Biomedical Engineering Reference
In-Depth Information
Replacing the dimethylamino group of TCMDC-135308
with a methoxy group resolves the CPDB signature
alert as well as the ToxTree Benigni/Bossa Structure
Alerts for carcinogenicity and mutagenicity as provided
by OpenTox. The image illustrates the absence of
CPDB signature alerts
Figure 2.7
Bursi Salmonella mutagenicity' models are still positive. In addition, the
'IST DSSTox Carcinogenic Potency DBS MultiCellCall' model is now
positive. As expected, physico-chemical properties such as pK
a
or XLogP
are not, or only marginally, affected (no change to pK
a
, XLogP changes
from 0.845 to 0.551), and also, no new positive toxicity predictions are
obtained due to the change.
Thus, our bioisosteric replacement of the dimethylamino group has
resolved several toxicity predictions, while hopefully only marginally
affecting the compound's activity. As it turns out, the methoxy variant we
constructed based on TCMDC-135308 exists in TCAMS as well. It is
TCMDC-134670. Its activity against
P. falciparum
3D7 is almost
identical to that of TCMDC-135308 (101% growth inhibition at 2 μM,
XC50 = 670 nM), whereas its activity against
P. falciparum
DD2 is
slightly decreased (from 63% to 42% growth inhibition at 2 μM).
TCMDC-134670 is also less active in the
in vitro
hepatotoxicity assay
reported (-1% growth inhibition of human HepG2 cells at a concentration
of 10 μM, compared to 5% obtained with TCMDC-135308).
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