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appears to indicate biological discrimination by
M. tuberculosis
, the specifics
regarding the level at which recognition occurs is not yet determined. It is impor-
tant to indicate that the mycobactin analogs must be interfering with the iron
acquisition system considering that non metal-binding precursors (
O
-benzyl pro-
tected hydroxamates) do not display any antibiotic activity. Although it has been
demonstrated that mycobactin T can acquire iron from the lipid droplets inside
macrophages and act cooperatively with carboxymycobactin T to recover metal
from other sources such as transferrin and lactoferrin, much remains to be learned
from these fascinating molecules.
The lack of anti-TB activity of all of the analogs described above, except for
the Boc-protected 2,3-diaminoproprionate
23
and the
p
-aminosalicylate (PAS)
analogs
47
-
49
, reflected the growingly apparent remarkable iron transport selec-
tivity of mycobacteria. However, further studies revealed two exciting leads for
the development of anti-TB agents based on studies of mycobactins: the discovery
of new classes of non-iron metabolism based small heterocycle inhibitors and the
ability to utilize
23
for the preparation of mycobactin-like drug conjugates (sidero-
mycins) with exquisitely selective anti-TB activity [
56
,
57
].
5.6 Small Molecule Anti-TB Agents Derived from Studies of
the Oxazoline Component of Mycobactins
During the process of screening the synthetic mycobactins, analogs and com-
ponents, a double benzyl protected form
51
of the
o
-hydroxyphenyl oxazoline
component
50
was found to have moderate but very selective inhibitory activ-
ity against
M. tuberculosis
, presumably through an iron trafficking independent
mechanism since its iron binding constituent was masked. Phenyl oxazoline,
52
without the benzyloxy group was synthesized and tested to confirm that related
non-iron binding compounds possessed anti-TB activity. In fact, the activity of
52
was enhanced relative to the dibenzyl protected lead compound (
51
) and, again,
the compound was found to be extraordinarily potent against
M. tuberculosis,
while not active against other forms of mycobacteria or other Gram-positive or
Gram-negative bacteria. These early results prompted extensive structure-activity
relationship (SAR) studies of related hydrophobic oxazoline, oxazole and similar
heterocycles. The results are summarized in the generalized structure
53
below
(Fig.
5.12
) [
63
,
64
-
65
].
While developing the SAR of the oxazolines, oxazoles and related compounds,
many other heterocyclic cores were prepared, derivatized and screened, includ-
ing imidazopyridines, which have emerged as tremendously potent and selective
anti-TB agents [
66
]. Imidazopyridines have nanomolar anti-TB activity, includ-
ing similarly potent activity against multi-drug resistant (MDR) and extensive
drug resistant (XDR) clinical isolates of
M. tuberculosis
, but are not broadly active
against all types of mycobacteria or other Gram-positive or Gram-negative bacte-
ria. The compounds are easily synthesized, appear to be very drug like with ideal
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