M. K. Khera et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5266–5269
5269
Table 2
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Human CYP inhibition profile of compound 3e
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Compound
% CYP inhibition (at 10
l
M)
18. Zhou, J.; Bhattacharjee, A.; Chen, S.; Chen, Y.; Duffy, E.; Farmer, J.; Goldberg, J.;
Hanselmann, R.; Ippolito, J. A.; Lou, R.; Orbin, A.; Oyelere, A.; Salvino, J.;
Springer, D.; Tran, J.; Wang, D.; Wub, Y.; Johnson, G. Bioorg. Med. Chem. Lett.
2008, 18, 6175.
1A2
4.3
2C9
40.9
2C19
36.2
2D6
5.6
3A4
37.7
3e
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20. Ji, F. Q.; Niu, C. W.; Chen, C. N.; Chen, Q.; Yang, G. F.; Xi, Z.; Zhan, C. G.
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26. Docking experiments were carried out using Surflex in SYBYL 7.3 molecular
modeling package installed on a silicon graphics fuel workstation running on
the IRIX 6.5 operating system. Crystal Structure of E. coli 50S large subunit of
ribosome (PDB ID 2AW4) was taken and its working model was built using
residues within 30 Å of A2541 by using information from Mankin et al.27
27. Leach, K. L.; Swaney, S. M.; Colca, J. R.; McDonald, W. G.; Blinn, J. R.; Thomasco,
L. M.; Gadwood, R. C.; Shinabarger, D.; Xiong, L.; Mankin, A. S. Mol. Cell. 2007,
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heterocycles. The acetamide derivatives 3a, 3b and 3e were found
to display an excellent antibacterial activity profile against all the
Gram-positive pathogens tested. Compound 3e was found to be
4–16-fold more potent than Linezolid and also was devoid of any
CYP liability up to a concentration of 10 lM. Further modifications
in this series of compounds including the impact on antibacterial
activity of additional fluorine atoms on the aromatic rings and sub-
stitutions on the triazolopyrimidine ring will be the subject of fur-
ther communications.
Acknowledgments
We thank the analytical chemistry, microbiology and drug
metabolism and pharmacokinetics departments of Ranbaxy
Research Laboratories for their support. We also thank Ms Rajni
Miglani for performing the molecular docking studies.
28. Kalia, V.; Miglani, R.; Purnapatre, K. P.; Mathur, T.; Singhal, S.; Khan, S.; Voleti,
S. R.; Upadhyay, D. J.; Saini, K. S.; Rattan, A.; Raj, V. S. Antimicrob. Agents
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WO/06 038100.
31. Srinivasan, V.; Jebaratnam, D. J.; Budil, D. E. J. Org. Chem. 1999, 64, 5644.
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34. Minimum inhibitory concentrations (MICs) were determined as per the CLSI
guidelines 2009, 29(2), M07-A8.
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