Chemistry Reference
In-Depth Information
reaction time of binary fragment combinations from6 days to 6 h and for the multi-fragment
combinations to 24 h. Fragment concentrations could also be lowered considerably (azide
fragments, 4.6 M; acetylene fragments, 24 M) with 15 L of reaction mixture required
for HPLC-SIM-MS analysis.
With AChE as the target for
in situ
Click chemistry, a total of 58 fragments have now
been screened, with eight fragment combinations undergoing conversion to triazoles in
the presence of AChE (Figure 7.16). Interestingly, the regioisomer contribution of these
fragment combinations has so far exclusively been attributed to the
syn
-triazoles as determ-
ined by comparison of HPLC retention times against authentic samples. The inhibition
properties for all hit triazoles have also been determined and have proven to be the most
potent noncovalent inhibitors of AChE yet reported, with
K
i
s in the femtomole range
(Figure 7.16).
NH
2
NH
2
H
2
N
H
2
N
N
N
N
NH
2
N
NH
2
NH
2
NH
2
N
N
N
N
N
N
N
N
N
N
N
N
NH
NH
NH
NH
N
N
N
N
syn
-TZ2PA6
K
d
(eAChE) 99 fM
K
d
(mAChE) 410 fM
syn
-TZ2PA5
K
d
(eAChE) 100 fM
K
d
(mAChE) 2.3 pM
syn
-TA2PZ6
K
d
(eAChE) 830 fM
K
d
(mAChE) 610 fM
syn
-TA2PZ5
K
d
(eAChE) 540 fM
K
d
(mAChE) 3.0 pM
OMe
OMe
OMe
OMe
OMe
OMe
MeO
MeO
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NH
NH
NH
NH
N
N
N
N
syn
-(S)-TZ2PIQA6
K
d
(eAChE) 96 fM
K
d
(mAChE) 1.1 pM
syn
-(S)-TZ2PIQA5
K
d
(eAChE) 33 fM
K
d
(mAChE) 500 fM
syn
-(R)-TZ2PIQA6
K
d
(eAChE) 360 fM
K
d
(mAChE) 1.7 fM
syn
-(R)-TZ2PIQA5
K
d
(eAChE) 36 fM
K
d
(mAChE) 100 fM
Figure 7.16
Summary of
in situ
Click chemistry hits targeting AChE.
