A series of naphthalimide azoles: Design, synthesis and bioactive evaluation as potential antimicrobial agents

Article abstract of DOI:10.1007/s11426-013-4873-1

A series of naphthalimide azoles as potential antibacterial and antifungal agents were conveniently and efficiently synthesized starting from commercially available 6-bromobenzo[de]isochromene-1,3-dione. All the new compounds were characterized by NMR, IR

Full text of DOI:10.1007/s11426-013-4873-1

SCIENCE CHINA
Chemistry
July 2013 Vol.56 No.7: 952–969
doi: 10.1007/s11426-013-4873-1
• ARTICLES •
A series of naphthalimide azoles: Design, synthesis and bioactive
evaluation as potential antimicrobial agents
DAMU Guri L. V.1†§, WANG QingPeng1§, ZHANG HuiZhen1§, ZHANG YiYi1,
LV JingSong1, 2* & ZHOU ChengHe1*
1School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
2School of Chemistry and Chemical Engineering, Bijie University, Guizhou 551700, China
Received December 31, 2012; accepted February 20, 2013; published online April 17, 2013
A series of naphthalimide azoles as potential antibacterial and antifungal agents were conveniently and efficiently synthesized
starting from commercially available 6-bromobenzo[de]isochromene-1,3-dione. All the new compounds were characterized by
NMR, IR, MS and HRMS spectra. Their antimicrobial activities were evaluated against four Gram-positive bacteria, four
Gram-negative bacteria and two fungi using two-fold serial dilution technique. The biological assay indicated that most of the
prepared compounds exhibited inhibition to the tested strains. In particular, the triazolium derivatives not only gave higher ef-
ficacy than their corresponding precursory azoles, but also demonstrated comparable or even better potency than the reference
drugs Chloromycin, Orbifloxacin and Fluconazole. Some factors including structural fragments, pH and ClogP values of the
target molecules were also preliminarily discussed.
naphthalimide, triazole, imidazole, triazolium, imidazolium, thiol, thione, antibacterial, antifungal, antimicrobial
tioxidative [16] ones and so on. Numerous efforts have been
1 Introduction
oriented to the development of naphthalimide derivatives as
potential drugs, such as Amonafide, Mitonafide, Elinafide
and Bisnafide [17] with remarkable anti-cancer activitities
through interactions with DNA [18, 19]. This provoked
great interest to expand the potential use of naphthalimides
in other medicinal aspects especially as a new type of anti-
bacterial and antifungal drugs. Recent research revealed that
the combination of naphthalimide with six-membered
nitrogen-heterocycle like piperazinyl moiety led to remark-
able enhancement of antibacterial and antifungal activities, as
well as broad bioactive spectrum of target compounds [20].
Heterocyclic triazole compounds have attracted increas-
ing attention for their large antimicrobial potentiality, espe-
cially as antifungal agents for the treatment of infective
diseases [21]. Some triazole drugs such as Fosfluconazole,
Voriconazole and so on are extensively employed as anti-
fungal agents in clinic [22, 23]. However, drug resistances
due to the extensive use of these drugs have seriously in-
Naphthalimide derivatives are being actively investigated
for their spacious potential in medicinal chemistry [1–3],
supramolecular recognization and assembly [4–6] and ma-
terial sciences [7, 8]. The special structural characteristics of
naphthalimide moiety with a naphthalene framework and
imide moiety endow its derivatives with desirable large
π-conjugated backbone and strong hydrophobicity. There-
fore, the naphthalimides could easily exert diverse weak
interactions such as π-π stacking and hydrogen bonds with
various enzymes and receptors in biological organisms [9,
10]. For example, naphthalimide-based derivatives exhibit-
ed various bioactivities including anticancer [11], antimi-
crobial [12, 13], antitrypanosomal [14], analgesic [15], an-
†Postdoctoral fellow from Indian Institute of Chemical Technology (IICT), India
§The three authors contributed equally to this work
*Corresponding authors (email: zhouch@swu.edu.cn, ljs1234@swu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2013
chem.scichina.com www.springerlink.com

Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
953
fluenced their therapeutic effects, thus the pursuit of new
azole derivatives, especially novel chemical matter with
potential distinct action mechanisms, has aroused great in-
terest in medicinal chemistry [24, 25]. Our recent primary
work [26] manifested that some structurally simple naph-
thalimides in combination with five-membered triazole ring
exhibited prominent antimicrobial efficacy especially to-
wards the drug-resistant bacterium MRSA. Herein a series
of naphthalimide triazole compounds including alkyl, aryl,
sulfur-substituted triazoles and their triazolium derivatives
as well as some imidazole analogs of triazoles were synthe-
sized and evaluated for their antibacterial and antifungal
efficacy.
Thio-triazole moiety, which was found to be helpful for
bioactivity, was introduced by displacing the bromo group
in naphthalimide to yield compounds 4a–c.
(5) It was reported that the conversion of triazoles into
triazoliums would reinforce water solubility and modulate
physicochemical properties, thus improving antibacterial
and antifungal efficacy and broadening antimicrobial spec-
trum [39, 40]. Reasonably, the naphthalimide triazoles were
transformed into corresponding triazoliums by diverse ha-
lobenzyl halides.
(6) Imidazole as a bioisostere of triazole has been exten-
sively used in drug design, and some imidazole drugs like
Miconazole, Econazole and Ketoconazole have been play-
ing important roles in the treatment of fungal infections [41,
42]. Hence, the naphthalimide imidazoles and imidazoliums
as analogs of the triazoles and triazoliums were prepared to
evaluate their antimicrobial efficiency.
The synthetic routes of target naphthalimide azole deriv-
atives and the corresponding azoliums were shown in
Scheme 1.
Our target molecules were designed on the bases of the
following considerations (see Figure 1):
(1) The prominent antimicrobial activities of triazole
compounds [27, 28] might be mainly ascribed to the triazole
ring. The unique aromatic triazole moiety could readily ex-
ert the adjustable interactions with various enzymes and
receptors in biosystem by diverse non-covalent forces such
as hydrogen bond, π-π stacking, ion-dipole, hydrophobic
effect, van der Waals force and so on [29, 30]. In addition,
naphthalimide nucleus recently proved to play important
roles via various weak non-covalent interactions in antibac-
terial and antifungal aspects [31, 32], and its derivatives
exhibited excellent potency as a new type of antimicrobial
drugs. Therefore, it was of great interest to combine triazole
moiety with naphthalimide fragment to generate a series of
hybrids as potential antimicrobial agents.
(2) With the aim of exploring suitable linker connecting
the naphthalimide and triazole moiety for better antimicro-
bial activity [33], variable aliphatic chains in different
lengths were incorporated to naphthalimide triazole system.
(3) Many literatures have showed that substituents on
triazole ring remarkably affected the antimicrobial efficacy
of triazole compounds [34–36]. Therefore, diverse substit-
uents such as alkyl, aryl, thioether and thione groups were
investigated for their contribution to antimicrobial activities.
(4) The substitution at naphthalimide core could impact
the electron density and influence their interactions with
cells and tissues, thus affecting the bioactivities [37, 38].
2 Experimental
2.1 Materials and measurements
Melting points were recorded on X–6 melting point appa-
ratus and uncorrected. TLC analysis was done using
pre-coated silica gel plates. FT-IR spectra were carried out
on Bruker RFS100/S spectrophotometer (Bio-Rad, Cam-
bridge, MA, USA) using KBr pellets in the 400–4000 cm–1
range. NMR spectra were recorded on a Bruker AV 300 or
Varian 400 spectrometer using TMS as an internal standard;
NAPH = naphthalimide, Ph = phenyl ring, Im = imidazole
group and Ar = aromatic ring. The chemical shifts were
reported in parts per million (ppm), the coupling constants
(J) are expressed in hertz (Hz) and signals were described as
singlet (s), doublet (d) and triplet (t) as well as multiplet (m).
The mass spectra (MS) were recorded on LCMS–2010A
and the high-resolution mass spectra (HRMS) were record-
ed on an IonSpec FT-ICR mass spectrometer with ESI re-
source. All commercially available chemicals and solvents
were used without further purification.
2.2 Synthesis
6-Bromo-1H-benzo[de]isoquinoline-1,3(2H)-dione (2)
A mixture of 6-bromobenzo[de]isochromene-1,3-dione 1
(15.0 g, 54.1 mmol) and aqueous ammonia (500 mL) was
heated at 45 °C for 8 h. TLC (eluent: chloroform) showed
the reaction was complete. The mixture was cooled to the
room temperature, the resulting solid was collected by fil-
tration and dried to give crude product 2 (14.2 g) as brown
powder, which was used in the following reaction without
further purification. Yield: 95.2%; mp: 297–298 °C in
Figure 1 Design of target naphthalimide azoles.

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Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
Scheme 1 Synthetic routes of naphthalimide triazoles 2–11. Conditions and reagents: i) aqueous ammonia, 45 °C, 8 h; ii) alkyl dibromide, K2CO3, THF,
40 °C, 12 h; iii) halobenzyl triazole-thiol, KOH, DMF, 100 °C, 12 h; iv) 1,2,4-triazole, K2CO3, CH3CN, 40 °C, 12 h; v) imidazole, NaH, THF, 65 °C, 12 h; vi)
halobenzyl triazole-thiol, K2CO3, CH3CN, 40 °C, 12 h; vii) halobenzyl halide, CH3CN, reflux, 24 h; viii) 2,4-difluorobenzyl bromide, CH3CN, reflux, 24 h;
ix) 2,4-difluorobenzyl bromide, CH3CN, reflux, 24 h.
agreement with the commercial material (mp: 296–297 °C)
[26].
6-Bromo-2-(4-bromobutyl)-1H-benzo[de]isoquinoline-1,3
(2H)-dione (3b)
Compound 3b was prepared according to the procedure
described for compound 3a, starting from compound 2 (1.42
g, 5.0 mmol), 1,4-dibromobutane (1.19 g, 5.5 mmol) and
potassium carbonate (1.04 g, 7.5 mmol). The pure product
3b (1.57 g) was obtained as pale yellow solid. Yield: 76.3%;
mp: 137−138 °C; IR (KBr) ν: 3120, 3099 (Ar–H), 2964,
6-Bromo-2-(3-bromopropyl)-1H-benzo[de]isoquinoline-1,3
(2H)-dione (3a)
A mixture of compound 2 (1.42 g, 5.0 mmol) and potassium
carbonate (1.04 g, 7.5 mmol) in DMF (15 mL) was stirred at
60 °C for 20 min, then 1,3-dibromopropane (1.10 g, 5.5
mmol) was added. The resulting mixture was stirred for
another 8 h at 40 °C. After the reaction came to the end
(monitored by TLC, eluent: chloroform/petroleum = 1/4,
V/V), the mixture was cooled to room temperature and ex-
tracted with dichloromethane (3 × 30 mL). The combined
organic extracts were washed with water (2 × 20 mL), dried
over anhydrous sodium sulfate, and concentrated under the
reduced pressure to give the crude product, which was fur-
ther purified by silica gel column chromatography (eluent:
chloroform/petroleum = 3/1, V/V) to afford the desired
compound 3a (1.41 g) as pale yellow solid. Yield: 71.0%;
mp: 154−156 °C in agreement with the literature (mp:
154−155 °C) [1].
2855 (CH2), 1659 (C
=O), 1591, 1570, 1510, 1457 (aro-
1
matic frame), 1351, 1234, 1104,1061, 763, 621 cm–1; H
NMR (400 MHz, CDCl3) δ(ppm): 8.67 (d, 1H, J = 7.1 Hz,
NAPH-H), 8.59 (d, 1H, J = 8.3 Hz, NAPH-H), 8.42 (d, 1H,
J = 7.8 Hz, NAPH-H), 8.06 (d, 1H, J = 7.8 Hz, NAPH-H),
7.87 (t, 1H, J = 7.9 Hz, NAPH-H), 4.22 (t, 2H, J = 7.9 Hz,
NAPH-CH2), 3.48 (t, 2H, J = 7.4 Hz, BrCH2), 1.99−1.91 (m,
4H, BrCH2CH2CH2); ESI-MS (m/z): 410/412/414 (1/2/1)
[M+H]+; HRMS (ESI) calcd. for C16H13Br2NO2 [M+H]+,
409.9391; found, 409.9394.
6-Bromo-2-(5-bromopentyl)-1H-benzo[de]isoquinoline-1,3
(2H)-dione (3c)
Compound 3c was prepared according to the procedure de-

Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
955
scribed for compound 3a, starting from compound 2 (1.42 g,
5.0 mmol), 1,5-dibromopentane (1.26 g, 5.5 mmol) and po-
tassium carbonate (1.04 g, 7.5 mmol). The pure product 3c
(1.41 g) was obtained as pale yellow solid. Yield: 68.1%;
mp: 123−124 °C; IR (KBr) ν: 3210, 3100 (Ar–H), 2965,
2856 (CH2), 1659 (C=O), 1571, 1500, 1461 (aromatic
frame), 1349, 1227, 967, 773, 621 cm–1; 1H NMR (300 MHz,
CDCl3) δ(ppm): 8.65 (d, 1H, J = 7.1 Hz, NAPH-H), 8.58 (d,
1H, J = 8.4 Hz, NAPH-H), 8.41 (d, 1H, J = 7.7 Hz,
NAPH-H), 8.06 (d, 1H, J = 7.7 Hz, NAPH-H), 7.85 (t, 1H, J
= 7.9 Hz, NAPH-H), 4.26 (t, 2H, J = 7.1 Hz, NAPH-CH2),
3.40 (t, 2H, J = 7.4 Hz, BrCH2), 1.98−1.86 (m, 4H,
Br-CH2CH2CH2CH2), 1.79−1.75 (m, 2H, BrCH2CH2CH2);
ESI-MS (m/z): 424/426/428 (1/2/1) [M+H]+; HRMS
(ESI) calcd. for C17H15Br2NO2 [M+H]+, 423.9548; found,
423.9553.
form). The reaction mixture was cooled to room tempera-
ture, the resultant yellow precipitate was collected by filtra-
tion, washed with water (3 × 30 mL) and chloroform (3 ×
20 mL). The pure product 4a (0.75 g) was obtained as yel-
low solid. Yield: 82.1%; mp: 234−236 °C; IR (KBr) ν: 3176,
3110, 3069 (N–H, Ar–H), 2847 (CH2), 1705, 1693 (C=O),
1588, 1515, 1488 (aromatic frame), 1377, 1001, 846, 782,
758, 716, 645 cm–1; 1H NMR (300 MHz, DMSO-d6) δ(ppm):
11.85 (s, 1H, NAPH NH), 9.24 (s, 1H, S-Tri 5-H),
8.51−8.49 (m, 2H, NAPH-H), 8.23 (d, 1H, J = 7.8 Hz,
NAPH-H), 8.02 (d, 1H, J = 7.7 Hz, NAPH-H), 7.88 (t, 1H, J
= 7.8 Hz, NAPH-H), 7.67 (s, 1H, 2,4-Cl2Ph 3-H), 7.60 (d,
1H, J = 7.8 Hz, 2,4-Cl2Ph 5-H), 7.42 (d, 1H, J = 7.8 Hz,
2,4-Cl2Ph 6-H), 4.51 (s, 2H, CH2); ESI-MS (m/z): 456
[M+H]+; HRMS (ESI) calcd. for C21H12Cl2N4O2S [M+H]+,
455.0136; found, 455.0135.
6-Bromo-2-(6-bromohexyl)-1H-benzo[de]isoquinoline-1,3
6-(1-(3,4-Dichlorobenzyl)-1H-1,2,4-triazol-3-ylthio)-1H-be-
(2H)-dione (3d)
nzo[de]isoquinoline-1,3(2H)-dione (4b)
Compound 3d was prepared according to the procedure
described for compound 3a, starting from compound 2 (1.42
g, 5.0 mmol), 1,6-dibromohexane (1.34 g, 5.5 mmol) and
potassium carbonate (1.04 g, 7.5 mmol). The pure product
3d (1.54 g) was obtained as white solid. Yield: 70.0%;
mp: 119−120 °C in agreement with the literature (mp:
119−120 °C) [1].
Compound 4b was prepared according to the procedure
described for compound 4a starting from compound 2 (0.55
g, 2.0 mmol), 1-(3,4-dichlorobenzyl)-1H-1,2,4-triazole-3-
thiol (0.57 g, 2.2 mmol) and potassium hydroxide (0.13 g,
2.4 mmol). The pure product 4b (0.78 g) was obtained as
yellow solid. Yield: 86.8%; mp: 146−148 °C; IR (KBr) ν:
3181, 3107, 3070 (N–H, Ar–H), 2848 (CH2), 1703 (C=O),
1588, 1513, 1487 (aromatic frame), 1372, 1216, 1032, 846,
783, 715, 646 cm–1; 1H NMR (300 MHz, DMSO-d6) δ(ppm):
11.93 (s, 1H, NAPH NH), 9.22 (s, 1H, S-Tri 5-H),
8.53−8.51 (m, 2H, NAPH-H), 8.21 (d, 1H, J = 8.4 Hz,
NAPH-H), 8.02 (d, 1H, J = 7.8 Hz, NAPH-H), 7.87 (t, 1H, J
= 8.1 Hz, NAPH-H), 7.76–7.72 (m, 1H, 3,4-Cl2Ph 5-H),
7.52–7.44 (m, 2H, 3,4-Cl2Ph 2,6-H), 4.45 (s, 2H, CH2);
ESI-MS (m/z): 456 [M+H]+, HRMS (ESI) calcd. for
C21H12Cl2N4O2S [M+H]+, 455.0136; found, 455.0136.
6-Bromo-2-(8-bromooctyl)-1H-benzo[de]isoquinoline-1,3
(2H)-dione (3e)
Compound 3e was prepared according to the procedure de-
scribed for compound 3a, starting from compound 2 (1.42 g,
5.0 mmol), 1,8-dibromooctane (1.49 g, 5.5 mmol) and po-
tassium carbonate (1.04 g, 7.5 mmol). The pure product 3e
(1.66 g) was obtained as white solid. Yield: 71.3%; mp:
121−124 °C; IR (KBr) ν: 3111, 3087 (Ar–H), 2975, 2863
(CH2), 1662 (C=O), 1585, 1571, 1503, 1466 (aromatic
1
frame), 1350, 1230, 1104,1082, 785, 748, 630 cm–1; H
6-(1-(2,4-Difluorobenzyl)-1H-1,2,4-triazol-3-ylthio)-1H-ben-
NMR (300 MHz, CDCl3) δ(ppm): 8.64 (d, 1H, J = 7.0 Hz,
NAPH-H), 8.56 (d, 1H, J = 8.2 Hz, NAPH-H), 8.41 (d, 1H,
J = 7.6 Hz, NAPH-H), 8.07 (d, 1H, J = 7.6 Hz, NAPH-H),
7.88 (t, 1H, J = 8.0 Hz, NAPH-H), 4.18 (t, 2H, J = 7.2 Hz,
NAPH-CH2), 3.41 (t, 2H, J = 7.4 Hz, BrCH2), 1.96−1.68 (m,
4H, BrCH2CH2(CH2)4CH2), 1.34−1.20 (m, 8H, BrCH2 (CH2)4);
ESI-MS (m/z): 466/468/470 (1/2/1) [M+H]+; HRMS (ESI)
calcd. for C20H21Br2NO2 [M+H]+, 464.9939; found,
464.9935.
zo[de]isoquinoline-1,3(2H)-dione (4c)
Compound 4c was prepared according to the procedure de-
scribed for compound 4a starting from compound 2 (0.55 g,
2.0 mmol), 1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-thiol
(0.50 g, 2.2 mmol) and potassium hydroxide (0.13 g, 2.4
mmol). The pure product 4c (0.64 g) was obtained as yellow
solid. Yield: 75.7%; mp: 223−226 °C; IR (KBr) ν: 3175,
3108, 3072 (N–H, Ar–H), 2852 (CH2), 1709, 1684 (C=O),
1589, 1501, 1487, 1432 (aromatic frame), 1374, 1219, 1137,
967, 851, 784, 716, 644 cm–1; 1H NMR (300 MHz,
DMSO-d6) δ(ppm): 11.90 (s, 1H, NAPH NH), 9.20 (s, 1H,
S-Tri 5-H), 8.50−8.47 (m, 2H, NAPH-H), 8.23 (d, 1H, J =
8.4 Hz, NAPH-H), 8.00 (d, 1H, J = 7.7 Hz, NAPH-H), 7.87
(t, 1H, J = 7.8 Hz, NAPH-H), 7.60−7.52 (m, 1H, 2,4-F2Ph
3-H), 7.28−7.03 (m, 2H, 2,4-F2Ph 5,6-H), 4.43 (s, 2H, CH2);
ESI-MS (m/z): 423 [M+H]+; HRMS (ESI) calcd. for
C21
6-(1-(2,4-Dichlorobenzyl)-1H-1,2,4-triazol-3-ylthio)-1H-be-
nzo[de]isoquinoline-1,3(2H)-dione (4a)
A
mixture of 1-(2,4-dichlorobenzyl)-1H-1,2,4-triazole-
3-thiol (0.57 g, 2.2 mmol) and potassium hydroxide (0.13 g,
2.4 mmol) in DMF (10 mL) was stirred at 60 °C for 20 min,
then compound 2 (0.55 g, 2.0 mmol) was added. After that,
the mixture was heated at 100 °C for about 12 h until the
reaction was completed (monitored by TLC, eluent: chloro-
H12F2N4O2S [M+H]+, 423.0727; found, 423.0725.

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Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
2-(3-(1H-1,2,4-Triazol-1-yl)propyl)-6-bromo-1H-benzo[de]
isoquinoline-1,3(2H)-dione (5a)
Tri-CH2CH2CH2); ESI-MS (m/z): 413/415 (1/1) [M+H]+;
HRMS (ESI) calcd. for C19H17BrN4O2 [M+H]+, 413.0613;
found, 413.0610.
A mixture of 1H-1,2,4-triazole (0.50 g, 2.2 mmol) and po-
tassium carbonate (0.35 g, 2.5 mmol) in acetonitrile (10 mL)
was stirred at 60 °C for 20 min, then cooled to room tem-
perature. Compound 3a (0.79 g, 2.0 mmol) was added and
the resulting mixture was stirred at 40 °C. After the reaction
came to the end (monitored by TLC, eluent: chloro-
form/petroleum = 1/3, V/V), the mixture was cooled to room
temperature, evaporated under the reduced pressure and
extracted with dichloromethane (3 × 30 mL). The combined
organic phase was dried over anhydrous sodium sulfate and
concentrated. The resulting residue was purified via silica
gel column chromatography (eluent: chloroform/methanol
= 30/1, V/V) to give compound 5a (0.58 g) as white solid.
Yield: 75.0%; mp: 193−194 °C in agreement with the liter-
ature (mp: 193−194 °C) [26].
2-(6-(1H-1,2,4-Triazol-1-yl)hexyl)-6-bromo-1H-benzo[de]iso-
quinline-1,3(2H)-dione (5d)
Compound 5d was prepared according to the procedure
described for compound 5a, starting from compound 3d
(0.88 g, 2.0 mmol), 1H-1,2,4-triazole (0.50 g, 2.2 mmol)
and potassium carbonate (0.35 g, 2.5 mmol). The pure
product 5d (0.65 g) was obtained as white solid. Yield:
76.0%; mp: 181–182 °C in agreement with the literature
(mp: 181–182 °C) [1].
2-(8-(1H-1,2,4-Triazol-1-yl)octyl)-6-bromo-1H-benzo[de]iso-
quinoline-1,3(2H)-dione (5e)
Compound 5e was prepared according to the procedure de-
scribed for compound 5a, starting from compound 3e (0.93
g, 2.0 mmol), 1H-1,2,4-triazole (0.50 g, 2.2 mmol) and po-
tassium carbonate (0.35 g, 2.5 mmol). The pure product 5e
(0.68 g) was obtained as white solid. Yield: 74.6%; mp:
184–187 °C; IR (KBr) ν: 3017 (Ar–H), 2985, 2934 (CH2),
1711, 1655 (C=O), 1586, 1503, 1460 (aromatic frame),
2-(4-(1H-1,2,4-Triazol-1-yl)butyl)-6-bromo-1H-benzo[de]iso-
quinoline-1,3(2H)-dione (5b)
Compound 5b was prepared according to the procedure
described for compound 5a, starting from compound 3b
(0.82 g, 2.0 mmol), 1H-1,2,4-triazole (0.50 g, 2.2 mmol)
and potassium carbonate (0.35 g, 2.5 mmol). The pure
product 5b (0.57 g) was obtained as white solid. Yield:
71.3%; mp: 158–160 °C; IR (KBr) ν: 3087 (Ar-H), 2981,
2934 (CH2), 1715, 1655 (C=O), 1589, 1507, 1482 (aromatic
frame), 1340, 1270, 1222, 1143, 1067, 869, 780, 714 cm–1;
1H NMR (400 MHz, CDCl3) δ(ppm): 8.65 (d, 1H, J = 7.6
Hz, NAPH-H), 8.58 (d, 1H, J = 8.2 Hz, NAPH-H), 8.41 (d,
1H, J = 7.8 Hz, NAPH-H), 8.19 (s, 1H, Tri 3-H), 8.05 (d,
1H, J = 7.8 Hz, NAPH-H), 7.94 (s, 1H, Tri 5-H), 7.85 (t, 1H,
J = 8.0 Hz, NAPH-H), 4.29 (t, 2H, J = 7.2 Hz, NAPH-CH2),
4.22(t, 2H, J = 7.4 Hz, Tri-CH2), 2.04−1.97 (m, 2H,
Tri-CH2CH2), 1.80−1.73 (m, 2H, NAPH-CH2CH2); ESI-MS
(m/z): 399/401 (1/1) [M+H]+; HRMS (ESI) calcd. for
C18H15BrN4O2 [M+H]+, 399.0457; found, 399.0452.
1
1362, 1225, 872, 781, 750, 679 cm–1; H NMR (300 MHz,
CDCl3) δ(ppm): 8.67 (d, 1H, J = 8.4 Hz, NAPH-H), 8.54 (d,
1H, J = 7.4 Hz, NAPH-H), 8.42 (d, 1H, J = 7.9 Hz,
NAPH-H), 8.11 (s, 1H, Tri 3-H), 8.07 (d, 1H, J = 7.9 Hz,
NAPH-H), 7.99 (s, 1H, Tri 5-H), 7.85 (t, 1H, J = 8.1 Hz,
NAPH-H), 4.19−4.13 (m, 4H, Tri-CH2(CH2)6CH2), 1.95−
1.91 (m, 2H, Tri-CH2CH2), 1.73−1.70 (m, 2H, NAPH-
CH2CH2), 1.41−1.34 (m, 8H, Tri-CH2CH2(CH2)4); ESI-MS
(m/z): 455/457 (1/1) [M+H]+; HRMS (ESI) calcd. for
C22H23BrN4O2 [M+H]+, 455.1083; found, 455.1087.
2-(3-(1H-Imidazol-1-yl)propyl)-6-bromo-1H-benzo[de]iso-
quinoline-1,3(2H)-dione (6a)
To a stirring suspension of sodium hydride (0.06 g, 2.5
mmol) in THF (10 mL) was added 1H-imidazole (0.15 g,
2.2 mmol). The mixture was heated at 60 °C for 20 min and
then cooled to room temperature. Compound 3a (0.79 g, 2.0
mmol) was added and the reaction system was stirred at
65 °C under nitrogen. After the reaction came to the end
(monitored by TLC, eluent: chloroform/methanol = 10/1,
V/V), the resultant mixture was quenched with ice water and
neutralized by 2 mol/L HCl. The solution was extracted
with dichloromethane (3 × 30 mL), the combined organic
extracts were washed with brine, dried over sodium sulfate
and concentrated. The residue was purified via silica gel
column chromatography (eluent: chloroform/methanol =
10/1, V/V) to afford the desired product 6a (0.58 g) as white
solid. Yield: 60.9%; mp: 186−187 °C; IR (KBr) ν: 3210
(Ar–H), 2856 (CH2), 1659 (C=O), 1595, 1573, 1498, 1452
(aromatic frame), 1340, 1225, 967, 713, 631 cm–1; 1H NMR
(300 MHz, CDCl3) δ(ppm): 8.64 (d, 1H, J = 7.2 Hz,
NAPH-H), 8.57 (d, 1H, J = 8.4 Hz, NAPH-H), 8.40 (d, 1H,
2-(5-(1H-1,2,4-Triazol-1-yl)pentyl)-6-bromo-1H-benzo[de]iso-
quinoline-1,3(2H)-dione (5c)
Compound 5c was prepared according to the procedure de-
scribed for compound 5a, starting from compound 3c (0.85
g, 2.0 mmol), 1H-1,2,4-triazole (0.50 g, 2.2 mmol) and po-
tassium carbonate (0.35 g, 2.5 mmol). The pure product 5c
(0.64 g) was obtained as white solid. Yield: 76.8%; mp:
153–154 °C; IR (KBr) ν: 3074 (Ar–H), 2981, 2934 (CH2),
1715, 1654 (C=O), 1589, 1507, 1400 (aromatic frame),
1
1361, 1340, 1223, 1144, 1013, 869, 779, 749, 679 cm–1; H
NMR (400 MHz, CDCl3) δ(ppm): 8.65 (d, 1H, J = 7.6 Hz,
NAPH-H), 8.58 (d, 1H, J = 8.1 Hz, NAPH-H), 8.41 (d, 1H,
J = 7.8 Hz, NAPH-H), 8.14 (s, 1H, Tri 3-H), 8.05 (d, 1H, J
= 7.8 Hz, NAPH-H), 7.93 (s, 1H, Tri 5-H), 7.86 (t, 1H, J =
7.9 Hz, NAPH-H), 4.23−4.15 (m, 4H, NAPH-
CH2(CH2)3CH2), 2.06−1.98 (m, 2H, Tri-CH2CH2), 1.83−
1.76 (m, 2H, NAPH-CH2CH2), 1.48−1.41 (m, 2H,

Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
957
J = 7.8 Hz, NAPH-H), 8.04 (d, 1H, J = 7.8 Hz, NAPH-H),
7.85 (t, 1H, J = 8.0 Hz, NAPH-H), 7.59 (s, 1H, Im 2-H),
7.04 (s, 1H, Im 5-H), 7.01 (s, 1H, Im 4-H), 4.20−4.24 (t, 2H,
J = 7.2 Hz, NAPH-CH2), 4.11−4.06 (t, 2H, J = 7.4 Hz,
Im-CH2), 2.31−2.21 (m, 2H, Im-CH2CH2); ESI-MS (m/z):
384/386 (1/1) [M+H]+; HRMS (ESI) calcd. for
C18H16BrN3O2 [M+H]+, 384.0348; found, 384.0343.
148–150 °C in agreement with the literature (mp:
148–150 °C) [26].
2-(8-(1H-Imidazol-1-yl)octyl)-6-bromo-1H-benzo[de]isoqui-
noline-1,3(2H)-dione (6e)
Compound 6e was prepared according to the procedure de-
scribed for compound 6a, starting from compound 3e (0.93
g, 2.0 mmol), 1H-imidazole (0.15 g, 2.2 mmol) and potas-
sium carbonate (0.35 g, 2.5 mmol). The pure product 6e
(0.74 g) was obtained as white solid. Yield: 65.7%; mp:
137–139 °C; IR (KBr) ν: 3115 (Ar–H), 2933, 2854 (CH2),
1670, 1659 (C=O), 1589, 1551, 1487 (aromatic frame),
1345, 1229, 1109, 1072, 751, 713, 664 cm–1; 1H NMR (300
MHz, CDCl3) δ(ppm): 8.66 (d, 1H, J = 7.2 Hz, NAPH-H),
8.60 (d, 1H, J = 8.3 Hz, NAPH-H), 8.43 (d, 1H, J = 7.7 Hz,
NAPH-H), 8.04 (d, 1H, J = 7.7 Hz, NAPH-H), 7.87 (t, 1H, J
= 7.9 Hz, NAPH-H), 7.51 (s, 1H, Im 2-H), 7.07 (s, 1H, Im
5-H), 6.96 (s, 1H, Im 4-H), 4.17 (t, 2H, J = 7.2 Hz,
NAPH-CH2), 3.95 (t, 2H, J = 7.2 Hz, Im-CH2), 1.77−1.74
(m, 4H, NAPH-CH2CH2, Im-CH2CH2), 1.46−1.38 (m, 8H,
Im-CH2CH2(CH2)4); ESI-MS (m/z): 454/456 (1/1) [M+H]+;
HRMS (ESI) calcd. for C20H18BrN3O2 [M+H]+, 454.1130;
found, 454.1126.
2-(4-(1H-Imidazol-1-yl)butyl)-6-bromo-1H-benzo[de]isoqui-
noline-1,3(2H)-dione (6b)
Compound 6b was prepared according to the procedure
described for compound 6a, starting from compound 3b
(0.82 g, 2.0 mmol), 1H-imidazole (0.15 g, 2.2 mmol) and
potassium carbonate (0.35 g, 2.5 mmol). The pure product
6b (0.51 g) was obtained as white solid. Yield: 63.3%; mp:
168–169 °C; IR (KBr) ν: 3110 (Ar-H), 2956, 2856 (CH2),
1660 (C=O), 1570, 1503, 1465 (aromatic frame), 1341,
1230, 967, 751, 743, 624 cm–1; 1H NMR (300 MHz, CDCl3)
δ(ppm): 8.66 (d, 1H, J = 7.4 Hz, NAPH-H), 8.60 (d, 1H, J =
8.4 Hz, NAPH-H), 8.42 (d, 1H, J = 7.7 Hz, NAPH-H), 8.06
(d, 1H, J = 7.7 Hz, NAPH-H), 7.87 (t, 1H, J = 8.0 Hz,
NAPH-H), 7.53 (s, 1H, Im 2-H), 7.06 (s, 1H, Im 5-H), 6.95
(s, 1H, Im 4-H), 4.22 (t, 2H, J = 6.9 Hz, NAPH-CH2), 4.04
(t, 2H, J = 7.1 Hz, Im-CH2), 1.94−1.85 (m, 2H, Im-
CH2CH2), 1.81−1.74 (m, 2H, NAPH-CH2CH2); ESI-MS
(m/z): 398/400 (1/1) [M+H]+; HRMS (ESI) calcd. for
C19H17BrN3O2 [M+H]+, 398.0504; found, 398.0500.
6-Bromo-2-(4-(1-(2,4-dichlorobenzyl)-1H-1,2,4-triazol-3-
ylthio)butyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (7a)
A mixture of 1-(2,4-dichlorobenzyl)-1H-1,2,4-triazole-3-
thiol (0.64 g, 2.4 mmol) and potassium carbonate (0.41 g,
3.0 mmol) in acetonitrile (10 mL) was stirred at 60 °C for
20 min, then cooled to room temperature. Compound 3b
(0.82 g, 2.0 mmol) was added and the mixture was stirred at
40 °C for about 12 h (monitored by TLC, eluent: chloro-
form/petroleum = 1/3, V/V). After the reaction came to the
end, the reactant mixture was cooled to room temperature
and evaporated. The residue was treated with water (50 mL)
and extracted with chloroform (3 × 50 mL). The combined
organic layer was dried over anhydrous sodium sulfate and
concentrated. The crude product was purified via silica gel
column chromatography (eluent: petroleum ether/CH2Cl2 =
3/1, V/V) to afford compound 7a (0.46 g) as white solid.
Yield: 39.1%; mp: 117−119 °C; IR (KBr) ν: 3066 (Ar–H),
2950, 2865 (CH2), 1701, 1664 (C=O), 1588, 1504, 1469
(aromatic frame), 1357, 1234, 1177, 1028, 930, 866, 782,
2-(5-(1H-Imidazol-1-yl)pentyl)-6-bromo-1H-benzo[de]iso-
quinoline-1,3(2H)-dione (6c)
Compound 6c was prepared according to the procedure de-
scribed for compound 6a, starting from compound 3c (0.85
g, 2.0 mmol), 1H-imidazole (0.15 g, 2.2 mmol) and potas-
sium carbonate (0.35 g, 2.5 mmol). The pure product 6c
(0.49 g) was obtained as white solid. Yield: 58.7%; mp:
143–145 °C; IR (KBr) ν: 3210 (Ar-H), 2854 (CH2), 1659
(C=O), 1589, 1572, 1498 (aromatic frame), 1351, 1345,
1230, 961, 751, 733, 634 cm–1; 1H NMR (300 MHz, CDCl3)
δ(ppm): 8.64 (d, 1H, J = 7.1 Hz, NAPH-H), 8.57 (d, 1H, J =
8.4 Hz, NAPH-H), 8.40 (d, 1H, J = 7.8 Hz, NAPH-H), 8.04
(d, 1H, J = 7.8 Hz, NAPH-H), 7.85 (t, 1H, J = 7.8 Hz,
NAPH-H), 7.50 (s, 1H, Im 2-H), 7.04 (s, 1H, Im 5-H), 6.93
(s, 1H, Im 4-H), 4.16 (t, 2H, J = 7.0 Hz, NAPH-CH2), 3.97
(t, 2H, J = 7.2 Hz, Im-CH2), 1.91−1.83 (m, 4H, NAPH-
CH2CH2, Im-CH2CH2), 1.48−1.41 (m, 2H, Im-CH2CH2CH2);
ESI-MS (m/z): 412/414 (1/1) [M+H]+; HRMS (ESI) calcd.
for C20H18BrN3O2 [M+H]+, 412.0661; found, 412.0657.
1
752 (C-S-C) cm–1; H NMR (300 MHz, CDCl3) δ(ppm):
8.65 (d, 1H, J = 7.2 Hz, NAPH-H), 8.58 (d, 1H, J = 8.5 Hz,
NAPH-H), 8.40 (d, 1H, J = 7.9 Hz, NAPH-H), 8.05 (d, 1H,
J = 7.9 Hz, NAPH-H), 7.88−7.84 (m, 2H, NAPH-H, Tri
5-H), 7.38−7.31 (m, 2H, 2,4-Cl2Ph 3,5-H), 7.15−7.12 (m,
1H, 2,4-Cl2Ph 6-H), 4.47 (s, 2H, 2,4-Cl2Ph-CH2), 4.16 (t,
2H, J = 7.0 Hz, NAPH-CH2), 4.04 (t, 2H, J = 6.8 Hz,
S-CH2), 1.86−1.79 (m, 2H, NAPH-CH2CH2), 1.74−1.67 (m,
2H, S-CH2CH2); ESI-MS (m/z): 591 [M+H]+; HRMS (ESI)
calcd. for C25H19BrCl2N4O2S [M+H]+, 588.9867; found,
588.9865.
2-(6-(1H-Imidazol-1-yl)hexyl)-6-bromo-1H-benzo[de]isoqui-
noline-1,3(2H)-dione (6d)
Compound 6d was prepared according to the procedure
described for compound 6a, starting from compound 3d
(0.88 g, 2.0 mmol), 1H-imidazole (0.15 g, 2.2 mmol) and
potassium carbonate (0.35 g, 2.5 mmol). The pure product
6d (0.59 g) was obtained as white solid. Yield: 69.0%; mp:

958
Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
6-Bromo-2-(4-(1-(3,4-dichlorobenzyl)-1H-1,2,4-triazol-3-yl
thio)butyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (7b)
(m, 2H, Tri 5-H, NAPH-H), 7.86 (t, 1H, J = 8.0 Hz,
NAPH-H), 7.42−7.36 (m, 2H, 2,4-Cl2Ph 3,5-H), 7.15−7.12
(m, 1H, 2,4-Cl2Ph 6-H), 4.38 (s, 2H, 2,4-Cl2Ph-CH2),
4.21−4.19 (m, 4H, NAPH-CH2, Tri-CH2), 2.01−1.94 (m, 2H,
NAPH-CH2CH2), 1.74−1.67 (m, 2H, Tri-CH2CH2); ESI-MS
(m/z): 591 [M+H]+; HRMS (ESI) calcd. for
C25H19BrCl2N4O2S [M+H]+, 588.9867; found, 588.9869.
Compound 7b was prepared according to the procedure
depicted for compound 7a, starting from 1-(3,4-dichloro-
benzyl)-1H-1,2,4-triazole-3-thiol (0.64 g, 2.4 mmol), com-
pound 3b (0.82 g, 2.0 mmol) and potassium carbonate (0.41
g, 3.0 mmol). The pure product 7b (0.42 g) was obtained as
yellow solid. Yield: 35.6%; mp: 108−109 °C; IR (KBr) ν:
3069 (Ar–H), 2951, 2927 (CH2), 1700, 1660 (C=O), 1588,
1504, 1468 (aromatic frame), 1348, 1232, 1177, 1132, 1029,
780, 750 (C–S–C) cm–1; 1H NMR (300 MHz, CDCl3)
δ(ppm): 8.64 (d, 1H, J = 7.0 Hz, NAPH-H), 8.58 (d, 1H, J =
8.5 Hz, NAPH-H), 8.40 (d, 1H, J = 7.9 Hz, NAPH-H), 8.04
(d, 1H, J = 7.9 Hz, NAPH-H), 7.87−7.82 (m, 2H, NAPH-H,
Tri 5-H), 7.46−7.33 (m, 2H, 3,4-Cl2Ph 2,5-H), 7.23−7.16 (m,
1H, 3,4-Cl2Ph 6-H), 4.36 (s, 2H, 3,4-Cl2Ph-CH2), 4.17 (t,
2H, J = 7.0 Hz, NAPH-CH2), 4.06 (t, 2H, J = 6.9 Hz,
S-CH2), 1.92−1.82 (m, 2H, NAPH-CH2CH2), 1.77−1.66 (m,
2H, S-CH2CH2); ESI-MS (m/z): 591 [M+H]+; HRMS (ESI)
calcd. for C25H19BrCl2N4O2S [M+H]+, 588.9867; found,
588.9867.
6-Bromo-2-(4-(2-(3,4-dichlorobenzyl)-5-thioxo-2,5-dihydro-
1H-1,2,4-triazol-1-yl)butyl)-1H-benzo[de]isoquinoline-1,3
(2H)-dione (8b)
Compound 8b (0.44 g) was obtained in process of preparing
compound 7b as yellow solid. Yield: 37.4%; mp:
109−111 °C; IR (KBr) ν: 3112 (Ar–H), 2937 (CH2), 1699,
1660 (C=O), 1585, 1568, 1500, 1461 (aromatic frame),
1352, 1274 (C=S), 1180, 1036, 926, 850, 783, 659 (C–S–C)
cm–1; 1H NMR (300 MHz, CDCl3) δ(ppm): 8.63 (d, 1H, J =
7.4 Hz, NAPH-H), 8.58 (d, 1H, J = 8.3 Hz, NAPH-H), 8.44
(d, 1H, J = 7.8 Hz, NAPH-H), 8.08−8.05 (m, 2H, Tri 5-H,
NAPH-H), 7.78 (t, 1H, J = 7.9 Hz, NAPH-H), 7.49−7.31 (m,
2H, 3,4-Cl2Ph 2,5-H), 7.22−7.17 (m, 1H, 3,4-Cl2Ph 6-H),
4.30 (s, 2H, 3,4-Cl2Ph-CH2), 4.24−4.18 (m, 4H, NAPH-CH2,
Tri-CH2), 1.99−1.94 (m, 2H, NAPH-CH2CH2), 1.79−1.72
(m, 2H, Tri-CH2CH2); ESI-MS (m/z): 591 [M+H]+; HRMS
(ESI) calcd. for C25H19BrCl2N4O2S [M+H]+, 588.9867;
found, 588.9864.
6-Bromo-2-(4-(1-(2,4-difluorobenzyl)-1H-1,2,4-triazol-3-
ylthio)butyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (7c)
Compound 7c was prepared according to the procedure de-
picted for compound 7a, starting from 1-(2,4-difluoroben-
zyl)-1H-1,2,4-triazole-3-thiol (0.55 g, 2.4 mmol), bromide
3b (0.82 g, 2.0 mmol) and potassium carbonate (0.41 g, 3.0
mmol). The pure product 7c (0.36 g) was obtained as yellow
solid. Yield: 32.5%; mp: 125−127 °C; IR (KBr) ν: 3072
6-Bromo-2-(4-(2-(2,4-difluorobenzyl)-5-thioxo-2,5-dihydro-
1H-1,2,4-triazol-1-yl)butyl)-1H-benzo[de]isoquinoline-1,3
(2H)-dione (8c)
Compound 8c (0.38 g) was obtained in process of preparing
compound 7c as yellow solid. Yield: 34.7%; mp:
121−124 °C; IR (KBr) ν: 3114 (Ar–H), 2949, 2866 (CH2),
1700, 1660 (C=O), 1616, 1590, 1503, 1435 (aromatic
frame), 1359, 1273 (C=S), 1135, 1088, 967, 851, 782, 665
(C–S–C) cm–1; 1H NMR (300 MHz, CDCl3) δ(ppm): 8.66 (d,
1H, J = 7.2 Hz, NAPH-H), 8.59 (d, 1H, J = 8.3 Hz,
NAPH-H), 8.42 (d, 1H, J = 7.9 Hz, NAPH-H), 8.09−8.04
(m, 2H, Tri 5-H, NAPH-H), 7.86 (t, 1H, J = 8.0 Hz,
NAPH-H), 7.43−7.38 (m, 1H, 2,4-F2Ph 6-H), 6.80−6.75 (m,
1H, 2,4-F2Ph 3,5-H), 4.30 (s, 2H, 2,4-F2Ph-CH2), 4.24−4.18
(m, 4H, NAPH-CH2, Tri-CH2), 1.99−1.94 (m, 2H,
NAPH-CH2CH2), 1.79−1.72 (m, 2H, Tri-CH2CH2); ESI-MS
(m/z): 557/559 (1/1) [M+H]+; HRMS (ESI) calcd. for
C25H19BrF2N4O2S [M+H]+, 557.0458; found, 557.0455.
(Ar–H), 2951 (CH2), 1701, 1661 (C
=O), 1590, 1572, 1503,
1461 (aromatic frame), 1357, 1235, 1136, 1097, 967, 850,
782, 750 (C–S–C) cm–1; 1H NMR (300 MHz, CDCl3)
δ(ppm): 8.65 (d, 1H, J = 6.9 Hz, NAPH-H), 8.58 (d, 1H, J =
8.3 Hz, NAPH-H), 8.40 (d, 1H, J = 7.8 Hz, NAPH-H), 8.05
(d, 1H, J = 7.8 Hz, NAPH-H), 7.88−7.83 (m, 2H, NAPH-H,
Tri 5-H), 7.33−7.27 (m, 1H, 2,4-F2Ph 3-H), 6.82−6.77 (m,
2H, 2,4-F2Ph 5,6-H), 4.40 (s, 2H, 2,4-F2Ph-CH2), 4.17 (t,
2H, J = 6.9 Hz, NAPH-CH2), 4.05 (t, 2H, J = 6.9 Hz,
S-CH2), 1.87−1.83 (m, 2H, NAPH-CH2CH2), 1.75−1.66 (m,
2H, S-CH2CH2); ESI-MS (m/z): 557/559 (1/1) [M+H]+;
HRMS (ESI) calcd. for C25H19BrF2N4O2S [M+H]+, 557.0458;
found, 557.0457.
6-Bromo-2-(4-(2-(2,4-dichlorobenzyl)-5-thioxo-2,5-dihydro-
1H-1,2,4-triazol-1-yl)butyl)-1H-benzo[de]isoquinoline-
1,3(2H)-dione (8a)
1-(3-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)propyl)-4-(2,4-difluorobenzyl)-1H-1,2,4-triazol-4-ium
bromide (9a)
Compound 8a (0.41 g) was obtained in process of preparing
compound 7a as yellow solid. Yield: 34.9%; mp:
102−105 °C; IR (KBr) ν: 3115 (Ar-H), 2923 (CH2), 1698,
A mixture of compound 5a (0.38 g, 1.0 mmol) and
1-(bromomethyl)-2,4-difluorobenzene (0.52 g, 2.5 mmol) in
acetonitrile (5 mL) was stirred at 83 °C and monitored by
TLC (eluent: chloroform/methanol = 30/1, V/V). After the
reaction came to the end, the solvent was evaporated under
reduced pressure. The residue was washed with petroleum
1660 (C=O), 1588, 1569, 1503, 1467 (aromatic frame),
1348, 1270 (C
=
S), 1233, 1188, 1047, 930, 867, 848, 781,
718, 641 cm–1; 1H NMR (300 MHz, CDCl3) δ(ppm): 8.66 (d,
1H, J = 7.2 Hz, NAPH-H), 8.59 (d, 1H, J = 8.5 Hz,
NAPH-H), 8.42 (d, 1H, J = 7.8 Hz, NAPH-H), 8.09−8.04

Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
959
ether (3 × 30 mL) to give pure compound 9a (0.45 g) as
white solid. Yield: 75.0%; mp: 205−207 °C; IR (KBr) ν:
3099, 3016 (Ar–H), 2979 (CH2), 1699, 1660 (C=O), 1588,
1570, 1508 (aromatic frame), 1361, 1341, 1233, 1148, 1099,
977, 781, 622 cm–1; 1H NMR (400 MHz, DMSO-d6) δ(ppm):
10.10 (s, 1H, Tri 3-H), 9.31 (s, 1H, Tri 5-H), 8.58−8.53 (m,
2H, NAPH-H), 8.30 (d, 1H, J = 7.9 Hz, NAPH-H), 8.24 (d,
1H, J = 7.9 Hz, NAPH-H), 8.01 (t, 1H, J = 8.0 Hz,
NAPH-H), 7.67−7.64 (m, 1H, 2,4-F2Ph 3-H), 7.43−7.38 (m,
1H, 2,4-F2Ph 5-H), 7.23−7.20 (m, 1H, 2,4-F2Ph 6-H), 5.56
(s, 2H, 2,4-F2Ph-CH2), 4.45 (t, 2H, J = 7.2 Hz, Tri N1-CH2),
4.08 (t, 2H, J = 6.4 Hz, NAPH-CH2), 2.32−2.26 (m, 2H,
NAPH-CH2CH2); ESI-MS (m/z): 512/514 (1/1) [M–Br+H]+;
HRMS (ESI) calcd. for C24H18Br2F2N4O2 [M–Br+H]+,
512.0654; found, 512.0652.
N1-CH2), 4.09 (t, 2H, J = 8.4 Hz, NAPH-CH2), 2.35−2.28
(m, 2H, Tri N1-CH2CH2); ESI-MS (m/z): 545 [M–Cl]+;
HRMS (ESI) calcd. for C24H18BrCl3N4O2 [M–Cl+H]+,
544.0063; found, 544.0071.
1-(3-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)propyl)-4-(2-chlorobenzyl)-1H-1,2,4-triazol-4-ium chlo-
ride (9d)
Compound 9d was prepared according to the procedure
described for compound 9a, starting from compound 5a
(0.38 g, 1.0 mmol) and 1-chloro-2-(chloromethyl)benzene
(0.40 g, 2.5 mmol). The pure product 9d (0.40 g) was pro-
duced as white solid. Yield: 73.1%; mp: 181−183 °C; IR
(KBr) ν: 3120, 3009 (Ar–H), 2964 (CH2), 1660 (C=O),
1590, 1510, 1454 (aromatic frame), 1340, 1234, 1080, 966,
1
754, 618 cm–1; H NMR (400 MHz, DMSO-d6) δ(ppm):
1-(3-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)propyl)-4-(2,4-dichlorobenzyl)-1H-1,2,4-triazol-4-ium
chloride (9b)
10.14 (s, 1H, Tri 3-H), 9.35 (s, 1H, Tri 5-H), 8.57−8.54 (t,
2H, NAPH-H), 8.31 (d, 1H, J = 7.9 Hz, NAPH-H), 8.25 (d,
1H, J = 7.9 Hz, NAPH-H), 8.02 (t, 1H, J = 8.8 Hz,
NAPH-H), 7.57−7.47 (m, 4H, 2-ClPh-H), 5.63 (s, 2H, Tri
N4-CH2), 4.48 (t, 2H, J = 9.2 Hz, Tri N1-CH2), 4.10 (t, 2H, J
= 8.4 Hz, NAPH-CH2), 2.33−2.28 (m, 2H, Tri N1-CH2CH2);
ESI-MS (m/z): 511 [M–Cl]+; HRMS (ESI) calcd. for
C24H19BrCl2N4O2 [M–Cl+H]+, 510.0453; found, 510.0458.
Compound 9b was prepared according to the procedure
described for compound 9a, starting from compound 5a
(0.38 g, 1.0 mmol) and 2,4-dichloro-1-(chloromethyl)ben-
zene (0.49 g, 2.5 mmol). The pure product 9b (0.46 g) was
obtained as white solid. Yield: 80.0%; mp: 214−216 °C; IR
(KBr) ν: 3126 (Ar–H), 2960 (CH2), 1658 (C=O), 1617,
1588, 1501 (aromatic frame), 1385, 1345, 1232, 1113, 965,
854, 780, 618 cm–1; 1H NMR (400 MHz, DMSO-d6) δ(ppm):
10.17 (s, 1H, Tri 3-H), 9.37 (s, 1H, Tri 5-H), 8.59−8.52 (m,
2H, NAPH-H), 8.30 (d, 1H, J = 7.6 Hz, NAPH-H), 8.24 (d,
1H, J = 7.6 Hz, NAPH-H), 8.02 (t, 1H, J = 7.8 Hz,
NAPH-H), 7.80 (s, 1H, 2,4-Cl2Ph 3-H), 7.65−7.63 (m, 1H,
2,4-Cl2Ph 5-H), 7.59−7.57 (m, 1H, 2,4-Cl2Ph 6-H), 5.64 (s,
2H, Tri N4-CH2), 4.49 (t, 2H, J = 7.2 Hz, Tri N1-CH2), 4.10
(t, 2H, J = 6.6 Hz, NAPH-CH2), 2.35−2.28 (m, 2H, Tri
N1-CH2CH2); ESI-MS (m/z): 545 [M–Cl]+; HRMS (ESI)
calcd. for C24H18BrCl3N4O2 [M–Cl+H]+, 544.0063; found,
544.0068.
1-(3-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)propyl)-4-(3-chlorobenzyl)-1H-1,2,4-triazol-4-ium chlo-
ride (9e)
Compound 9e was prepared according to the procedure de-
scribed for compound 9a, starting from compound 5a (0.38
g, 1.0 mmol) and 1-chloro-3-(chloromethyl)benzene (0.40 g,
2.5 mmol). The pure product 9e (0.37 g) was obtained as
white solid. Yield: 68.6%; mp: 212−213 °C; IR (KBr) ν:
3119, 3010 (Ar–H), 2976 (CH2), 1660 (C=O), 1570, 1528,
1
1461 (aromatic frame), 1341, 1234, 976, 779, 621 cm–1; H
NMR (400 MHz, DMSO-d6) δ(ppm): 10.16 (s, 1H, Tri 3-H),
9.33 (s, 1H, Tri 5-H), 8.58−8.55 (m, 2H, NAPH-H), 8.31 (d,
1H, J = 8.3 Hz, NAPH-H), 8.24 (d, 1H, J = 8.3 Hz,
NAPH-H), 8.01 (t, 1H, J = 7.5 Hz, NAPH-H), 7.57−7.49 (m,
4H, 3-ClPh-H), 5.53 (s, 2H, Tri N4-CH2), 4.46 (t, 2H, J =
9.2 Hz, Tri N1-CH2), 4.09 (t, 2H, J = 8.4 Hz, NAPH-CH2),
2.32−2.28 (m, 2H, Tri N1-CH2CH2); ESI-MS (m/z): 511
[M–Cl]+; HRMS (ESI) calcd. for C24H19BrCl2N4O2
[M–Cl+H]+, 510.0453; found, 510.0450.
1-(3-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)propyl)-4-(3,4-dichlorobenzyl)-1H-1,2,4-triazol-4-ium
chloride (9c)
Compound 9c was prepared according to the procedure de-
scribed for compound 9a, starting from compound 5a (0.38
g, 1.0 mmol) and 1,2-dichloro-4-(chloromethyl)benzene
(0.49 g, 2.5 mmol). The pure product 9c (0.41 g) was ob-
tained as white solid. Yield: 70.4%; mp: 211−213 °C; IR
(KBr) ν: 3099, 3016 (Ar–H), 2979 (CH2), 1699, 1660 (C=O),
1588, 1570, 1508 (aromatic frame), 1361, 1341, 1233, 1148,
1-(3-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)propyl)-4-(4-nitrobenzyl)-1H-1,2,4-triazol-4-ium bromide
(9f)
1
1099, 977, 781, 622 cm–1; H NMR (400 MHz, DMSO-d6)
Compound 9f was prepared according to the procedure de-
scribed for compound 9a, starting from compound 5a (0.38
g, 1.0 mmol) and 1-(bromomethyl)-4-nitrobenzene (0.54 g,
2.5 mmol). The pure product 9f (0.49 g) was obtained as
white solid. Yield: 81.3%; mp: 242−243 °C; IR (KBr) ν:
3125, 3034 (Ar–H), 2985 (CH2), 1660 (C=O), 1570, 1511,
δ(ppm): 10.17 (s, 1H, Tri 3-H), 9.35 (s, 1H, Tri 5-H),
8.57−8.54 (m, 2H, NAPH-H), 8.31 (d, 1H, J = 8.4 Hz,
NAPH-H), 8.23 (d, 1H, J = 8.4 Hz, NAPH-H), 8.01 (t, 1H, J
= 7.7 Hz, NAPH-H), 7.86 (s, 1H, 3,4-Cl2Ph 3-H), 7.76−7.72
(m, 1H, 3,4-Cl2Ph 5-H), 7.56−7.51 (m, 1H, 3,4-Cl2Ph 6-H),
5.54 (s, 2H, Tri N4-CH2), 4.46 (t, 2H, J = 9.6 Hz, Tri
1
1459 (aromatic frame), 1351, 1234, 957, 767, 633 cm–1; H

