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Fig. 5.19
Rationally designed nucleoside antibiotics. Non-hydrolyzable linker [
77
]
Fig. 5.20
Rationally designed nucleoside antibiotics. SAR of the glycosyl portion [
78
]
inhibition of MbtA (
K
AP
I
=
3.30
+
0.57
μ
M) and retained moderate anti-TB activ-
ity (MIC
99
=
25
μ
M), while
74
was found inactive in both assays. Molecular dock-
ing with salicyl-adenylating DhbE showed that the analogs deviated from a planar
conformation necessary for activity. Compound
75
was also tested and was found to
display reduced activity (MIC
99
=
50
μ
M), providing evidence that the potent inhi-
bition of
65
and
69
was not due to hydrolysis and release of a cytotoxic byproduct.
In subsequent work, Somu et al. [
78
] explored variation on the glycosyl region
of the nucleoside inhibitors (Fig.
5.20
). Carbocyclic analog
79
displayed reduced
activity (MIC
99
=
1.56
μ
M) compared to the previously synthesized
77
(Et
3
N
adduct of
65
) and
78
(Et
3
N adduct of
69
). The removal of hydroxyl groups in the
sugar ring reduced or eliminated all inhibitory activity
80
(MIC
99
=
25
μ
M),
81
(MIC
99
=
1.56
μ
M),
82
(MIC
99
> 200
μ
M). The antibiotics were tested against
purified mycobactin TA and in general, the observed inhibitory activity correlated
with the whole-cell assays. Among the exceptions, analog
83
was found inactive in
vivo (MIC
99
> 200
μ
M) while inhibiting MbtA (
K
AP
I
=
0.061
μ
M). This observa-
tion was consistent with the idea that these compounds are actively transported
that the sugar moiety is important for recognition.
Utilizing molecular modeling, Neres elaborated the SAR of the base moi-
ety of the nucleoside adenylate-inhibitors (Fig.
5.21
) [
79
]. Compounds
102
-
104
displayed potent growth inhibition against
M. tuberculosis
under iron-deficient
(MIC
99
=
0.049
μ
M) and iron-sufficient conditions (MIC
99
=
0.39
μ
M), repre-
senting the most potent compounds of this class reported to date. In general, it
was evident that at least one H-bond donor at
N
-6 was essential for activity.
Substitution at the
N
-6 position with alkyl groups increased the inhibitory activity
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