Synthesis and activities of naphthalimide azoles as a new type of antibacterial and antifungal agents

Article abstract of DOI:10.1016/j.bmcl.2011.05.042

Naphthalimide-derived azoles as a new type of antimicrobial agents were synthesized and evaluated for their efficiency in vitro against eight bacteria and two fungi by two fold serial dilution technique. Most title compounds exhibited good antimicrobial p

Full text of DOI:10.1016/j.bmcl.2011.05.042

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4349–4352
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and activities of naphthalimide azoles as a new type
of antibacterial and antifungal agents
⇑
Yi-Yi Zhang, Cheng-He Zhou
Laboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Naphthalimide-derived azoles as a new type of antimicrobial agents were synthesized and evaluated for
their efficiency in vitro against eight bacteria and two fungi by two fold serial dilution technique. Most
title compounds exhibited good antimicrobial potency with low MIC values ranging from 1 to 16 lg/
mL. Notably, some synthesized compounds displayed comparable or even better antibacterial and anti-
fungal activities against some tested strains than the reference drugs Orbifloxacin, Chloromycin and
Fluconazole, respectively.
Received 28 January 2011
Revised 23 April 2011
Accepted 13 May 2011
Available online 18 May 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Naphthalimide
1,2,4-Triazole
Imidazole
Antibacterial
Antifungal
Cyclic imides have received special attention due to their
widely potential pharmaceutical applications in antimicrobial
especially antibacterial field.1 Naphthalimides, one type of cyclic
which have been playing roles in anti-infective therapy especially
as first-choice antifungal drugs. So far a large number of azole
drugs including triazole (Fluconazole, Itraconazole) and imidazole
(Miconazole, Ketoconazole) ones have been extensively used in
the treatment of various infectious diseases with excellent safety
profile, favorable pharmacokinetic characteristics and wide biolog-
ical activities.11 However, the increasing emergence of pathogenic
bacterial strains and concerns about multidrug-resistance, espe-
cially the explosion of New Delhi metallo-b-lactamase 1 (NDM-1)
superbugs very recently,12 have made most of the first-line clinical
antibiotics ineffective. This situation has stimulated an urgent need
to develop more effective antimicrobial agents with novel chemical
structures which are helpful for overcoming drug-resistance and
improving the antimicrobial potency.
In view of such stimulating properties and as an extension of
our studies on the development of azole compounds,13 herein a
series of new naphthalimide-based azoles including 1,2,4-triazole
and its analogue imidazole were synthesized and evaluated for
their antibacterial and antifungal efficiency. Many researches pro-
vided evidence that alkyl linkers could modulate the physicochem-
ical properties and thus improve biological potency.14 With the
aim of better understanding of structure–activity relationship
and increasing flexibilities, different lengths of alkyl chains were
introduced into the target compounds to investigate the influences
of linkers on bioactive profiles. Furthermore, our previous studies
have clearly pointed out that the transformation of azolyl ring into
its corresponding azolium by halogen-containing aromatic com-
pounds could efficiently increase the bioactivity due to affecting
the diffusion and interaction with bacterial cells and tissues by
imides with strong hydrophobicity and desirable large
gated backbone, could easily interact with various active targets
in biological system via non-covalent forces such as stacking,
p-conju-
p–p
and exhibit diverse biological activities including anticancer,2 anti-
bacterial,3 antitrypanosomal,4 analgesic,5 photobiological,6 antino-
ciceptive7 potency etc. Some naphthalimide derivatives such as
Amonafide and Elinafide for the treatment of cancers acting by
intercalating deoxyribonucleic acid (DNA), have been on the clini-
cal trials stage.8 This encourages much effort towards other bioac-
tivities of naphthalimides especially their antibacterial and
antifungal behavior.9 Recently, a lot of researches showed that
the introduction of some nitrogen-containing heterocyclic moie-
ties into naphthalimide backbone was beneficial to the pharma-
ceutical properties. It has been found that naphthalimide in
combination with piperazinyl and thiazolyl moieties could inhibit
effectively the growth of Escherichia coli and Pseudomonas aerugin-
osa with equivalent activities in comparison with the standard
drug Ciprofloxacin.10 However, to the best of our knowledge, other
azole napthalimides have been seldom observed. It is of great
interest for us to investigate azole-containing naphthalimides as
a new type of antimicrobial agents.
