enzyme and its potential as a new TB drug target. Toxicity
studies were also performed with these lead compounds
against the human embryonic kidney cell line HEK293
(see Supplementary Information). Gratifyingly, these analogues
displayed similarly low cytotoxicity when compared to THL, a
drug approved for use in humans. Specifically, analogues
displayed no significant effect on cell activity up to concentra-
tions of 50 mM (over 10 times the concentration required for
complete inhibition of M. tuberculosis growth in vitro).
In summary, we have reported the first potent inhibitors of
the M. tuberculosis lipase, Rv3802c. Located in the myco-
bacterial cell wall, this enzyme is essential for viability and, as
such, represents an exciting new TB drug target. Several of the
analogues synthesised in this study exhibited sub-micromolar
inhibition of the enzyme. In general, compounds that displayed
potent activity against the enzyme also possessed encouraging
antibacterial activity against M. tuberculosis in vitro and now
serve as novel TB drug leads for further investigation. Future
studies will involve screening the lead compounds (12, 17, 18
and 20) in M. tuberculosis-infected mice models to gauge the
efficacy of the inhibitors as anti-tubercular agents in vivo.
These compounds also represent leads for the design and
synthesis of second-generation inhibitors, work towards which
is currently underway in our laboratories.
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5168 Chem. Commun., 2011, 47, 5166–5168
This journal is The Royal Society of Chemistry 2011