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compound with DTm values below 15 have IC50 values
above 1 lM. The compound with the highest DTm has
an activity below 0.10 lM, while the compound with
the lowest DTm has an activity of greater than
100 lM. These results are consistent with kinetoplast
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previously.19 In contrast to controls (Fig. 3A), the
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The azaterphenyl diamidines were found to have potent
activity against L. d. axenic amastigotes. A marked
dependence on location of the ring N-atom(s) relative
to the amidine groups was noted. A general correlation
between DTm and IC50 values was observed. TEM stud-
ies showed a dramatic dilation of the mitochondrion
and evidence of disintegration of the kinetoplast of the
amastigotes which is consistent with targeting DNA.
Unfortunately, both 4a and 4b were not effective in a
Leishmania infected macrophage assay suggesting that
these diamidines are not delivered well to the parasites
within the macrophage host cell. Further studies focus-
ing on macrophage delivery are necessary to take advan-
tage of the potent intrinsic antileishmanial activity of
these azaterphenyl diamidines.
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Acknowledgment
18. Stephens, C. E.; Brun, R.; Salem, M.; Werbovetz, K. A.;
Tanious, F.; Wilson, W. D.; Boykin, D. W. Bioorg. Med.
Chem. Lett. 2003, 13, 2065.
This work was supported by an award from the Bill and
Melinda Gates Foundation.
´
19. Delfın, D. A.; Bhattacharjee, A. K.; Yakovich, A. J.;
Werbovetz, K. A. J. Med. Chem. 2006, 49, 4196.
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Buendia, A.; Kaiser, M.; Brun, R.; Ruiz-Perez, L. M.;
Johansson, N. G.; Gonzalez-Pacanowska, D.; Gilbert, I.
H. J. Med. Chem. 2005, 48, 5942.
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