It is well known that azole compounds such as triazole and
imidazole ones are an important class of antimicrobial agents
⇑
Corresponding author. Tel./fax: +86 23 68254967.
E-mail address: zhouch@swu.edu.cn (C.-H. Zhou).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.042

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Y.-Y. Zhang, C.-H. Zhou / Bioorg. Med. Chem. Lett. 21 (2011) 4349–4352
enhancing solubility and membrane permeability.15 Based on
these, some title azoles were converted into their corresponding
triazoliums and imidazoliums by various halogen-containing aryl
groups.
growth inhibition of the microorganisms compared with that of
the current antimicrobial drugs Fluconazole, Chloromycin and
Orbifloxacin in clinic. The antibacterial and antifungal data were
depicted in Table 1.
The target naphthalimide azoles were prepared via multistep
reactions from 4-bromo-1,8-naphthalic anhydride 1 and their syn-
thetic process was outlined in Scheme 1. The commercially avail-
able compound 1 was treated with aqueous ammonia to give
intermediate 4-bromo-1,8-naphthalimide 2 in 95% yield, and then
further N-alkylated with a series of dibromides in DMF at 40 °C to
produce the corresponding halides 3a–d with the yields of 41–78%.
The target naphthalimide triazoles 4a–d were conveniently and
efficiently obtained in 71–83% yields by the reaction of bromides
3a–d respectively with 1,2,4-triazole in acetonitrile at 55 °C using
potassium carbonate as base. Unfortunately, under the same con-
dition above, imidazoles 6a–d were obtained in very low yields,
which demonstrated that potassium carbonate was unfavorable
for this reaction, probably its basicity was too weak to form imid-
azole carbanion. Therefore, sodium hydride was selected as base in
the reaction of imidazole with bromides 3a–d, which easily affor-
ded the imidazole derivatives 6a–d with good yields ranging from
58% to 69% at 45À70 °C in anhydrous tetrahydrofuran under a
stream of nitrogen. The quaternization of naphthalimide triazoles
4a–d and imidazoles 6a–d by halobenzyl halides yielded their cor-
responding triazoliums 5a–i and imdazoliums 7a–d in good yields
after purification. Some synthetic data were given in Table 1. These
new compounds were confirmed by 1H NMR, 13C NMR, IR, MS and
HR-MS spectra.16
The antibacterial results in Table 1 showed that all the target
compounds except triazole derivatives were active against both
Gram-positive and Gram-negative bacteria. Particularly, triazoli-
ums 5a–i and imidazoliums 7a–d showed broad antimicrobial
spectrum and could effectively inhibit the growth of the tested
strains in vitro in comparison with their corresponding precursors
4 and 6.
For the tested naphthalimide-derived triazoles 4a–d and 5a–i,
triazoliums 5a–i exhibited good activities against all the tested
bacterial strains with MIC values ranging from 1 to 32
while their precursor triazoles 4a–d were less sensitive even at
high tested concentration (MIC P 256 g/mL). Compounds 5a–f,
lg/mL,
l
the quaternization products of (CH2)3 linked triazole 4a by diverse
substituted benzyl halides, displayed significant antibacterial effi-
cacy. Especially, 2,4-diflurorobenzyl and 2,4-dichlorobenzyl deriv-
atives 5a–b gave comparable or even better activities in
comparison with reference drugs Chloromycin and Orbifloxacin
at the concentrations 1–8 lg/mL against all the tested bacteria ex-
cept for S. aureus. Particularly, compound 5a with 2,4-difluroroben-
zyl group, showing superior potency to that with dichlorobenzyl
one, gave the strongest inhibition against P. aeruginosa which
was 16-fold more potent than Chloromycin and comparable to
Orbifloxacin. Meanwhile, it was noteworthy that compound 5a
also exhibited good anti-MRSA efficiency (MIC = 4 lg/mL), and
The in vitro antimicrobial activities for all synthesized com-
pounds were evaluated for four Gram-positive organisms viz.
