindered compounds, either C-3 (H) and C-5 (H)- or C-3 (Me) and C-5 (H) -substituted ones 5a, 5c, 5d, 5f, 5g, 5i and 5j prefer chair conformation, whereas the sterically more hindered C-3 (Me) and C-5 (Me) -substituted ones 5b, 5e, 5h, and 5k prefer twist-boat conformation. Among the oxime ethers tested, 1,3,5-trimethyl-2,6-diphenylpiperidin-4-one O-(2-chlorophenylmethyl)oxime (5h) exhibited good antibacterial property against Bacillus subtilis, with minimum inhibitory concentration (MIC) closer to that of reference drug, streptomycin. Compounds, 1,3-dimethyl-2,6-diphenylpiperidin-4-one O-(2-chlorophenylmethyl)oxime (5g) and 1,3-dimethyl-2,6-diphenylpiperidin-4-one O-(2-bromophenylmethyl)oxime (5j) showed potent antifungal activity against Aspergillus flavus and Candida-51, respectively. The later compound 5j is more active than the reference drug while the activity of the former one 5g is similar to that of the reference drug, amphotericin B in terms of MIC. The present results may be used as key steps for the construction of novel chemical entities with better pharmacological profiles than standard drugs. (c) 2006 Elsevier SAS. All rights reserved.