D. Dou et al. / Bioorg. Med. Chem. Lett. 22 (2012) 377–379
379
X
NBoc
ii
NH
iii
O
H
N
R4
N
N
N
i
O
O
O
O
X = CO
CH2
SO2
8
7
9a-m
R4
X
R4
X
CO
CO
CO
CO
CO
CO
CO
p-phenoxyphenyl
m-phenoxyphenyl
p-hydroxyphenyl
p-isopropoxyphenyl
p-chlorophenyl
p-cyanophenyl
p-methoxyphenyl
9a
CO
p-chlorobenzyl
m-phenoxyphenyl
m-hydroxyphenyl
p-isopropoxyphenyl
n-butyl
9h
9i
9j
9k
9l
9m
9b
9c
9d
9e
9f
CH2
CH2
CH2
SO2
SO2
p-cyanophenyl
9g
Scheme 3. Reagents and reaction conditions: (i) 1-Boc-piperazine/NaHB(OAc)3/CH2Cl2; (ii) TFA/CH2Cl2; (iii) EDCI/R4COOH/DMF or R4CHO/NaHB(OAc)3/CH2Cl2 or R4SO2Cl/
TEA/CH2Cl2.
removal of the Boc with trifluoroacetic acid, gave compound 8.
Compound 8 was either acylated with EDCI activated carboxylic
acid, or alkylated using reductive amination with substituted
benzaldehyde and sodium triacetoxyborohydride, or sulfonylated
with sulfonyl chloride in the presence of triethylamine to give
compounds 9a–m (Scheme 3). Several derivatives were found
to possess anti-norovirus activity, however, potency and toxicity
were highly sensitive to structural variations. The best com-
pound in this group, tertiary sulfonamide 9l, had a therapeutic
index of 18.
In summary, this preliminary report demonstrates for the first
time that functionalized piperazine compounds exhibit notewor-
thy anti-norovirus activity in a cell-based system. Two first-gener-
ation piperazine derivatives (compounds 6a and 9l) have been
identified that could potentially serve as a starting point for further
optimization studies in conjunction with mechanism of action
studies aimed at identifying the molecular target(s) with which
these compounds interact. Taken together, these results hold sig-
nificant promise for the development of inhibitors directed against
norovirus infection.
References and notes
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Supplementary data
Supplementary data associated with this article can be found, in
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