Staphylococcus aureus ATCC 25923, methicillin-resistant S. aureus
N 315 (MRSA), Bacillus subtilis ATCC 6633, Micrococcus luteus and
four Gram-negative organisms viz. Bacillus proteus, E. coli JM 109,
P. aeruginosa and Bacillus typhi as well as two fungi viz. Candida
albicans ATCC 76615 and Candida mycoderma by microbroth dilu-
tion method.17 All target compounds were evaluated at the con-
was equivalent to Chloromycin and Orbifloxacin. This result sug-
gested that the existence of fluorine atom should be of special
importance in medicine due to its high lipophilicity which could
be helpful for the biological transportation and distribution of
compounds.18 It was reasonable that 2,4-difluorobenzyl triazoli-
ums 5g–i with different alkyl linkers were synthesized selectively,
and they also gave good antibacterial profiles (MIC = 2–32
especially compounds 5g–h which showed prominent anti-P. aeru-
ginosa ability (MIC = 2 g/mL) with 8-fold more efficient than Chlo-
lg/mL),
centrations ranging from 0.5 to 512
lg/mL and scored for
l
minimal inhibitory concentrations (MICs,
lg/mL) as the level of
romycin. These antibacterial data indicated that the azolium
X2
O
Br
O
Br
Br
X1
Br
X1
N
N
N
n
N
O
N N
N
n
CH3CN
N
O
X2
5a-i
4a-d
f, n = 1, X1 = NO2, X2 = H,
5: a, n = 1, X1 = F, X2 = 2-F;
b, n = 1, X1 = Cl, X2 = 2-Cl;
c, n = 1, X1 = Cl, X2 = 3-Cl;
d, n = 1, X1 = H, X2 = 2-Cl;
e, n = 1, X1 = Cl, X2 = H;
g, n = 2, X1 = F,
h, n = 3, X1 = F,
i, n = 4, X1 = F,
X2 = 2-F;
X2 = 2-F;
X2 = 2-F;
HN N
N
CH3CN/
K2CO3
O
O
O
N
Br
Br
Br
DMF, K2CO3
.
NH3 H2O
O
O
NH
Br
n
Br
Br
n
O
O
3a-d
8a-d
1
2
N
NH
NaH/THF
F
O
Br
F
O
N
O
Br
N
Br
F
Br
N
O
N
n
N
N
n
CH3CN
F
6a-d
7a-d
3, 4, 6-8: a, n = 1; b, n = 2; c, n = 3; d, n = 4
Scheme 1. Synthetic route of naphthalimide-derived azoles.

Y.-Y. Zhang, C.-H. Zhou / Bioorg. Med. Chem. Lett. 21 (2011) 4349–4352
4351
Table 1
Some characteristic, in vitro antibacterial and antifungal activities as MIC (
l
g/mL) for synthetic compounds 4–7
Gram-negative bacteria
Compds
Mp (°C)
Yield (%)
Gram-positive bacteria
Fungi
C. mycoderma
S. aureus
MRSA
B. subtilis
M. luteus
B. proteus
E .coli
P. aeruginosa
B. typhi
C. albicans
4a
4b
4c
4d
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
193–194
158–160
153–154
181–182
205–207
214–215
210–211
181–183
212–213
242–243
216–218
214–215
212–213
186–187
168–169
143–145
148–150
228–230
208–210
240–242
236–238
—
75
71
77
83
75
80
70
73
68
81
65
60
84
60
63
58
69
71
70
68
73
—
>512
>512
>512
>512
16
16
16
16
32
32
16
32
16
16
16
64
64
4
>512
>512
>512
>512
4
16
16
16
8
16
16
16
32
16
16
128
64
4
256
>512
>512
>512
4
>512
>512
>512
>512
8
256
256
>512
>512
8
>512
>512
>512
>512
4
256
256
256
>512
1
>512
>512
>512
>512
4
16
16
32
16
32
8
16
16
16
16
128
32
8
256
>512
>512
>512
8
8
16
8
16
32
16
16
32
64
64
128
32
32
32
16
32
1
256
>512
>512
>512
4
8
8
4
4
4
8
32
32
16
32
16
32
16
16
32
64
16
8
16
16
8
32
32
16
16
16
32
32
16
16
32
16
8
16
4
32
—
4
2
16
16
8
16
8
16
16
8
32
2
16
32
16
16
32
16
64
64
32
64
32
32
16
16
32
4
32
16
16
32
16
16
64
128
8
8
4
32
—
1
8
2
8
32
16
8
32
64
8
32
16
64
128
8
16
16
64
—
6d
7a
7b
7c
8
2
8
16
—
1
8
8
8
16
16
—
2
2
16
16
—
2
4
16
32
—
1
8
16
32
—
1
8
7d
Fluconazole
Orbifloxacin
Chloromycin
—
—
—
—
1
16
—
—
—
—
4
8
moiety could effectively inhibit the growth of bacteria strains. The
antimicrobial efficacy of triazoliums bridged by (CH2)3 and (CH2)4
groups seems better than those of (CH2)5 and (CH2)6 ones.
