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Z. Jiang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4090–4094
O
of furan (S1, S4, S5), thiophene (S2) and pyrrole (S3, S6) derivatives
were designed and synthesized. Sampangine was synthesized
according to the procedure of Peterson et al.13 The synthetic route
of sampangine derivatives were depicted in Schemes 1–5. Starting
from 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol (1), it was brom-
ized by Br2 to give dibromo intermediate 2, which was subse-
quently oxidized to quinone intermediate 3. BCD ring
intermediate 5 was obtained through the hetero Diels–Alder reac-
tion of quinone 3 with hydrazone 4, followed by an in situ elimina-
tion of dimethylammonium bromide from the cycloadduct. The
H3C
N
H3C
N
H3C
N
H
N
b
c
a
OBn
OBn
21
OH
22
O
23
20
O
N
H3C
O
H3C
N
N
N
N
d
e
4
condensation of
5 with dimethylformamide dimethyl acetal
O
24
S6
provided furan derivative S1 in good yield. Other sampangine
derivatives were obtained by a similar synthetic strategy using
various starting materials (Schemes 2–5). Based on compound
S2, bromination and chlorination using N-bromosuccinimide
(NBS) and N-chlorosuccinimide (NCS) afforded target compounds
S2a–d (Scheme 6). Subsequently, treating compound S2b with
1-methylpiperazine or CH3ONa yielded compounds S2e and S2f,
respectively. Catalyzed by HOAc, 2-substituted derivatives S2g–j
were obtained by condensation of intermediate 10 with various
aromatic aldehydes and NH4Cl (Scheme 6).
Scheme 5. Reagents and conditions: (a) MeI, NaH, DMF, 25 °C, 5 h, 55%; (b) 5% Pd-C,
MeOH, 40 psi, 25 °C, 4 h, 91%; (c) Fremy’s salt, KH2PO4 aq, acetone/H2O, 3 h, 52%; (d)
xylene, 140 °C, 6 h, 45%; (e) (1) DMFDMA, DMF, 120 °C, 2 h, (2) NH4Cl, HOAc, 120 °C,
1 h, 42% (2 steps).
and sampangine. Compound S2 was more active than fluconazole
and sampangine for Trichophyton rubrum (MIC = 2
lg/mL) and
Microsporum gypseum (MIC = 2 g/mL). SAR analysis revealed that
l
the replacement of D-ring phenyl group of sampangine by 2,2-
dimethyl-2,3-dihydrofuran and thiophene was favorable for the
antifungal activity. Particularly, the thiophene derivative S2
showed potent fungistatic activity with a broad spectrum (MIC
In vitro antifungal assay18 revealed that most of the target com-
pounds, except compound S3, showed broad-spectrum inhibitory
activity against the tested human fungal pathogens (Table 1). Clin-
ically, the treatment of Aspergillus fumigatus infection still remains
a significant challenge in current antifungal therapy. For example,
the first-line antifungal agent fluconazole is inactive against Asper-
range: 0.25–8 lg/mL). In contrast, other furan and pyrrole ana-
logues generally showed decreased antifungal activity. Moreover,
water solubility was also determined for several scaffold hopping
derivatives (Table 1). Most of the compounds showed better solu-
bility than sampangine. Particularly, compound S2, the most active
gillus fumigatus (MIC >64
showed good inhibitory activity (MIC = 1
l
g/mL). In contrast, compound S1 and S2
g/mL), which was also
l
more potent than lead compound sampangine. Cryptococcus neo-
formans infections frequently involve the brain and are often life-
threatening. Compound S2 revealed excellent inhibitory activity
one, also exhibited the best solubility (48
almost four fold higher than that of sampangine (12.6
l
g/mL), which was
l
g/mLÀ1).
Due to potent and broad-spectrum antifungal activity of thio-
phene derivative S2, it was subjected to further SAR analysis
(Table 2). First, various groups were introduced at positions 4
and 9 (S2a–S2f). The results of antifungal assay revealed that the
attachment of bromine on position 4 (S2b) or 9 (S2a) resulted in
the decreased antifungal activity. Similarly, the presence of 4-
methylpiperazinyl (S2e) or 4-methyloxyl (S2f) groups at position
4 was also unfavorable for the antifungal activity. Interestingly,
against Cryptococcus neoformans with a MIC value of 0.25
lg/mL,
whose activity was comparable to fluconazole (MIC = 0.25
lg/mL)
and superior to sampangine (MIC = 2 lg/mL). On the strains of Can-
dida spp., the sampangine derivatives generally showed decreased
activity. Only compound S1 was highly active against Candida glab-
rata (MIC = 0.125 lg/mL). For the dermatophytes, most of the com-
pounds were moderately active, which was similar to fluconazole
O
O
O
O
N
N
c
a
b
H3C
N
H3C
N
H3C
CH3
N
H
N
4
HO2C
N
O
O
CH3
O
S3
11
13
12
Scheme 3. Reagents and conditions: (a) sarcosine, paraformaldehyde, toluene, reflux (Dean Stark), 4.5 h, 15%; (b) xylene, 140 °C, 6 h, 39%; (c) (1) DMFDMA, DMF, 120 °C, 2 h,
(2) NH4Cl, HOAc, 120 °C, 1 h, 62% (2 steps).
O
c
a
b
d
HO2C
O
O
O
4
O
OCH3
OH
N
OCH3
O
14
15
16
17
O
O
O
O
N
N
O
N
O
e
+
+
O
O
N
N
O
CH3
O
CH3
19
S4
S5
18
Scheme 4. Reagents and conditions: (a) Cu, quinoline, 240 °C, 2 h, 64%; (b) BBr3, DCM, À78 °C, 2 h, 50%; (c) Fremy’s salt, KH2PO4 aq, acetone/H2O, 1 h, 42%; (d) xylene, 140 °C,
6 h, 35%; (e) (1) DMFDMA, DMF, 120 °C, 2 h, (2) NH4Cl, HOAc, 120 °C, 1 h, 58% (2 steps).