10.1002/cmdc.201900165
ChemMedChem
COMMUNICATION
(I) and 3 – 9 fold more effective against T. brucei than T. cruzi. The References:
most active adduct, with the best selectivity, was the
phenylacetoxy hydrazone 1b (EC50=11±0.9 nM and SITb=770).
The spacer between the phenyl ring and the carbonyl group seems
to have a significant impact on activity and cytotoxicity. It seems
that the present structural modification comprising of a phenyl ring
insertion between the adamantane core and the hydrazone side
chain has improved the pharmacological characteristics of the new
molecules, in terms of activity and toxicity, compared to the
adamantane carbohydrazones (IV), we previously reported.[22] The
direct attachment of the hydrazone linker to the phenyl ring
decreased the potency, and a one or two methylene spacer was
associated with enhanced activity. Adducts 1b, 1c and 2b, 2c
exhibited higher trypanocidal activity than analogues 1a and 2a,
respectively. Conversely, the replacement of one methylene by an
oxygen atom had a detrimental impact on activity. The position of
substitution on the adamantane core (C-1, C-2), influenced
cytotoxicity and the C-1 substituted hydrazones 1b (SITb=770) and
1c (SITb=520) were found to be more selective than the
corresponding C-2 substituted adducts 2b (SITb=235) and 2c
(SITb=215). The same pattern was also observed in the T. cruzi
results. The third series of derivatives, the 5-nitro-furonic
carboxamides 3a-c, exhibited reduced activity in comparison to
the hydrazones, which implies that these analogues may follow the
same mechanistic pathway as nifurtimox. [30–32] This observation is
in agreement with our previous test results on adamantane
carbohydrazones (IV). [22]
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Experimental Section
General procedure for the preparation of hydrazones 1a-d and 2a-d.
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General procedure for the preparation of carboxamides 3a-c.
5-Nitro-2-furoic acid (240 mg, 1.52 mmol) was treated with SOCl2 (10 mL)
at 60-65 oC for 60 min. Excess SOCl2 was removed under reduced
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Conflicts of interest
The authors have no conflicts to declare
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Acknowledgements
We thank Dr. Dimitra Benaki, Department of Pharmacy, Division
of Pharmaceutical Chemistry, National and Kapodistrian
University of Athens for NMR experiments.
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Keywords: 4-(adamant-1-yl)phenyl substitution • 4-(adamant-2-
yl)phenyl substitution • hydrazone • nifurtimox • trypanocidal
activity
3
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