Fluconazole. More importantly, compound 5a even exhibited the
same inhibition against C. mycoderma (MIC = 4 g/mL) to the refer-
ence antifungal drug Fluconazole, making it possible to be further
l
The naphthalimide-based imidazoles 6a–d, in contrast to their
triazole analogs, showed more effective activities in vitro against
all the tested bacterial strains. This showed that imidazolyl ring
was more sensitive to bacteria in comparison with triazolyl moi-
ety. Particularly, compounds 6a–b were able to inhibit the growth
investigated as anti-C. mycoderma agent.
In conclusion, a series of naphthalimide-based azoles and their
corresponding azoliums were synthesized for the first time via an
easy, convenient and efficient synthetic procedure starting from
commercial 4-bromo-1,8-naphthalic anhydride. The antimicrobial
tests demonstrated that most naphthalimide-derived azoles
bridged by flexible alkyl chains showed broad antibacterial spec-
of the tested antibacterial strains with MIC values of 8–32 lg/mL
compared to other imidazoles. Considering the advantages of fluo-
rine atom in medicine and based on the previous findings of triazo-
liums, 2,4-difluorobenzyl group was also incorporated into
imidazoliums 7a–d and resulted in the enhancement of antibacte-
rial efficiency as expected, which had further confirmed that the
existence of electropositive moiety should be helpful for the anti-
bacterial activities in naphthalimide azoles.19 Moreover, compared
to triazoliums 5a–i, imidazoliums 7a–d displayed comparable or
even better potency against the tested strains. Especially com-
pounds 7a–b, with (CH2)3 and (CH2)4 linkers respectively, gave
trum and gave low inhibitory concentrations of 1–16 lg/mL
against tested strains. Noticeably, naphthalimide triazolium 5a
and imidazoliums 7a–b displayed good antimicrobial activities
against almost all the pathogenic bacterial strains, especially for
MRSA with comparable activity to the reference drug Chloromycin.
Furthermore, triazoliums 5a–b and 5g–h showed excellent anti-
bacterial efficacy against P. aeruginosa (MIC = 1–4
were 4- to 8-fold more potent than Chloromycin (MIC = 16
l
g/mL), which
g/
l
mL). These observations indicated that azoliums with electroposi-
tive moieties could be beneficial for the antibacterial and anti-
fungal potency efficiently. Factors like spacers between
naphthalimide and azoles could affect the antimicrobial profiles
to some extent, while the formation of azoliums by a variety of hal-
ogen-substituted aryl groups displayed good and comparable
activities. All these results should be a good starting point to opti-
mize the structure to obtain potent antimicrobial agents with these
simple scaffolds. Further researches, including the in vivo bioactive
evaluation, the incorporation of different linkers (alkyl, aryl and
heterocyclic moieties) and diverse heterocyclic azoles (pyrazole,
oxazole, carbazole, benzimidazole, benzotriazole etc.) into naph-
thalimide backbone as well as various functional groups (ester, ke-
tone, amino ones and metal, etc.) linked to azolyl rings are
underway and the findings are expected to report in due course.
low inhibitory concentrations (MIC = 4 and
2 lg/mL) against
MRSA, which suggested they could be served as potential anti-
MRSA agents in comparison with clinical drugs Chloromycin
(MIC = 4
these two compounds also revealed the best antibacterial potential
at the same level (MIC = 4 and 8 g/mL) against S. aureus, which
were equivalent to Orbifloxacin (MIC = 2 g/mL) and Chloromycin
(MIC = 2 g/mL).
