MEDI 471 |
| Abstract: Potent inhibitors of menaquinones (2-methyl-3-polyprenyl-1,4-naphthoquinones) synthesis (specifically menaquinone A (MenA)) in Mycobacterium tuberculosis have been identified, which are also effective inhibitors of mycobacterial growth. Since utilization of menaquinone is a characteristic of Gram-positive organisms, these compounds are also active against organisms such as methicillin resistant Stapylococcus aureus and Staphylococcus epidermidis, and are expected to be effective against Bacillus anthracis and Listeria monocytogenes as well. The compounds identified as MenA inhibitors, ((alkylamino)octyloxyphenyl)(phenyl)methanones and their related molecules, were synthesized in a few steps via Friedel-Crafts acylation, alkylation, and amination reactions with high overall yields. A series of MenA inhibitors exhibited excellent growth-inhibitory activity against only Gram-positive bacteria (MIC values 2~8 microgram/mL). The MenA inhibitors were also effective against Mycobacterium spp. and showed MIC values as low as 1 microgram/mL. Interestingly, representative molecules were highly effective against the NRP stage 2 bacilli described in the Wayne low oxygen model (320-, 180-fold more activity against NRP stage 2 bacilli than ethanbutol and isoniazid, respectively). Growth of drug resistant Gram-positive organisms, including MRSA and MRSE, were sensitive to the MenA inhibitors, indicating that menaquinone synthesis is a valid drug target in Gram-positive organisms. The results are expected to be of significance in terms of discovering new lead compounds that can be developed into new drugs to combat Gram-positive NIAID category A, B and C priority pathogens, as well as, emerging diseases caused by Gram-positive bacteria.
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General Oral Session
1:30 PM-4:50 PM, Thursday, August 23, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |