De Novo design and synthesis of novel RNA polymerase inhibitors as potential anti-tuberculosis agents

MEDI 326

Anil K. Agarwal, chmaka@leeds.ac.uk1, Julian G. Hurdle, bmbjgh@bmb.leeds.ac.uk2, Amer I. AlOmar2, Ian Chopra, I.Chopra@leeds.ac.uk2, A Peter Johnson, a.p.johnson@chemistry.leeds.ac.uk1, and Colin W. G. Fishwick, C.W.G.Fishwick@leeds.ac.uk1. (1) School of Chemistry, University of Leeds, Leeds, LS2 9JT, United Kingdom, (2) Institute of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
In silico approaches, and particularly de novo inhibitor design, have been established as powerful tools in drug discovery. The de novo molecular design program SPROUT has been applied to the X-ray crystal structure of T. aquaticus RNA polymerase in complex with rifampicin. The resulting design templates were used to synthesize a series of small molecule inhibitors of RNAP efficiently in 5-6 steps as single enantiomers. The synthesised compounds were evaluated for their selective in vitro RNAP activity against E. coli using SYBR Green assay. Among the synthesised compounds, 1 and 3 were found to be the most active compounds with 62 % and 54 % inhibition of the RNAP activity at 50 μg/ml concentrations respectively. Consistent with this activity, compounds 1 and 3 also show 96 % and 100 % inhibition of protein synthesis in a S. aureus transcription/translation assay at concentrations of 5 and 50 μg/ml respectively.

 

General Poster Session
7:00 PM-9:00 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006