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The 4-aminopiperidine series has limited anti-tubercular and anti-staphylococcus aureus activity
N Susantha Chandrasekera1, Torey Alling2, Mai Bailey3,4
1TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Seattle, WA, 98102, USA. Susantha.Chandrasekera@idri.org.
Background:
Tuberculosis (TB) caused by Mycobacterium tuberculosis is the leading cause of death from a bacterial infection. The 4-aminopiperidine (PIP) series has been reported as having anti-bacterial activity against M. tuberculosis. We explored this series for its potential to inhibit aerobic growth of M. tuberculosis. We examined substitution at the N-1 position and C-4 position of the piperidine and modifications of the piperidine moiety systematically to delineate structure-activity relationships influencing potency. Compounds were tested for growth-inhibitory activity against virulent M. tuberculosis. A selected set of compounds were also tested for its activity against Staphylococcus aureus.
Results:
The compound with a norbornenylmethyl substituent at the N-1 position and N-benzyl-N-phenethylamine at the C-4 position of the piperidine (1) was the only active compound with a minimum inhibitory concentration (MIC) of 10 μM against M. tuberculosis. Compounds were not active against S. aureus.
Conclusions:
We were unable to derive any other analogs with MIC < 20 μM against M. tuberculosis. Therefore we conclude that the lack of activity is a liability in this series precluding it from further development.
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