C. M. Reid et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5399–5401
5401
Table 1
that while the trypanocidal activity of 5 and 6 is only moderate,
this approach of tagging C2-substituted polyazamacrocycles with
motifs recognised by a specific trypanosome receptor has produced
compounds with selective anti-protozoal activity and with low
toxicity to human cells (cf. 4, Table 1). Future variants could be de-
signed that have more potency against trypanosomes, and these
new compounds could also be tagged with delivery moieties that
could further enhance their selectivity.
Anti-protozoal activity of polyazamacrocycles 4, 5, 6, 11 and 12
NH HN
NH HN
R
R
Estimated T. brucei
P. falciparum HEK
logP
EC50
(l
M) EC50
(l
M)
EC50
(lM)
In summary, we have developed efficient synthetic routes for
the preparation of two novel C2-substituted polyazamacrocycles
tagged with amidine motifs recognised by the T. brucei P2 amino-
purine transporter. Biological testing of these compounds showed
that despite their low logP values, anti-protozoal activity was still
observed against T. brucei. The lack of any anti-protozoal activity
against P. falciparum or HEK indicates that the compounds are
selectively accumulated by trypanosomes. Work is currently
underway to extend this approach with more potent analogues
and also to probe the mechanism of cytotoxicity of these C2-
substituted 1,4,7,10-tetraazacyclododecanes.
2.2
1.3
<1.5
24.9
49
NH
NH2
À1.44
22.0
>100
>200
Acknowledgments
5
Financial support from EPSRC (DTA award to C.M.R.) and the
University of Glasgow is gratefully acknowledged. We thank
Mhairi Stewart for assistance with establishing assays.
NH
N
NH2
À1.64
À0.65
À1.12
41.2
>200
>200
>100
>100
>100
>200
>200
>200
H
Supplementary data
6
CN
Supplementary data associated with this article can be found, in
11
References and notes
NH2
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