lg/mL) and Orbifloxacin (MIC = 1 lg/mL). Moreover,
l
l
l
The antifungal evaluation in vitro showed that most naphthali-
mide-based azoles 4À7 were less sensitive to the tested fungi com-
pared to the bacterial strains. As seen from Table 1, all
naphthalimide derivatives showed antifungal efficiency to some
extent except for triazoles 4a–d, which were similar to the antibac-
terial results. Furthermore, naphthalimide triazoliums 5a–i exhib-
ited better bioactive properties than imidazoles 6a–d and their
corresponding imidazoliums 7a–d on the whole, which further
confirmed the fact that triazole nucleus was in favor of antifungal
potency.19 Compounds 5a–b with (CH2)3 or (CH2)4 linker, showed
excellent antifungal activities against C. albicans and C. mycoderma
Acknowledgments
This work was partially supported by Natural Science Founda-
tion of Chongqing (CSCT: 2007BB5369, 2009BB5296) and South-
west University (SWUB2006018, XSGX0602).
with MIC values of 4 and 8 lg/mL, which were nearly close to

4352
Y.-Y. Zhang, C.-H. Zhou / Bioorg. Med. Chem. Lett. 21 (2011) 4349–4352
(1.44 g) as white solid. Yield 75%; mp 193À194 °C; IR (KBr)
2981, 2934, 2866, 1698, 1659, 1588, 1507, 1346, 1269, 1238, 1140, 1051, 864,
754, 750, 650 cmÀ1 1H NMR (300 MHz, CDCl3) d: 8.67 (d, 1H, J = 7.2 Hz, NAPH-
H), 8.60 (d, 1H, J = 8.4 Hz, NAPH-H), 8.43 (d, 1H, J = 7.8 Hz, NAPH-H), 8.28 (s, 1H,
Tri 3-H), 8.07 (d, 1H, J = 7.8 Hz, NAPH-H), 7.93 (s, 1H, Tri 5-H), 7.88 (t, 1H,
J = 8.0 Hz, NAPH-H), 4.23À4.33 (m, 4H, naphthalimide-CH2CH2CH2), 2.38À2.44
(m, 2H, naphthalimide-CH2CH2) ppm; 13C NMR (100 MHz, CDCl3) d: 163.6,
151.9, 143.3, 133.4, 132.1, 131.3, 131.1, 130.5, 128.8, 128.0, 122.7, 121.8, 47.5,
37.6, 28.4 ppm; ESI–MS (m/z): 407 [M+Na]+, 385 [M+H]+; HR-MS (TOF) calcd
for C17H13BrN4O2 [M+H]+, 385.0300; found, 385.0297.
m: 3120, 3061,
References and notes
;
1. Cechinel-Filho, V.; Campos, F.; Corrêa, R.; Nunes, J. R.; Yunes, R. A. Quím. Nova
2003, 26, 230.
2. (a) Ingrassia, L.; Lefranc, F.; Kiss, R.; Mijatovic, T. Curr. Med. Chem. 2009, 16,
1192; (b) Lv, M.; Xu, H. Curr. Med. Chem. 2009, 16, 4797.
3. Fuente, R. D. L.; Sonawane, N. D.; Arumainayagam, D.; Verkman, A. S. Br. J.
Pharmacol. 2006, 149, 551.
4. Muth, M.; Hoerr, V.; Glaser, M.; Ponte-Sucre, A.; Moll, H.; Stich, A.; Holzgrabe,
U. Bioorg. Med. Chem. Lett. 2007, 17, 1590.
5. Andricopulo, A. D.; Muller, L. A.; Cechinel, V.; Cani, G. S.; Roos, J. F.; Correa, R.;
Santos, A. R. S.; Nunes, R. J.; Yunes, R. A. Farmaco. 2000, 55, 319.
6. Xu, Y. F.; Qian, X. H.; Yao, W.; Mao, P.; Cui, J. N. Bioorg. Med. Chem. 2003, 11,
5427.
