Y.-R. Li et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
Table 4
anti-inflammatory effects at 50 mg/kg administered via the
intraperitoneal route, with inhibition ranging from 58.30% to
93.59%. It is worth noting that compound 7l exhibited the stron-
gest inflammatory inhibition at 93.59%, higher than ibuprofen
(29.56%) and indomethacin (45.23%). Compounds 7h, 7m and 8c
displayed slightly improved activity compared with the reference
drugs. Compounds 8f, 8g, 8i and 8l, however, did not exhibit any
anti-inflammatory activity at the same dosage, indicating that
the aminoguanidine moiety was more beneficial to biological
activity than the furan-2-carbohydrazide moiety.
Anti-inflammatory activity of compounds 7l administered orally at different times
before xylene application
Time(h)
Dose (mg/kg)
Inhibition (%)
Indometacin
7l
1
2
3
4
5
50
50
50
50
50
50
29.69
9.93
23.02
23.60⁄⁄⁄
41.43
34.89⁄⁄
26.87
—
50.86⁄⁄⁄
4.39
35.18
—
24
In view of its considerable anti-inflammatory activity, com-
pound 7l was chosen for further evaluation. A dose of 50 mg/kg
was administered via the oral route at different intervals (1, 2, 3,
4, 5 and 24 h) for xylene application. As shown in Table 4,24 the
activity profile of compound 7l was distinct from that of indo-
methacin, for which the activity showed no regularity as the inter-
val lengthened. The activity of compound 7l peaked at 3 h and
exhibited more potent activity than indomethacin. In addition,
the effect of dosage on the activity of compound 7l was also tested
at concentrations of 12.5, 25 and 50 mg/kg, 3 h after oral adminis-
tration, and showed a maximal effect with an ear inflammation
inhibition rate of 56.67% at 12.5 mg/kg. Whereas lower activity
was observed at 25 mg/kg administered 3 h after xylene applica-
tion (Table 5).24
In conclusion, based on our previous work, three novel series of
1,3-diaryl pyrazole derivatives bearing aminoguanidine or furan-2-
carbohydrazide moieties were synthesized, characterized, and
evaluated for antibacterial (including Gram-positive and Gram-
negative bacterial strains) and anti-inflammatory activities. The
results showed that most compounds exhibited moderate to good
levels of antibacterial and anti-inflammatory activities. In particu-
lar, compounds 6g, 6l and 7l exhibited the greatest antibacterial
activities against Gram-positive bacterial strains (S. aureus RN
4220, S. aureus KCTC 209, S. aureus KCTC 503, S. mutans 3065, MRSA
CCARM 3167 and 3506, QRSA CCARM 3505 and 3519), and Gram-
negative strains (E. coli KCTC 1924, E. coli CCARM 1356, S. typhimur-
ium 2421), and antifungal activity (C. albicans 7535) with MIC val-
**: 0.001 < p < 0.01, ***p < 0.001 compared with vehicle group.
—: no anti-inflammatory activity.
MRSA CCARM 3506, showed the same potency as moxifloxacin
(MIC = 1 g/mL), 4 to 8-fold more potent activity relative to the
standard drug norfloxacin (MIC = 4–8 g/mL), and 64-fold more
potent activity relative to oxacillin (MIC > 64 g/mL). Compounds
6c, 6g, 6h, 6l-n and 7l exhibited 2 to 4-fold more potent activity
relative to gatifloxacin and moxifloxacin (MIC = 4–8 g/mL) with
MIC values of 2 g/mL against QRSA CCARM 3505 and 3519, but
weaker than that of oxacillin (MIC = 1 g/mL). Regretfully, com-
l
l
l
l
l
l
pounds in series 8 did not exhibit any inhibitory activity against
MRSA CCARM (3167 and 3506) and QRSA CCARM (3505 and 3519)
strains.
Analysis of these results revealed several structure–activity
relationships. First, a comparison of the activities across the three
different series of compounds revealed a general order of antibac-
terial activity of 6 > 7 > 8, which indicated that the aminoguanidine
moiety was critical for the anti-bacterial activity of pyrazole
derivatives. Second, none of the pyrazole derivatives previously
reported by our group showed any activity against the Gram-neg-
ative bacteria E. coli 1924 and 1356, and P. aeruginosa 2742 and
2004.5,9 However, the introduction of an aminoguanidine moiety
resulted in moderate to good levels of inhibition against the
Gram-negative strains. In series 7, only the compound 7l exhibited
an equal potency to those compounds (most of which exhibited
strong activity against all of the microorganisms tested) in series
6, indicating that the 2,4-dinitrophenyl moiety is beneficial for
the activity and the chloro substituent at the 3-position might be
critical for the activity. Third, no clear pattern was found for the
structure/activity relationship between the anti-bacterial activity
and the position and physicochemical properties of different sub-
stituents on the phenyl ring, indicating that the electronic effect
of the substituent on the benzene ring is not critical. As a result,
derivatives 6g, 6l and 7l are promising target compounds to be
investigated further.
ues of 1–8 lg/mL, higher than those observed for the positive
controls. Compound 7c exhibited a good level of broad antimicro-
bial inhibition against all of the strains (including P. aeruginosa
2742 and 2004). Regarding anti-inflammatory activity, compound
7l showed the most potent ear inflammation inhibition rate
(93.59%), which was higher than that of ibuprofen (29.56%) and
indomethacin (45.23%) at 50 mg/kg (ip). These results suggested
that introduction of aminoguanidine into the pyrazole ring was
beneficial to antibacterial activity, providing valuable information
for the design of Gram-negative bacteria inhibitors. The mecha-
nism of action of these compounds remains unknown and further
investigations are currently underway in our laboratories.
All of the synthesized compounds were also evaluated for their
anti-inflammatory activity and the results are shown in Table 3.24
In the primary screening, we used dimethyl sulfoxide as the vehicle
and ibuprofen and indomethacin as the reference drugs. In this
test, compounds were screened in a xylene-induced ear-edema
test in mice, in which anti-inflammatory activity was assessed by
the ability of the test compounds to prevent edema. The data
revealed that most of the test compounds showed significant
Acknowledgment
This work was supported by the National Science Foundation of
China (Grant numbers 81260468, 81060257, and 81460524).
Supplementary data
Table 5
Supplementary data associated with this article can be found, in
Anti-inflammatory activity of compound 7l administered orally at different doses
Time (h)
Dose (mg/kg)
Inhibition (%)
Indometacin
7l
53.66⁄⁄⁄
39.28⁄⁄⁄
56.67⁄⁄⁄
52.69⁄⁄⁄
53.89⁄⁄⁄
56.27⁄⁄⁄
References and notes
3
3
3
50
25
12.5
***: p < 0.001 compared with vehicle group.