Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis - Iron Acquisition by the Genus Mycobacterium - page 71

Fig. 5.7 Diaminopropionate modified mycobactin analogs [ 56 , 57 , 58 ]
[ 56 , 57 ]. However, the free amine 24 obtained by removal of the protecting group
for subsequent derivatization and preparation of antibiotic conjugates was found to
be completely inactive. Anticipating that most likely the loss of activity was due
to the removal of the bulky hydrophobic N -Boc group and generation of a posi-
tively charged amine that might not be taken up or localized in the same lipophilic
region of the mycobacterial cellular envelope, the free amine was reacylated with
a pivaloyl group to give derivative 25 . Interestingly, while pivalate derivative 25
differs only by one oxygen relative to the active N -Boc protected compound, the
pivaloyl analog 25 was devoid of antibiotic activity. No reason for this remarkable
difference has been determined but it is interesting to speculate that the active N -
Boc protected compound might actually serve as a prodrug that is hydrophobically
assimilated and acid sensitive Boc group “deprotected” to generate the positively
charged amine in the local environment. The pivaloyl derivative 25 would be inert
towards such mild deacylation conditions [ 57 , 58 ].
The impressive activity of the N -Boc-protected 2,3-diaminoproprionate analog,
23 , prompted further structure-activity-relationship (SAR) studies, including mod-
ifications of each portion of the mycobactins as shown in generalized structure 27
(Fig. 5.8 ). For example, replacement of the o -hydroxyphenyl oxazoline (segment
“A-B”) with dihydroxybenzoylglycine gave catechol-containing mycobactins 28
and 29 . Based on the results obtained with analogs 18 and 19 , both epimers at
the ester position were synthesized [ 59 ]. The iron-binding capabilities of these
mycobactins were corroborated through the chrome azurol S (CAS) assay [ 60 ].
However, both analogs did not display growth inhibition against M. tuberculosis
(MIC > 6.25 μ g/mL, >7.75 μ M), perhaps stressing the importance of the oxazo-
line moiety in biological recognition. Interestingly, 28 and 29 were efficiently used
as growth promoters by strains of M. smegmatis [ 59 ].