7. De Souza, M. M.; Correa, R.; Cechinel, V.; Grabchev, I.; Bojinov, V. Pharmazie.
2002, 57, 430.
8. (a) Costanza, M. E.; Berry, D.; Henderson, I. C.; Ratain, M. J.; Wu, K.; Shapiro, C.;
Duggan, D.; Kalra, J.; Berkowitz, I.; Lyss, A. P. Clin. Cancer Res. 1995, 1, 699; (b)
Braña, M. F.; Ramos, A. Curr. Med. Chem. – Anti-Cancer Agents. 2001, 1, 237.
9. (a) Abuo-Rahma, G. E. D. A. A.; Sarhan, H. A.; Gad, G. F. M. Bioorg. Med. Chem.
2009, 17, 3879; (b) Mohammadkhodaei, Z.; Mokhtari, J.; Nouri, M. Color.
Technol. 2010, 126, 81.
10. (a) Kamal, A.; Satyanarayana, M.; Devaiah, V.; Rohini, V.; Yadav, J. S.; Mullick,
B.; Nagaraja, V. Lett. Drug Des. Discovery 2006, 3, 494; (b) Wu, A. B.; Xu, Y. F.;
Qian, X. H.; Wang, J.; Liu, J. W. Eur. J. Med. Chem. 2009, 44, 4674; (c) Kamal, A.;
Adil, S. F.; Tamboli, J. R.; Siddardh, B.; Murthy, U. S. N. Lett. Drug Des. Discovery
2009, 6, 201.
11. (a) Khalafi-Nezhad, A.; Rad, M. N. S.; Mohabatkar, H.; Asrari, Z.;
Hemmateenejada, B. Bioorg. Med. Chem. 2005, 13, 1931; (b) Mann, J.; Baron,
A.; Opoku-Boahen, Y.; Johansson, E.; Parkinson, G.; Kelland, L. R.; Neidle, S. J.
Med. Chem. 2001, 44, 138; (c) Adams, J. L.; Bocham, J. C.; Gallagher, T. F.; Kassis,
S.; Webb, E. F.; Hall, R.; Sorenson, M.; Garigipati, R.; Grisvold, D. E.; Lee, J. C.
Bioorg. Med. Chem. Lett. 2001, 11, 2867; (d) Ujjinamatada, R. K.; Baier, A.;
Borowski, P.; Hosmane, R. S. Bioorg. Med. Chem. Lett. 2007, 17, 2285; (e) Rostom,
S. A. F.; Ashour, H. M. A.; Razik, H. A. A. E.; Fattah, A. E. F. H. A. E.; El-Din, N. N.
Bioorg. Med. Chem. 2009, 17, 2410.
12. Kumarasamy, K. K.; Toleman, M. A.; Walsh, T. R.; Bagaria, J.; Butt, F.;
Balakrishnan, R.; Chaudhary, U.; Doumith, M.; Giske, C. G.; Irfan, S.;
Krishnan, P.; Kumar, A. V.; Maharjan, S.; Mushtaq, S.; Noorie, T.; Paterson, D.
L.; Pearson, A.; Perry, C.; Pike, R.; Rao, B.; Ray, U.; Sarma, J. B.; Sharma, M.;
Sheridan, E.; Thirunarayan, M. A.; Turton, J.; Upadhyay, S.; Warner, M.;
Welfare, W.; Livermore, D. M.; Woodford, N. Lancet Infect. Dis. 2010, 10, 597.
13. (a) Wan, K.; Zhou, C. H. Bull. Korean Chem. Soc. 2010, 31, 2003; (b) Gan, L. L.;
Fang, B.; Zhou, C. H. Bull. Korean Chem. Soc. 2010, 31, 3684; (c) Wei, J. J.; Jin, L.;
Wan, K.; Zhou, C. H. Bull. Korean Chem. Soc. 2011, 32, 229.
14. Wang, X. L.; Wan, K.; Zhou, C. H. Eur. J. Med. Chem. 2010, 45, 4631.
15. (a) Zhang, F. F.; Gan, L. L.; Zhou, C. H. Bioorg. Med. Chem. Lett. 2010, 20, 1881; (b)
Luo, Y.; Lu, Y. H.; Gan, L. L.; Zhou, C. H.; Wu, J.; Geng, R. X.; Zhang, Y. Y. Arch.