960
Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
NMR (400 MHz, DMSO-d6) δ(ppm): 10.19 (s, 1H, Tri 3-H),
9.38 (s, 1H, Tri 5-H), 8.55−8.53 (m, 2H, NAPH-H),
8.33−8.22 (m, 4H, 4-NO2Ph 3,5-H, NAPH-H), 8.01 (t, 1H,
J = 7.9 Hz, NAPH-H), 7.75 (d, 2H, J = 9.6 Hz, 4-NO2Ph
2,6-H), 5.69 (s, 2H, Tri N4-CH2), 4.48 (t, 2H, J = 9.2 Hz, Tri
N1-CH2), 4.11 (t, 2H, J = 8.4 Hz, NAPH-CH2), 2.34−2.29
(m, 2H, Tri N1-CH2CH2); ESI-MS (m/z): 521 [M–Br]+;
HRMS (ESI) calcd. for C24H19Br2N5O4 [M–Br+H]+,
521.0693; found, 521.0698.
1H, J = 7.8 Hz, NAPH-H), 8.02 (t, 1H, J = 8.0 Hz,
NAPH-H), 7.70−7.65 (m, 1H, 2,4-F2Ph 3-H), 7.42−7.37 (m,
1H, 2,4-F2Ph 5-H), 7.24−7.20 (m, 1H, 2,4-F2Ph 6-H), 5.55
(s, 2H, Tri N4-CH2), 4.37 (t, 2H, J = 7.2 Hz, Tri N1-CH2),
4.03 (t, 2H, J = 7.5 Hz, NAPH-CH2), 1.94−1.90 (m, 2H, Tri
N1-CH2CH2), 1.69−1.66 (m, 2H, NAPH-CH2CH2), 1.39−
1.36 (m, 2H, Tri N1-CH2CH2CH2); ESI-MS (m/z): 541
[M–Br+H]+; HRMS (ESI) calcd. for C26H23Br2F2N4O2
[M–Br+H]+, 540.0967; found, 540.0972.
1-(4-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)butyl)-4-(2,4-difluorobenzyl)-1H-1,2,4-triazol-4-ium bro-
mide (9g)
1-(5-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)pentyl)-4-(2,4-dichlorobenzyl)-1H-1,2,4-triazol-4-ium
chloride (9j)
Compound 9g was prepared according to the procedure de-
scribed for compound 9a, starting from compound 5b (0.40
g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluorobenzene
(0.52 g, 2.5 mmol). The pure product 9g (0.41 g) was ob-
tained as white solid. Yield: 65.8%; mp: 216−218 ℃ in
agreement with the literature (mp: 216−219 °C) [31].
Compound 9i was prepared according to the procedure de-
scribed for compound 9a, starting from compound 5c (0.41
g, 1.0 mmol) and 2,4-dichloro-1-(chloromethyl)benzene
(0.49 g, 2.5 mmol). The pure compound 9j (0.41 g) was
obtained as white solid. Yield: 66.5%; mp: 202−204 °C; IR
(KBr) ν: 3136 (Ar–H), 2957 (CH2), 1659 (C
=O), 1588, 1500,
1441 (aromatic frame), 1385, 1341, 1234, 975, 827, 756,
627 cm–1; 1H NMR (400 MHz, DMSO-d6) δ(ppm): 10.16 (s,
1H, Tri 3-H), 9.30 (s, 1H, Tri 5-H), 8.58−8.56 (m, 2H,
NAPH-H), 8.35 (d, 1H, J = 7.6 Hz, NAPH-H), 8.25 (d, 1H,
J = 7.6 Hz, NAPH-H), 8.03 (t, 1H, J = 8.4 Hz, NAPH-H),
7.76−7.72 (m, 1H, 2,4-Cl2Ph 3-H), 7.61−7.55 (m, 2H,
2,4-Cl2Ph 5,6-H), 5.60 (s, 2H, Tri N4-CH2), 4.39 (t, 2H, J =
7.2 Hz, Tri N1-CH2), 4.03 (t, 2H, J = 7.2 Hz, NAPH-CH2),
1.96−1.89 (m, 2H, Tri N1-CH2CH2), 1.71−1.64 (m, 2H,
NAPH-CH2CH2), 1.40−1.33 (m, 2H, NAPH-CH2CH2CH2);
ESI-MS (m/z): 573 [M–Cl]+; HRMS (ESI) calcd. for
C26H22BrCl3N4O2 [M–Cl+H]+, 572.0376; found, 572.0370.
1-(4-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)butyl)-4-(2,4-dichlorobenzyl)-1H-1,2,4-triazol-4-ium chl-
oride (9h)
Compound 9h was prepared according to the procedure
described for compound 9a, starting from compound 5b
(0.40 g, 1.0 mmol) and 2,4-dichloro-1-(chlorome-
thyl)benzene (0.49 g, 2.5 mmol). The pure product 9h (0.46
g) was obtained as white solid. Yield: 77.1%; mp:
198−200 °C; IR (KBr) ν: 3126 (Ar–H), 2960 (CH2), 1658
(C=O), 1607, 1588, 1501, 1437 (aromatic frame), 1345,
1232, 975, 854, 756, 618 cm–1; 1H NMR (400 MHz,
DMSO-d6) δ(ppm): 10.16 (s, 1H, Tri 3-H), 9.29 (s, 1H, Tri
5-H), 8.57−8.52 (m, 2H, J = 7.2 Hz, NAPH-H), 8.33 (d, 1H,
J = 7.6 Hz, NAPH-H), 8.24 (d, 1H, J = 7.6 Hz, NAPH-H),
8.01 (t, 1H, J = 8.0 Hz, NAPH-H), 7.73 (s, 1H, 2,4-Cl2Ph
3-H), 7.58−7.52 (m, 2H, 2,4-Cl2Ph 5,6-H), 5.58 (s, 2H, Tri
N4-CH2), 4.42 (t, 2H, J = 6.8 Hz, Tri N1-CH2), 4.06 (t, 2H, J
= 7.2 Hz, NAPH-CH2), 1.96−1.90 (m, 2H, Tri N1-CH2CH2),
1.68−1.63 (m, 2H, NAPH-CH2CH2); ESI-MS (m/z): 559
[M–Cl]+; HRMS (ESI) calcd. for C25H20BrCl3N4O2
[M–Cl+H]+, 558.0219; found, 558.0212.
1-(6-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)hexyl)-4-(2,4-difluorobenzyl)-1H-1,2,4-triazol-4-ium bro-
mide (9k)
Compound 9k was prepared according to the procedure
described for compound 9a, starting from compound 5d
(0.43 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluoroben-
zene (0.52 g, 2.5 mmol). The pure product 9k (0.44 g) was
obtained as white solid. Yield: 69.0%; mp: 212−213 °C in
agreement with the literature (mp: 212−213 °C) [1].
1-(6-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)hexyl)-4-(2,4-dichlorobenzyl)-1H-1,2,4-triazol-4-ium
chloride (9l)
1-(5-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)pentyl)-4-(2,4-difluorobenzyl)-1H-1,2,4-triazol-4-ium
bromide (9i)
Compound 9l was prepared according to the procedure de-
scribed for compound 9a, starting from compound 5d (0.43
g, 1.0 mmol) and 2,4-dichloro-1-(chloromethyl)benzene
(0.49 g, 2.5 mmol). The pure compound 9l (0.43 g) was
obtained as white solid. Yield: 69.1%; mp: 206−207 °C; IR
(KBr) ν: 3126 (Ar–H), 2960 (CH2), 1660 (C=O), 1600,
1504, 1453 (aromatic frame), 1375, 1230, 945, 823, 734,
611 cm–1; 1H NMR (400 MHz, DMSO-d6) δ(ppm): 10.16 (s,
1H, Tri 3-H), 9.29 (s, 1H, Tri 5-H), 8.58−8.54 (m, 2H,
NAPH-H), 8.33 (d, 1H, J = 7.6 Hz, NAPH-H), 8.23 (d, 1H,
Compound 9i was prepared according to the procedure de-
scribed for compound 9a, starting from compound 5c (0.41
g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluorobenzene
(0.52 g, 2.5 mmol). The pure product 9i (0.33 g) was ob-
tained as white solid. Yield: 60.2%; mp: 214−215 °C; IR
(KBr) ν: 3165, 3034 (Ar–H), 2965 (CH2), 1660 (C=O),
1560, 1508, 1443 (aromatic frame), 1361, 1235, 1148, 1099,
973, 777, 629 cm–1; 1H NMR (400 MHz, DMSO-d6) δ(ppm):
10.18 (s, 1H, Tri 3-H), 9.30 (s, 1H, Tri 5-H), 8.59−8.56 (m,
2H, NAPH-H), 8.35 (d, 1H, J = 7.8 Hz, NAPH-H), 8.25 (d,

Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
961
J = 7.6 Hz, NAPH-H), 8.01 (t, 1H, J = 7.4 Hz, NAPH-H),
7.76−7.73 (m, 1H, 2,4-Cl2Ph 3-H), 7.59−7.53 (m, 2H,
2,4-Cl2Ph 5,6-H), 5.58 (s, 2H, Tri N4-CH2), 4.35 (t, 2H, J =
6.8 Hz, Tri N1-CH2), 4.00 (t, 2H, J = 7.6 Hz, NAPH-CH2),
1.88−1.81 (m, 2H, Tri N1-CH2CH2), 1.63−1.58 (m, 2H,
NAPH-CH2CH2), 1.38−1.29 (m, 4H, NAPH-(CH2)2CH2CH2);
ESI-MS (m/z): 587 [M–Cl]+; HRMS (ESI) calcd. for
C27H24BrCl3N4O2 [M–Cl+H]+, 586.0532; found, 586.0527.
1-(3-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)propyl)-3-(2,4-difluorobenzyl)-1H-imidazol-3-ium bro-
mide (10a)
Compound 10a was prepared according to the procedure
described for compound 9a starting from compound 6a
(0.38 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluoroben-
zene (0.52 g, 2.5 mmol). The pure compound 10a (0.31 g)
was obtained as white solid. Yield: 56.5%; mp: 228−230 °C
in agreement with the literature (227−230 °C) [31].
1-(8-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)octyl)-4-(2,4-difluorobenzyl)-1H-1,2,4-triazol-4-ium bro-
mide (9m)
1-(4-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)butyl)-3-(2,4-difluorobenzyl)-1H-imidazol-3-ium bromide
(10b)
Compound 9m was prepared according to the procedure
described for compound 9a, starting from compound 5e
(0.45 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluoroben-
zene (0.52 g, 2.5 mmol). The pure product 9m (0.48 g) was
obtained as white solid. Yield: 77.2%; mp: 201−203 °C; IR
(KBr) ν: 3198, 3115 (Ar–H), 2983 (CH2), 1659 (C=O),
1571, 1520, 1484 (aromatic frame), 1345, 1230, 971, 917,
Compound 10b was prepared according to the procedure
described for compound 9a starting from compound 6b
(0.40 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluoroben-
zene (0.52 g, 2.5 mmol). The pure compound 10b (0.39 g)
was obtained as white solid. Yield: 68.1%; mp: 208−210 °C;
IR (KBr) ν: 3153 (Ar–H), 2965, 2866 (CH2), 1663 (C=O),
1618, 1505, 1457, 1420 (aromatic frame), 1135, 848, 779,
1
750, 615 cm–1; H NMR (300 MHz, DMSO-d6) δ(ppm):
1
617 cm–1; H NMR (400 MHz, DMSO-d6) δ(ppm): 9.25 (s,
10.15 (s, 1H, Tri 3-H), 9.30 (s, 1H, Tri 5-H), 8.59−8.56 (m,
2H, NAPH-H), 8.35 (d, 1H, J = 6.9 Hz, NAPH-H), 8.26 (d,
1H, J = 6.9 Hz, NAPH-H), 8.04 (t, 1H, J = 8.1 Hz,
NAPH-H), 7.68−7.65 (m, 1H, 2,4-F2Ph 3-H), 7.43−7.37 (m,
1H, 2,4-F2Ph 5-H), 7.23−7.20 (m, 1H, 2,4-F2Ph 6-H), 5.55
(s, 2H, Tri N4-CH2), 4.37 (t, 2H, J = 7.2 Hz, Tri N1-CH2),
4.00 (t, 2H, J = 7.2 Hz, NAPH-CH2), 1.89−1.85 (m, 2H, Tri
N1-CH2CH2), 1.64−1.60 (m, 2H, NAPH-CH2CH2), 1.40−
1.31 (m, 8H, Tri N1-(CH2)2(CH2)4); ESI-MS (m/z): 583
[M–Br+H]+; HRMS (ESI) calcd. for C29H28Br2F2N4O2
[M–Br+H]+, 582.1436; found, 582.1439.
1H, Im 2-H), 8.58−8.53 (m, 2H, NAPH-H), 8.33 (d, 1H, J =
8.0 Hz, NAPH-H), 8.23 (d, 1H, J = 8.0 Hz, NAPH-H), 8.00
(t, 1H, J = 11.0 Hz, NAPH-H), 7.82 (s, 1H, Im 4-H), 7.77 (s,
1H, Im 5-H), 7.62−7.54 (m, 1H, 2,4-F2Ph 3-H), 7.37−7.31
(m, 1H, 2,4-F2Ph 5-H), 7.20−7.17 (m, 1H, 2,4-F2Ph 6-H),
5.46 (s, 2H, Im N3-CH2), 4.22 (t, 2H, J = 6.8 Hz, Im
N1-CH2), 4.05 (t, 2H, J = 9.5 Hz, NAPH-CH2), 1.89−1.84
(m, 2H, Im N1-CH2CH2), 1.63−1.58 (m, 2H, NAPH-
CH2CH2); ESI-MS (m/z): 525 [M–Br]+; HRMS (ESI) calcd.
for C26H21Br2F2N3O2 [M–Br+H]+, 525.0858; found,
525.0853.
1-(8-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)octyl)-4-(2,4-dichlorobenzyl)-1H-1,2,4-triazol-4-ium chlo-
ride (9n)
1-(5-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)pentyl)-3-(2,4-difluorobenzyl)-1H-imidazol-3-ium bromide
(10c)
Compound 9n was prepared according to the procedure
described for compound 9a, starting from compound 5e
(0.45 g, 1.0 mmol) and 2,4-dichloro-1-(chloromethyl) ben-
zene (0.49 g, 2.5 mmol). The pure compound 9n (0.41 g)
was obtained as white solid. Yield: 63.5%; mp: 198−201 °C;
IR (KBr) ν: 3198, 3116 (Ar–H), 2985 (CH2), 1659 (C=O),
1572, 1520, 1456 (aromatic frame), 1347, 1230, 982, 917,
Compound 10c was prepared according to the procedure
described for compound 9a starting from compound 6c
(0.41 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluoroben-
zene (0.52 g, 2.5 mmol). The pure compound 10c (0.36 g)
was obtained as white solid. Yield: 68.9%; mp: 240−242 °C;
IR (KBr) ν: 3132, 3072 (Ar–H), 2985, 2867 (CH2), 1662
(C=O), 1588, 1508, 1434 (aromatic frame), 1346, 1277,
1
750, 621 cm–1; H NMR (300 MHz, DMSO-d6) δ(ppm):
1
1140, 873, 751, 634 cm–1; H NMR (400 MHz, DMSO-d6)
10.15 (s, 1H, Tri 3-H), 9.31 (s, 1H, Tri 5-H), 8.58−8.55 (m,
2H, NAPH-H), 8.33 (d, 1H, J = 7.6 Hz, NAPH-H), 8.25 (d,
1H, J = 7.6 Hz, NAPH-H), 8.04 (t, 1H, J = 8.1 Hz,
NAPH-H), 7.68−7.65 (m, 1H, 2,4-Cl2Ph 3-H), 7.43−7.37 (m,
1H, 2,4-Cl2Ph 5-H), 7.22−7.18 (m, 1H, 2,4-Cl2Ph 6-H), 5.53
(s, 2H, Tri N4-CH2), 4.35 (t, 2H, J = 7.2 Hz, Tri N1-CH2),
3.99 (t, 2H, J = 6.3 Hz, NAPH-CH2), 1.88−1.84 (m, 2H, Tri
N1-CH2CH2), 1.63−1.60 (m, 2H, NAPH-CH2CH2), 1.38−
1.31 (m, 8H, Tri N1-(CH2)2(CH2)4); ESI-MS (m/z): 615
[M–Cl]+; HRMS (ESI) calcd. for C29H28BrCl3N4O2
[M–Cl+H]+, 614.0845; found, 614.0841.
δ(ppm): 9.24 (s, 1H, Im 2-H), 8.59−8.54 (m, 2H, NAPH-H),
8.34 (d, 1H, J = 8.1 Hz, NAPH-H), 8.23 (d, 1H, J = 8.1 Hz,
NAPH-H), 8.01 (t, 1H, J = 10.3 Hz, NAPH-H), 7.80 (s, 1H,
Im 4-H), 7.76 (s, 1H, Im 5-H), 7.62−7.54 (m, 1H, 2,4-F2Ph
3-H), 7.37−7.31 (m, 1H, 2,4-F2Ph 5-H), 7.21−7.15 (m, 1H,
2,4-F2Ph 6-H), 5.45 (s, 2H, Im N3-CH2), 4.17 (t, 2H, J = 7.2
Hz, Im N1-CH2), 4.01 (t, 2H, J = 6.5 Hz, NAPH-CH2),
1.89−1.80 (m, 2H, Im N1-CH2CH2), 1.68−1.61 (m, 2H,
NAPH-CH2CH2), 1.32−1.27 (m, 2H, Im N1-CH2CH2CH2);
ESI-MS (m/z): 539 [M–Br]+; HRMS (ESI) calcd. for
C27H23Br2F2N3O2 [M–Br+H]+, 539.1014; found, 539.1019.

962
Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
1-(6-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)hexyl)-3-(2,4-difluorobenzyl)-1H-imidazol-3-ium bromide
(10d)
was obtained as yellow solid. Yield: 78.4%; mp:
169–172 °C; IR (KBr) ν: 3078 (Ar–H), 2940 (CH2), 1700,
1659 (C=O), 1592, 1570, 1505, 1436 (aromatic frame),
1364, 1278 (C=S), 1236, 1141, 1094, 970, 853, 784, 647
cm–1; 1H NMR (300 MHz, DMSO-d6) δ(ppm): 10.19 (s, 1H,
Tri-H), 8.56−8.52 (m, 2H, NAPH-H), 8.31 (d, 1H, J = 7.9
Hz, NAPH-H), 8.21 (d, 1H, J = 7.9 Hz, NAPH-H), 7.99 (t,
1H, J = 7.9 Hz, NAPH-H), 7.57−7.30 (m, 3H, 2,4-Cl2Ph
3,5-H, 2,4-F2Ph 3-H), 7.16−6.96 (m, 3H, 2,4-Cl2Ph 6-H,
2,4-F2Ph 5,6-H), 5.38 (s, 2H, Tri N4-CH2), 4.45−4.39 (m,
4H, Tri N1-CH2, Tri N2-CH2), 4.07 (t, 2H, J = 6.3 Hz,
NAPH-CH2), 1.95−1.84 (m, 2H, NAPH-(CH2)2CH2),
1.72−1.59 (NAPH-CH2CH2); ESI-MS (m/z): 717 [M–Br]+;
HRMS (ESI) calcd. for C32H24Br2Cl2F2N4O2S [M–Br+H]+,
716.0221; found, 716.0218.
Compound 10d was prepared according to the procedure
described for compound 9a starting from compound 6d
(0.43 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluoroben-
zene (0.52 g, 2.5 mmol). The pure compound 10d (0.41 g)
was obtained as white solid. Yield: 71.5%; mp: 204−206 °C;
IR (KBr) ν: 3138, 3065 (Ar−H), 2965, 2860 (CH2), 1660
(C=O), 1576, 1500, 1431 (aromatic frame), 1346, 1199,
1
1130, 856, 747, 629 cm–1; H NMR (400 MHz, DMSO-d6)
δ(ppm): 9.25 (s, 1H, Im 2-H), 8.57−8.53 (d, 2H, J = 8.1 Hz,
NAPH-H), 8.32 (d, 1H, J = 7.9 Hz, NAPH-H), 8.21 (d, 1H,
J = 7.9 Hz, NAPH-H), 8.00 (t, 1H, J = 9.9 Hz, NAPH-H),
7.78 (s, 1H, Im 4-H), 7.75 (s, 1H, Im 5-H), 7.62−7.54 (m,
1H, 2,4-F2Ph 3-H), 7.37−7.31 (m, 1H, 2,4-F2Ph 5-H),
7.21−7.14 (m, 1H, 2,4-F2Ph 6-H), 5.43 (s, 2H, Im N3-CH2),
4.16 (t, 2H, J = 8.6 Hz, Im N1-CH2), 4.05 (t, 2H, J = 12.0
Hz, NAPH-CH2), 1.90−1.81 (m, 2H, Im N1-CH2CH2),
1.68−1.61 (m, 2H, NAPH-CH2CH2), 1.32−1.29 (m, 2H, Im
N1-CH2CH2CH2), 1.25−1.19 (m, 2H, NAPH-CH2CH2CH2);
ESI-MS (m/z): 553 [M–Br]+; HRMS (ESI) calcd. for
C28H26Br2F2N3O2 [M–Br+H]+, 553.1171; found, 553.1171.
2-(4-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)butyl)-1-(3,4-dichlorobenzyl)-4-(2,4-difluorobenzyl)-3-
thioxo-2,3-dihydro-1H-1,2,4-triazol-4-ium bromide (11b)
Compound 11b was prepared according to the procedure
described for compound 9a starting from compound 8b
(0.59 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluoroben-
zene (0.25 g, 1.25 mmol). The pure compound 11b (0.61 g)
was obtained as yellow solid. Yield: 76.2%; mp:
164−166 °C; IR (KBr) ν: 3071 (Ar–H), 2955 (CH2), 1700,
1659 (C=O), 1616, 1590, 1569, 1505, 1433 (aromatic
frame), 1349, 1280 (C=S), 1234, 1139, 1093, 971, 852, 783,
644 cm–1; 1H NMR (400 MHz, DMSO-d6) δ(ppm): 10.16 (s,
1H, Tri-H), 8.56−8.48 (m, 2H, NAPH-H), 8.33 (d, 1H, J =
7.8 Hz, NAPH-H), 8.23 (d, 1H, J = 7.8 Hz, NAPH-H), 8.00
(t, 1H, J = 7.7 Hz, NAPH-H), 7.65−7.28 (m, 3H, 3,4-Cl2Ph
2,5-H, 2,4-F2Ph 3-H), 7.21−6.97 (m, 3H, 3,4-Cl2Ph 6-H,
2,4-F2Ph 5,6-H), 5.38 (s, 2H, Tri N4-CH2), 4.43−4.39 (m,
4H, Tri N1-CH2, Tri N2-CH2), 4.08 (t, 2H, J = 7.1 Hz,
NAPH-CH2), 1.91−1.85 (m, 2H, NAPH-(CH2)2CH2),
1.75−1.64 (m, 2H, NAPH-CH2CH2); ESI-MS (m/z): 717
[M–Br]+; HRMS (ESI) calcd. for C32H24Br2Cl2F2N4O2S
[M–Br+H]+, 716.0221; found, 716.0225.
1-(8-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)octyl)-3-(2,4-difluorobenzyl)-1H-imidazol-3-ium bromide
(10e)
Compound 10e was prepared according to the procedure
described for compound 9a starting from compound 6e
(0.45 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluoroben-
zene (0.52 g, 2.5 mmol). The pure compound 10e (0.48 g)
was obtained as white solid. Yield: 72.1%; mp: 213−215 °C;
IR (KBr) ν: 3135, 3065 (Ar–H), 2973, 2859 (CH2), 1661
(C=O), 1588, 1508, 1470 (aromatic frame), 1346, 1196,
1130, 917, 856, 745, 630 cm–1; 1H NMR (400 MHz,
DMSO-d6) δ(ppm): 9.23 (s, 1H, Im 2-H), 8.58−8.54 (m, 2H,
NAPH-H), 8.33 (d, 1H, J = 7.9 Hz, NAPH-H), 8.23 (d, 1H,
J = 7.9 Hz, NAPH-H), 8.03 (t, 1H, J = 8.1 Hz, NAPH-H),
7.79 (s, 1H, Im 4-H), 7.72 (s, 1H, Im 5-H), 7.60−7.57 (m,
1H, 2,4-F2Ph 3-H), 7.38−7.33 (m, 1H, 2,4-F2Ph 5-H),
7.22−7.15 (m, 1H, 2,4-F2Ph 6-H), 5.45 (s, 2H, Im N3-CH2),
4.19 (t, 2H, J = 8.4 Hz, Im N1-CH2), 4.04 (t, 2H, J = 11.8
Hz, NAPH-CH2), 1.92−1.80 (m, 2H, Im N1-CH2CH2),
1.66−1.58 (m, 2H, NAPH-CH2CH2), 1.33−1.21 (m, 8H,
NAPH-CH2CH2(CH2)4); ESI-MS (m/z): 581 [M–Br]+;
HRMS (ESI) calcd. for C26H21Br2F2N3O2 [M–Br+H]+,
581.1484; found, 581.1485.
2-(4-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)butyl)-1,4-bis(2,4-difluorobenzyl)-3-thioxo-2,3-dihydro-
1H-1,2,4-triazol-4-ium bromide (11c)
Compound 11c was prepared according to the procedure
described for compound 9a starting from compound 8c
(0.59 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluoroben-
zene (0.25 g, 1.25 mmol). The pure compound 11c (0.54 g)
was obtained as light yellow solid. Yield: 71.3%; mp:
159−162 °C; IR (KBr) ν: 3079 (Ar–H), 2935 (CH2), 1701,
1658 (C=O), 1617, 1569, 1506, 1434 (aromatic frame),
1347, 1276 (C=S), 1235, 1141, 1094, 970, 852, 783, 643
cm–1; 1H NMR (300 MHz, DMSO-d6) δ(ppm): 10.16 (s, 1H,
Tri-H), 8.63−8.51 (m, 2H, NAPH-H), 8.34 (d, 1H, J = 7.8
Hz, NAPH-H), 8.24 (d, 1H, J = 7.8 Hz, NAPH-H), 8.01 (t,
1H, J = 7.9 Hz, NAPH-H), 7.57−7.30 (m, 2H, 2,4-F2Ph
3-H), 7.21−6.97 (m, 4H, 2,4-F2Ph 5,6-H), 5.38 (s, 2H, Tri
2-(4-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)butyl)-1-(2,4-dichlorobenzyl)-4-(2,4-difluorobenzyl)-3-
thioxo-2,3-dihydro-1H-1,2,4-triazol-4-ium bromide (11a)
Compound 11a was prepared according to the procedure
described for compound 9a starting from compound 8a
(0.59 g, 1.0 mmol) and 1-(bromomethyl)-2,4-difluoroben-
zene (0.25 g, 1.25 mmol). The pure compound 11a (0.62 g)

Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
963
N4-CH2), 4.43−4.39 (m, 4H, Tri N1-CH2, Tri N2-CH2), 4.08
3 Results and discussion
(t, 2H, J = 6.2 Hz, NAPH-CH2), 1.99−1.84 (m, 2H,
NAPH-(CH2)2CH2), 1.77−1.58 (m, 2H, NAPH-CH2CH2);
ESI-MS (m/z): 685 [M–Br]+; HRMS (ESI) calcd. for
C32H24Br2F4N4O2S [M–Br+H]+, 684.0812; found, 684.0815.
3.1 Synthesis of naphthalimide azoles
The target naphthalimide azoles were prepared via multi-
step reactions starting from 6-bromobenzo[de]isoch-
romene-1,3-dione 1 and the synthetic procedures were out-
lined in Scheme 1. The commercially available compound 1
was treated with aqueous ammonia to give intermediate
naphthalimide 2 in 95.2% yield, which was further reacted
with halobenzyl triazole-thiols, prepared from halobenzyl
halides and thiosemicarbazide [45], to produce the
thio-triazole derivatives 4a–c with high yields.
The experimental results showed that the reaction condi-
tions such as solvent, base and temperature remarkably af-
fected the formation of compounds 4a–c. N,N-Dimethyl-
formamide (DMF) was more favorable for this reaction to
give high yields (75.7–82.1%) than other solvents like eth-
anol (24.6–33.2%), chloroform (15.9–25.3%) and acetoni-
trile (33.5–38.4%). This might be attributed to the good
solubility of naphthalimide 2 in DMF. Furthermore, weak
base potassium carbonate brought less benefit for the pro-
duction of desired compounds, while strong base potassium
hydroxide led to good yields. Moreover, it was observed
that the reaction afforded better yield at higher temperature.
Consequently, the suitable condition for this reaction was
that the triazole-thiol reacted with naphthalimide 2 in DMF
at 100 ºC in the presence of potassium hydroxide. The de-
sired products 4a–c could be obtained in satisfactory yields
ranging from 75.7% to 86.8%.
The naphthalimide bromides 3a–e were conveniently
prepared in 68.1–76.3% yields by the N-alkylation of com-
pound 2 with a series of dibromides in DMF at 40 °C. The
further N-alkylation with 1,2,4-triazole in acetonitrile using
potassium carbonate as base produced the naphthalimide
triazoles 5a–e in satisfactory yields (71.3%–76.8%). How-
ever, the naphthalimide imidazoles 6a–e were prepared in
the presence of sodium hydride in anhydrous tetrahydrofu-
ran (THF) under a stream of nitrogen with 58.7–69.0%
yields. The reaction of naphthalimide bromide 3b with ha-
lobenzyl triazole-thiols in the presence of potassium car-
bonate afforded both triazole-thioethers 7a–c and tria-
zole-thiones 8a–c. The quaternization of triazoles 5a–e with
excessive halobenzyl halides in acetonitrile under reflux
afforded the corresponding triazoliums 9a–n with high
yields (60.2–81.3%). Imidazoliums 10a–e and thio-
triazoliums 11a–c were effectively synthesized under the
same condition starting from imidazoles 6a–e and tria-
zole-thiones 8a–c with yields of 56.5–72.1% and 71.3–
78.4%, respectively.
2.3 Biological assays
The in vitro minimal inhibitory concentrations (MICs) of
the target compounds were determined using the two-fold
serial dilution technique in 96-well microtest plates accord-
ing to the National Committee for Clinical Laboratory
Standards (NCCLS) [43, 44]. The tested microorganism
strains were provided by the School of Pharmaceutical Sci-
ences, Southwest University and the College of Pharmacy,
Third Military Medical University. Orbifloxacin, Chloro-
mycin and Fluconazole were used as standard drugs.
Antibacterial assays
The prepared compounds 3–11 were evaluated for their an-
tibacterial activities against S. aureus (ATCC25923),
MRSA (N315), B. subtilis (ATCC6633) and M. luteus as
Gram-positive bacteria, B. proteus (ATCC13315), E. coli
(JM109), P. aeruginosa and B. typhi as Gram-negative bac-
teria. The bacterial suspension was adjusted with sterile
saline to a concentration of 1 × 105 CFU. The tested com-
pounds were dissolved in DMSO as the stock solutions. The
tested compounds and reference drugs were prepared in
Mueller–Hinton broth (Guangdong huaikai microbial sci.&
tech co., Ltd, Guangzhou, Guangdong, China) by two fold
serial dilution to obtain the required concentrations of 512,
256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5 µg/mL. These dilutions
were inoculated and incubated at 37 °C for 24 h. To ensure
that the solvent had no effect on bacterial growth, a control
test was performed with test medium supplemented with
DMSO at the same dilutions as used in the experiment. The
MICs (in µg/mL) for intermediate 3, azoles 4–8 and
mono-azoliums 9–11 were summarized in Table 3.
Antifungal assays
The synthesized compounds were evaluated for their anti-
fungal activity against C. albicans (ATCC76615) and C.
mycoderma. A spore suspension in sterile distilled water
was prepared from 1-day old culture of the fungi growing
on Sabouraud agar (SA) media. The final spore concentra-
tion was 1–5 × 103 spore mL–1. From the stock solutions of
the tested compounds and reference antifungal Fluconazole,
dilutions in sterile RPMI 1640 medium (Neuronbc Labora-
ton Technology CO., Ltd, Beijing, China) were made to
generate eleven desired concentrations (from 0.5 to 512
µg/mL) of each tested compound. These dilutions were in-
oculated and incubated at 35 °C for 24 h. The drug MIC
was defined as the first well with an approximate 80% re-
duction in growth compared to the growth of the drug-free
well. The MICs (in µg/mL) were summarized in Table 3.
3.2 Spectral analysis
All new compounds were confirmed by NMR, IR, MS and
HRMS spectra. The analytical data were in accordance with

964
Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
the assigned structures, and the spectral data were given in
the experimental protocol section. Moreover, all the tested
compounds gave appropriate MS and HRMS peaks in
agreement with their molecular formula.
than thio-triazoles 7a–c and 8a–c (δ = 8.07–7.85 ppm) be-
cause of the strong electron-withdrawing effect of large
conjugated naphthalimide system. Furthermore, protons on
triazole ring of triazole-thiones 8a–c displayed relatively
downfield shifts ranging from 8.07 to 8.06 ppm in compar-
ison with the thioether compounds 7a–c (δ = 7.86–7.85
ppm), and this phenomenon was possibly ascribed to the
strong electron-withdrawing character of C=S in triazole-
thione structure. Moreover, the conversion of triazoles 8a–c
into their triazoliums 11a–c led to dramatic enhancement of
triazole proton shifts up to 10.19–10.16 ppm. These facts
indicated the formation of triazoliums on the thio-triazole
rings of compound 8. Additionally, all the other aromatic
and aliphatic protons appeared at the appropriate chemical
regions.
In IR spectra, the carbonyl group of cyclic imides in
naphthalimide derivatives 3–11 possessed characteristic
stretching frequencies ranging from 1715 to 1654 cm–1,
while the aromatic frame exhibited absorption between
1616 and 1500 cm–1. Furthermore, in comparison with
triazolethioethers 7a–c which gave absorption peaks of
C–S–C at region of 752–750 cm–1, thiones 8a–c and the
corresponding thio-triazoliums 11a–c displayed strong ab-
sorption in 1280–1270 cm–1 due to the stretching vibration
of C=S in triazole-thione moieties. In addition, the moderate
absorption band at 3210–3009 cm–1 was attributed to the
stretching vibration of aromatic C–H, while the aliphatic
ones showed absorption peaks in the range of 2985–2847
cm–1. All the other absorption bands were also observed at
expected regions.
3.3 Effect of pH values on the antibacterial and anti-
fungal activities
1
The pH values of the tested conditions were reported to
show significant influence on the antimicrobial evaluation
[46, 47]. Therefore, with the aim of investigating their ef-
fects on the naphthalimide derivatives, naphthalimide az-
oliums including mono-triazolium 9g, imidazolium 10b,
thio-triazoliums 11b–c were selected to evaluate their activ-
ities at different pH values, along with Chloromycin and
Fluconazole as reference drugs. The results in Table 2 indi-
cated that all the tested azoliums showed significantly better
efficiency in neutral to weakly basic conditions (pH =
7.0–7.5), in accordance with the pH values of mammal
bodies, than in acidic or basic solutions in inhibiting the
growth of tested strains, with MIC values ranging from 1 to
64 μg/mL. Notably, compound 9g gave quite low inhibitory
concentrations (< 4 μg/mL) toward bacteria MRSA, E. coli
and fungus C. albicans in pH = 7.0–7.5 conditions, which
were comparable or even better than the reference drugs
Chloromycin and Fluconazole. Especially in pH = 7.0 con-
dition, compound 9g gave 32-fold more effective anti-E.
coli (MIC = 1 μg/mL) activities than Chloromycin. In a
word, all the selected triazoliums were sensitive to the pH
values of the tested conditions, and the neutral to weakly
basic conditions (pH = 7.0–7.5), similar to the pH values in
body, were more favorable for inhibiting the growth of mi-
croorganisms including bacteria and fungi.
In H NMR spectra, naphthalimide triazoles 5a–e gave
two singlets with δ values of 7.99–7.88 and 8.28–8.08 ppm,
assigning to the two protons Ha and Hb on triazole rings as
shown in Table 1. The three protons of imidazoles 6a–e also
displayed appropriate chemical shifts separately at
7.59–7.50, 7.01–6.92 and 7.07–7.04 ppm according to their
structures. The further conversion of compound 5 to their
corresponding triazoliums 9a–n resulted in dramatically
downfield shifts of triazole protons Ha (δ = 9.38–9.29 ppm)
and Hb (δ = 10.22–10.10 ppm), due to the formation of
permanent positive charges leading to more elec-
tron-deficient triazole rings. The similar phenomenon was
also observed for imidazoliums 10a–e.
Naphthalimide triazoles 4a–c with thio-triazole moieties
linked to naphthalimide framework displayed larger shifts
for thio-triazole protons with δ values of 9.24–8.48 ppm
Table 1 Some 1H NMR data (δ/ppm) of naphthalimide triazoles and their
triazoliumsa)
Compds
5a
Ha
Hb
Compds
9f
Ha
Hb
7.88
7.94
7.93
7.93
7.99
9.31
9.37
9.35
9.35
9.33
8.28
9.38
9.29
9.29
9.30
9.30
9.29
9.29
9.30
9.31
10.19
10.17
10.16
10.18
10.16
10.17
10.16
10.15
10.15
5b
8.19
9g
3.4 Effect of ClogP values on antimicrobial activities
5c
8.14
9h
The lip/water partition of drugs exerted great effect on bio-
5d
8.08
9i
ities by influencing the absorption and transport of the
activ
5e
8.11
9j
compounds in biological organisms [48]. The calculated
lip/water partition coefficients (ClogP) of all the tested
compounds were shown in Table 3. It was revealed that
compounds with lower absolute values of ClogP exhibited
more efficient antimicrobial activities except for compounds
11a–c, which displayed effective bioactivity in spite of
9a
10.10
10.17
10.17
10.14
10.16
9k
9b
9l
9c
9m
9n
9d
9e
a) The assignment for Ha and Hb could be switched.

Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
965
Table 2 Effect of pH values on antimicrobial activities in vitro as MIC (μg/mL) for some naphthalimide derivatives
Compds
9g
64
32
32
16
8
10b
64
32
16
8
11b
64
32
32
16
4
11c
128
32
32
8
Chloromycin
Fluconazole
pH 5.5
pH 6.0
pH 6.5
pH 7.0
pH 7.5
pH 8.0
128
64
64
32
16
16

–
–
–
–
–
S. aureus
2
4
8
8
4
16
pH 5.5
pH 6.0
pH 6.5
pH 7.0
pH 7.5
pH 8.0
64
64
16
4
128
64
64
8
128
64
16
8
128
64
32
16
4
64
64
16
8
–
–
–
–
–
–
MRSA
4
8
2
8
16
16
4
4
32
pH 5.5
pH 6.0
pH 6.5
pH 7.0
pH 7.5
pH 8.0
64
16
8
32
32
8
64
32
16
4
128
32
16
8
128
128
128
32
–
–
–
–
–
–
E. coli
1
2
2
2
2
8
32
8
16
8
32
32
pH 5.5
pH 6.0
pH 6.5
pH 7.0
pH 7.5
pH 8.0
32
32
16
2
256
128
128
64
128
64
32
4
256
64
16
4
–
–
–
–
–
–
8
4
2
C. albicans
0.5
1
4
64
4
4
4
128
4
8
1
higher ClogP values (ClogP = 11.19–10.05). Mono-
azoliums 9–10 showed low ClogP values ranging from 3.63
to –1.83 in contrast to their precursors 5–6 (ClogP =
2.97–7.89), meaning that these azoliums possessed more
reasonable lip/water partition to give more potent antimi-
crobial efficacy. Furthermore, the (CH2)3 and (CH2)4 linked
compounds 9a–b, 9g–h and 10a–b, which were more sensi-
tive to the tested bacterial and fungal strains than their ana-
logs, possessed lower absolute ClogP values (ranging from
0.12 to 1.51) than their corresponding analogs with other
linkers and comparable to the reference drugs (absolute
ClogP = 0.44–1.09). In general, as revealed from the above
discussion, ClogP values of the tested molecules played
significant roles in their antimicrobial efficiency, and the
conversion of azole derivatives into azoliums remarkably
modulated their lip/water partition (except for thio-
triazoliums 11a–c), thereby leading to efficient antibacterial
and antifungal competence. Moreover, the linkers of the
target compounds significantly affected the ClogP values
and bioactivities, with the (CH2)3 and (CH2)4 linkers more
suitable for modulating lip/water partition, thus improving
antimicrobial potency of these naphthalimide triazole deriv-
atives.
growth of both Gram-positive and Gram-negative bacteria
except for compounds 3–5 and 7–8. Particularly, the
mono-triazoliums 9, 11 and imidazoliums 10a–e showed
efficient antimicrobial activities and broad spectrum in
comparison with their precursors 5, 6 and 8 as well as bro-
mides 3a–e. Recent reports revealed that triazole derivatives
were more suitable for microbial inhibition than imidazole
ones [49, 50]. Surprisingly, our results here manifested that
the naphthalimide imidazoles 6a–e gave superior antibacte-
rial efficiency to the corresponding triazoles 5a–e and
thio-triazoles 7a-c and 8a–c. Additionally, the modification
of naphthalene ring to yield compound 4 also improved
antibacterial efficacy to some extent.
Naphthalimide bromides 3a–e did not exhibit obvious
inhibition to the tested bacterial strains even at high concen-
tration of 512 μg/mL. No remarkable enhancements were
observed in the naphthalimide triazoles 5a–e, triazole-
thioethers 7a–c and thiones 8a–c by incorporating triazole
and thio-triazole groups into compounds 3a–e, as shown in
Table 3. Meanwhile, imidazoles 6a–e exerted moderate to
good antibacterial efficiency (MIC = 8–128 μg/mL), espe-
cially compounds 6a and 6b with (CH2)3 and (CH2)4 linker
were more active to all the tested bacterial strains than other
analogs with inhibitory concentrations below 16 μg/mL
except for B. subtilis and P. aeruginosa. Notably, com-
pound 6b exhibited equivalent efficacy against E. coli and P.
aeruginosa to the standard drug Chloromycin with MIC
values of 8 and 16 μg/mL, respectively.
3.5 Antibacterial activity
The antibacterial results in Table 3 indicated that all naph-
thalimide derivatives 3–11 could effectively inhibit the

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Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
Table 3 ClogP values and antimicrobial data as MIC (μg/mL) for naphthalimide azoles 3–11a,b,c)
Gram-positive bacteria
Gram-negative bacteria
Fungi
Compounds
ClogP
S.
aureus
B.
subtilis
M.
luteus
B.
proteus
E.
coli
P.
B.
typhi
C.
albicans
C.
MRSA
aeruginosa
mycoderma
>512
>512
>512
>512
>512
>512
>512
512
256
>512
>512
>512
>512
64
3a
3b
3c
4.67
5.05
5.58
6.16
7.16
5.55
5.43
4.41
2.97
3.23
3.76
4.29
5.34
3.64
3.96
4.49
5.01
6.07
7.56
7.44
6.42
7.89
7.77
6.75
0.12
1.26
1.14
0.54
0.54
–0.43
0.37
1.51
0.90
2.04
1.43
2.57
2.49
3.63
0.84
1.15
1.69
2.21
3.27
11.19
11.07
10.05
0.48
–1.09
–0.44
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
16
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
16
>512
>512
>512
>512
>512
>512
>512
>512
256
>512
>512
>512
>512
16
>512
>512
>512
>512
>512
128
512
64
>512
>512
>512
>512
>512
>512
>512
>512
256
256
>512
>512
>512
16
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
16
>512
>512
>512
>512
>512
>512
512
>512
256
256
256
>512
256
32
>512
>512
>512
>512
>512
128
>512
64
>512
>512
>512
>512
>512
>512
>512
>512
256
>512
>512
>512
>512
64
3d
3e
4a
4b
4c
5a
5b
5c
>512
>512
>512
>512
>512
16
>512
>512
>512
>512
>512
16
5d
5e
6a
6b
6c
16
16
32
16
16
8
16
16
64
32
64
128
64
64
64
32
32
64
128
32
128
32
64
6d
6e
64
16
128
128
512
512
512
>512
>512
>512
8
16
64
128
128
512
512
512
>512
>512
>512
2
32
64
64
64
32
64
64
64
64
7a
7b
7c
512
512
256
>512
>512
>512
16
512
512
64
512
512
512
>512
>512
>512
4
512
512
32
512
512
512
>512
>512
>512
4
512
512
512
>512
>512
>512
4
512
512
16
128
512
128
>512
>512
>512
4
8a
8b
8c
>512
>512
>512
4
>512
>512
>512
16
>512
>512
>512
8
9a
9b
9c
16
16
8
8
4
4
4
16
8
16
16
16
32
16
32
16
16
16
16
16
9d
9e
16
32
32
16
16
16
8
32
8
32
32
8
16
8
32
8
8
16
16
32
9f
32
16
16
32
16
16
32
32
32
16
9g
9h
9i
8
4
4
4
8
8
2
8
16
8
8
16
16
8
16
8
2
8
16
16
16
32
16
32
32
32
8
16
32
64
9j
16
32
16
32
16
16
4
16
16
32
9k
9l
16
16
16
4
32
16
16
16
32
32
32
16
16
16
16
8
4
16
32
64
9m
9n
10a
10b
10c
10d
10e
11a
11b
11c
A
32
32
16
32
16
16
8
16
64
64
32
64
32
32
16
16
8
32
64
128
32
4
4
8
8
8
8
32
8
32
8
2
8
8
16
8
16
8
32
16
8
8
16
4
4
16
16
16
16
16
16
16
16
32
32
32
64
32
32
32
32
32
64
64
32
32
64
32
32
32
4
4
512
512
512
2
4
4
8
8
4
8
16
4
2
2
4
2
4
2
4
8
4
4
2
4
4
4
2
4
8
2
1
1
4
1
1
1
–
–
B
2
4
4
8
2
8
16
8
–
–
C
–
–
–
–
–
–
–
–
1
4
a) Minimal inhibitory concentrations were determined by micro broth dilution method for microdilution plates; b)A = chloromycin, B = orbifloxacin, C
= fluconazole; c) MRSA, Methicillin-Resistant Staphylococcus aureus (N315); S. aureus, Staphylococcus aureus (ATCC25923); B. subtilis, Bacillus subtilis;
M. luteus, Micrococcus luteus (ATCC4698); E. coli, Escherichia coli (DH52); S. dysenteriae, Shigella dysenteriae; P. aeruginosa, Pseudomonas aeruginosa;
E. typhosa, Eberthella typhosa; C. albicans, Candida albicans (ATCC76615); C. mycoderma, Candida mycoderma.

Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
967
Triazoliums 9a–n and imidazoliums 10a–e, the quater-
nization products of naphthalimide triazoles 5a–e and im-
idazoles 6a–e, displayed significantly enhanced antibacteri-
al potency in comparison with their precursors. Especially
triazoliums 9a–n could effectively inhibit the growth of all
the tested bacterial strains at concentrations below 32
μg/mL (Table 3). Moreover, compounds 9a–b and 9g–h
with (CH2)3 and (CH2)4 linker exhibited efficient bioactivi-
ties (MIC = 2–16 μg/mL), which were superior to their an-
alogs 9c–f and 9i–n with other linkers. The 2,4-difluoro-
benzyl derived triazoliums 9a and 9g were more sensitive to
the tested bacteria than compounds 9b and 9h with
2,4-dichlorobenzyl substituent and other analogs especially
to MRSA, B. subtilis, M. luteus, P. aeruginosa and B. typhi
which were comparable or more potent than Orbifloxacin
and Chloromycin. Notably, compound 9b exhibited equi-
potent anti-B. proteus efficacy to Orbifloxacin (MIC = 4
μg/mL). Furthermore, imidazoliums 10a–b gave potent ac-
tivities with MIC values below 32 μg/mL to all tested bac-
teria, especially against S. aureus, MRSA, B. subtilis, M.
luteus, E. coli and B. typhi with MICs ranging from 2 to 8
μg/mL.
Remarkable enhancement of antibacterial efficiency was
obtained by the conversion of triazole-thiones 8a–c into its
triazoliums 11a–c. Moreover, in comparison with triazoli-
ums 9a–n and imidazoliums 10a–e, thio-triazoliums 11a–c
exhibited more potent efficiency toward all bacteria except
for B. subtilis. Compounds 11b and 11c with 3,4-dichloro-
benzyl and 2,4-difluorobenzyl groups exerted efficient an-
tibacterial abilities, which were relatively superior to the
2,4-dichlorobenzyl derivative 11a, especially against M.
luteus, E. coli, P. aeruginosa and B. typhi. Noticeably, both
Gram-positive and Gram-negative strains were sensitive to
compounds 11b–c at concentrations below 4 μg/mL except
for B. subtilis, while compound 11a displayed good activi-
ties toward S. aureus, MRSA, M. Luteus, B. Proteus and B.
typhi with low MIC values (MIC ≤ 4 μg/mL). Furthermore,
M. luteus and B. typhi were sensitive to compounds 11b–c
at concentration of 2 μg/mL, both of which were 4-fold
more potent than Chloromycin (MIC = 8 μg/mL) and com-
parable to Orbifloxacin (MIC = 1 μg/mL), while compound
11b possessed comparable or even better anti-MRSA and E.
coli activities than the reference drugs Chloromycin and
Orbifloxacin with inhibitory concentrations of 2 μg/mL. All
the above results suggested that the introduction of thione
moiety into triazoliums to yield thio-triazoliums resulted in
significant enhancement of antibacterial activities.
Gram-positive and Gram-negative bacteria in comparison
with the reference drugs (Orbifloxacin and Chloromycin)
and were more efficient than their corresponding precursors.
Moreover, triazoliums with (CH2)3 or (CH2)4 linker exerted
greater effects on improving antibacterial competence and
broadening antimicrobial spectrum than their analogs.
Thio-triazoliums 11a–c not only exhibited superior antibac-
terial efficacy to triazoliums 9a–n, but also demonstrated
comparable or even better potency than the clinical drugs.
Additionally, imidazoliums as analogs of triazoliums gave
potent antibacterial efficacy. Consequently, this series of
naphthalimide triazole derivatives particularly the
thio-triazoliums were worthy to be further investigated as
potential antibacterial drugs.
3.6 Antifungal activity
The antifungal results in Table 3 showed that some naph-
thalimide azoles especially azoliums 9−11 displayed good
activities against the tested fungi C. albicans and C. myco-
derma. Similar to the antibacterial results, triazoliums 9a–b
and 9g–h as well as imidazoliums 10a–b with (CH2)3 or
(CH2)4 spacer exhibited potent antifungal activities with
MIC values ranging from 4 to 32 μg/mL in contrast to their
precursors. Particularly, compound 9a displayed equipotent
inhibition against C. mycoderma to Fluconazole at the con-
centration of 4 μg/mL. Moreover, thio-triazoliums 11a–c
presented superior efficiency against the tested fungi to tri-
azoliums 9a–n and imidazoliums 10a–e. Furthermore, the
3,4-dichlorobenzyl and 2,4-difluorobenzyl derivatives 11b–
c (MIC = 1–8 μg/mL) seemed to be more potent in inhibit-
ing the growth of fungi than 2,4-dichlorobenzyl derivative
11a.
Clearly, all these prepared naphthalimide azoles exhibit-
ed broad antimicrobial spectrum, not only effectively inhib-
ited the growth of both Gram-positive and Gram-negative
bacteria including drug-resistant MRSA, but also showed
significant antifungal activity. Naphthalimide azoliums gave
stronger antimicrobial efficacy than the corresponding pre-
cursor azoles. Naphthalimide imidazoles displayed superior
antibacterial efficiency to the triazole derivatives. The sub-
stituents in azole ring and naphthalimide backbone had re-
markable effect on antimicrobial ability. These results sug-
gested great potential for this type of naphthalimide azoles
as antibacterial and antifungal agents and more efforts
should be necessary.
Thioethers 4a–c bearing thio-triazole group on the naph-
thalene ring gave no obvious antibacterial activities, which
were probably attributed to their weak dissolubility, except
for compound 4c exhibiting moderate potency to M. luteus
and B. typhi at 64 μg/mL (Table 3).
In general, some synthetic naphthalimide compounds
especially the triazoliums showed moderate to excellent
antibacterial activities toward all tested strains including
4 Conclusions
In summary, a series of naphthalimide triazoles and some
corresponding triazoliums as well as imidazole analogs
have been successfully prepared by convenient and efficient
procedures starting from commercial 6-bromobenzo
[de]isochromene-1,3-dione. All new compounds were con-

968
Damu GLV, et al. Sci China Chem July (2013) Vol.56 No.7
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firmed by NMR, IR, MS and HRMS spectra. The antimi-
crobial evaluation manifested that most naphthalimide tria-
zoliums exhibited better antimicrobial efficiency than the
precursory triazoles, especially compounds 9a–b and 9g–h
with (CH2)3 or (CH2)4 spacer exhibited superior bioactivities
(MIC = 2–32 μg/mL) to other analogs. Moreover, thio-
triazoliums 11b–c with 3,4-dichlorobenzyl and 2,4-
difluorobenzyl substituents displayed potent efficacy
against all the tested strains, particularly toward M. luteus
and B. typhi with MIC values of 2 μg/mL, respectively,
which were comparable or even better than the reference
drugs Chloromycin and Orbifloxacin. The imidazoliums
also showed efficient bioactivities in comparison with their
precursors. Additionally, low ClogP values and neutral to
weakly basic conditions (pH = 7.0–7.5) seemed to be fa-
vorable for antimicrobial competence. These observations
indicated that the factors like spacer, substituents, pH and
ClogP values could affect the antimicrobial properties to
some extent, and some naphthalimide triazole derivatives
especially the thio-triazoliums were worthy to be further
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