P. R. Patel et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6610–6614
6613
piperidine ring and a –Cl on –Ph has similar activity as
13e against all the organisms except P. aeruginosa and
S. faecalis. Against these two organisms, the –CH3
replacement caused a profound drop in the activity to lev-
els lower than that of 13e.
On the other hand, replacement of the –Cl by a –OCH3
(13g) remarkably enhanced the activity against all the
fungal strains. Against A. flavus and A. niger, 13g dis-
played activity at a minimum inhibitory concentration
of 16 lg mLÀ1. In 13g, substitution of a –CH3 on the
4-position of the piperidine ring (13h) showed no differ-
ence in the activity compared to 13g against A. flavus
and C. albicans, whereas the –CH3 substitution caused
a profound drop in the activity to the level lower than
that of 13g.
On the other hand, substitution of a –OCH3 in place of
the –Cl in 13e remarkably decreased the activity against
all the organisms except B. subtilis. Against B. subtilis,
the –OCH3 substitution noticeably enhanced the activity
displayed by the –Cl substituted analogue 13e. When a
–CH3 was introduced at the 4-position of the piperidine
moiety in 13g, an increase in the activity was observed
against E. coli, S. aureus, and S. faecalis whereas there
was no appreciable difference in the activity noticed
against K. pneumoniae, P. aeruginosa, and B. subtilis.
In summary, syntheses of guanylsulfonamides, 2-amino-
9-[4-(piperidin-1-sulfonyl)phenyl]-1,9-dihydropurin-6-ones,
were accomplished by the combination of three synthon
components. Firstly, the equivalent of synthon B, the
compound 6, was synthesized by the condensation of
guanidine and diethyl malonate, followed by chlorina-
tion, hydrolysis, and nitration reactions. Secondly, the
equivalent of synthon C, the compounds 10a–10h, was
synthesized by acetylation of anilines, followed by chlo-
rosulfonylation, condensation, and hydrolysis reactions.
Eventually, substitution reaction between 6 and 10a–10h
followed by reductive aminoformylation and intramolec-
ular cyclization reactions afforded the guanylsulfona-
mide 13a–13h, respectively. Most of the target chemical
entities 13a–13h exhibit modest antibacterial and anti-
fungal activities against a wide spectrum of pathogenic
bacterial and fungal strains. Particularly, the guanylsulf-
onamides 13e and 13f with –Cl displayed better antibac-
terial efficacy than that of the standard drug Norfloxacin
against S. aureus and S. faecalis, while 13e showed
antibacterial efficacy akin to that of Norfloxacin against
P. aeruginosa. Against the fungal strains A. flavus and A.
niger, the guanylsulfonamides 13g and 13h carrying
–OCH3 exhibited antifungal potency akin to that of the
standard drug Griseoflavin-16 except 13h against A. ni-
ger. The appreciable antibacterial and antifungal effica-
cies of the new guanylsulfonamides deserve further
investigation in order to establish the mode of action.
The antifungal activity of the guanylsulfonamides 13a–
13h on a panel of pathogenic fungal strains such
as Aspergillus flavus (NCIM-539), Aspergillus niger
(NCIM-590), and Candida albicans (NCIM-C27) was
evaluated using twofold serial dilution method. Dimethyl
sulfoxide and Griseoflavin-16, an antifungal drug
commonly used to cure fungal infection affecting the
skin, hair, and nail known as ringworm, were used as sol-
vent control and standard, respectively. The results are
presented in Table 2.
Of the guanylsulfonamides 13a–13h, 13a did not show
activity against all the fungal strains at the maximum
concentration (64 lg mLÀ1). In 13a, a –CH3 substitution
at the 4-position of the piperidine ring (13b) or a –F sub-
stitution at the 2-position of the –Ph (13c) also did not
exhibit activity at the maximum concentration against
all the fungal strains. However, 13d having –CH3 on
the 4-position of the piperidine ring and –F on the 2-po-
sition of the –Ph displayed activity at 64 lg mLÀ1
against A. flavus and C. albicans and at 32 lg mLÀ1
against A. niger.
Introduction of a –Cl instead of the –F on the 2-position
of the –Ph in 13c (resulting in analogue 13d) exhibited
activity at the maximum concentration against all the
fungal strains. In 13e, when the –H at 4-position of
the piperidine ring was replaced by a –CH3 resulting
in analogue 13f, the activity was enhanced to twofold
against A. flavus and A. niger, whereas, the activity
remained unchanged against C. albicans.
Acknowledgment
This work was supported by Korea Research Founda-
tion Grant (KRF-2006-005-J02401).
Supplementary data
Experimental details and characterization data for com-
pounds 8a–8d, 9a–9h, 10a–10h, 11a–11h, 12a–12h, and
13a–13h. Supplementary data associated with this article
Table 2. Antifungal activities of 2-amino-9-[2-substituted-4-(4-substi-
tuted piperidin-1-sulfonyl) phenyl]-1,9-dihydropurin-6-ones (13a–13h)
Compound
X
Y
MIC, lg mLÀ1
A. flavus A. niger C. albicans
13a
13b
H
H
—
—
—
—
—
—
32
64
32
16
32
16
—
—
—
64
64
64
32
32
8
H
CH3
H
13c
13d
F
References and notes
F
Cl
CH3 64
64
CH3 32
16
13e
13f
H
1. Appelbaum, P. C.; Hunter, P. A Int. J. Antimicrob. Agents
2000, 16, 5.
2. Ball, P. J. Antimicrob. Chemother. 2000, 46, 17.
3. (a) Narendra Sharath Chandra, J. N.; Sadashiva, C. T.;
Kavitha, C. V.; Rangappa, K. S. Bioorg. Med. Chem.
Cl
13g
13h
OCH3 H
OCH3 CH3 16
16
Griseoflavin-16