C.-K. Ryu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2577–2580
2579
R
O
O
O
R1
R2
Cl
Cl
S
S
N
N
N
N
N
N
c
e
NH2
O
6 : R= NO
2
8
b
R1
7 : R= NH
2
R2
4a-i
d
a
O
O
NO2
H
N
R1
R2
N
N
N
N
Cl
5
3a-h
f
O
O
O
O
NH2
H
N
R1
R2
g
N
N
d
N
N
N
N
9
10
3i-m
Scheme 1. Synthesis of phthalazine-5,8-dione derivatives. Reagents and conditions: (a) HONH2/EtOH–MeOH/KOH/3 h/55 ꢁC; (b) 6/H2/10% Pd/C/
abs EtOH/3 psi/2 h/rt; (c) 7/NaClO3/HCl/1 h/65 ꢁC; (d) arylamine (1 equiv)/EtOH/5 h/reflux/42–95%; (e) arylthiol (2 equiv)/EtOH/5 h/rt/55–86%; (f)
H2/10% Pd/C/EtOH/30 psi/4 h/rt; (g) H2SO4/K2Cr2O7/2 h/0 ꢁC.
fungal activity against Candida albicans, Candida trop-
icalis, Candida krusei, and Cryptococcus neoformans.
In contrast, 6,7-bis(arylthio)-phthalazine-5,8-diones
4a–i did not show significant antifungal activity
against C. krusei andC. neoformans, although many
of compounds 4a–i also showed potent antifungal
activity against C. albicans and Aspergillus niger.
Actually, the activity of compounds 3d, 3e, 3k,
and 3l was superior or comparable to that of 5-fluoro-
cytosine against all tested fungi. The compounds 3d,
3e, 3k, and 3l completely inhibited the growth of
all fungal species tested at the MIC level of
3.2–25 lg/mL.
In addition, phthalazine-5,8-diamine (7) and phthal-
azine-5-amine (9) exhibited no or poor, if any, anti-
fungal activity. The phthalazine-5,8-diones 3 and 4
showed, in general, more potent antifungal activity than
compounds 7 and 9. Thus, the quinone moiety in
phthalazine-5,8-diones 3 and 4 could be essential for
the activity, for example, as nonquinonoid compounds
7 and 9 lost the activity.
In conclusion, phthalazine-5,8-diones 3a–m and 4a–i
were synthesized by nucleophilic substitution of
6,7-dichlorophthalazine-5,8-dione (8) and phthalazine-
5,8-dione (10) with equivalent of arylamine.
6,7-Bis(arylthio)-phthalazine-5,8-diones
4a–i
were
In terms of structure–activity relationship, the 6-
synthesized by nucleophilic substitution on 6,7-dichlo-
ro-phthalazine-5,8-dione (8) with two equivalents of
appropriate arylthiols. Among those tested, many of
compounds 3a–m showed potent antifungal activity
against C. albicans, C. tropicalis, C. krusei, and C. neo-
formans. These phthalazine-5,8-diones may thus be a
promising lead for the development of antifungal
agents. Moreover, the results should encourage the syn-
thesis of phthalazine-5,8-dione analogs for improving
antifungal properties.
arylamino-phthalazine-5,8-diones
a
3
showed,
in
general, more potent antifungal activity than
the other 5,6-bis(arylthio)-phthalazine-5,8-diones 4.
The 6-arylamino-compounds 3 exhibited good activ-
ity, indicating a correlation that may offer insight
into the mode of action of these compounds.
The activity of 6-arylamino-7-chloro-phthalazine-
5,8-diones 3a–h was comparable to that of 6-aryla-
mino-phthalazine-5,8-diones 3i–m. Thus, the 7-chlo-
ro moiety of compounds 3a–h appears to be not
important factor to affect their antifungal activity.
The substituents (R1, R2: H, F, Cl, etc.) for the
6-arylamino and 6,7-bis(arylthio) moieties of com-
pounds 3 and 4 may contribute partially toward
biological potency.
Acknowledgment
This work was supported by Seoul R&BD Program
(10688).