Pharm. Chem. Life. Sci. 2009, 342, 386.
16. Experimental: Melting points are uncorrected and were recorded on XÀ6
melting point apparatus. IR spectra were recorded on a Bio-Rad FTS-185 (Bio-
Rad, Cambridge, MA, USA) by using KBr disks. 1H NMR and 13C NMR spectra
were recorded on a Bruker AV 300 or Varian 400 spectrometer using TMS as an
Synthesis of 1-(4-(4-bromo-1,8-naphthalimide-2-yl)butyl)-4-(2,4-difluorobenzyl)-
1H-1,2,4-triazolium bromide (5g).
A mixture of 2-(3-(1H-1,2,4-triazol-1-
yl)butyl)-4-bromo-1,8-naphthalimide (4b, 0.80 g, 2.0 mmol) and 2,4-
difluorobenzyl bromide (0.52 g, 2.5 mmol) in acetonitrile (15 mL) was stirred
at 83 °C. After the reaction came to the end, the solvent was evaporated under
reduced pressure. The residue was washed three times with petroleum ether
(30À60 °C) and dried to afford compound 5g (0.79 g) as white solid. Yield 65%;
mp 216À218 °C; IR (KBr)
m
;
: 3021, 2964, 1700, 1660, 1508, 1380, 1343, 1234,
1145, 1098, 780, 621 cmÀ1
1H NMR (400 MHz, DMSO-d6) d: 10.15 (s, 1H, Tri 3-
H), 9.28 (s, 1H, Tri 5-H), 8.57 (d, 2H, J = 7.2 Hz, NAPH-H), 8.33 (d, 1H, J = 8.0 Hz,
NAPH-H), 8.24 (d, 1H, J = 7.6 Hz, NAPH-H), 8.01 (t, 1H, J = 8.0 Hz, NAPH-H),
7.61À7.67 (m, 1H, 2,4-F2CH2Ph 6-H), 7.35À7.40 (m, 1H, 2,4-F2CH2Ph 5-H),
7.17À7.22 (m, 1H, 2,4-F2CH2Ph 3-H), 5.53 (s, 2H, Tri N4-CH2), 4.40 (t, 2H,
J = 7.2 Hz, Tri N1-CH2), 4.06 (t, 2H, J = 7.2 Hz, naphthalimide-CH2), 1.88À1.95
(m, 2H, Tri-CH2CH2), 1.62À1.70 (m, 2H, naphthalimide-CH2CH2), ppm; ESI–MS
(m/z): 527 [MÀBr]+; HR-MS (TOF) calcd for C25H20BrF2N4O2+ [M+H]+, 526.0810;
found, 526.0819.
Synthesis of 2-(6-(1H-imidazol-1-yl)hexyl)-4-bromo-1,8-naphthalimide (6d). To a
mixture of imidazole (0.34 g, 4.8 mmol) and NaH (0.12 g, 4.8 mmol) in THF
(10 mL) was added 4-bromo-2-(6-bromohexyl)-1,8-naphthalimide (1.76 g,
4.0 mmol). The reaction was stirred at room temperature for 48 h under a
stream of nitrogen. After the reaction came to the end (monitored by TLC,
eluent, chloroform/methanol, 10/1, V/V), THF was removed by
a rotary
evaporator. The resulting solution was extracted with CH2Cl2 (3 Â 30 mL). All
the combined CH2Cl2 solutions were dried over anhydrous Na2SO4 and then
evaporated under reduced pressure. The residue was purified via silica gel
column chromatography (chloroform/methanol, 10/1, V/V) to give compound
6d (1.17 g) as white solid. Yield 69%; mp 148À150 °C; IR (KBr)
2854, 1670, 1659, 1589, 1570, 1359, 1345, 1229, 1109, 1072, 751, 713,
664 cmÀ1 1H NMR (300 MHz, CDCl3) d: 8.66 (d, 1H, J = 7.2 Hz, NAPH-H), 8.59
m: 3119, 2933,
;
(d, 1H, J = 8.4 Hz, NAPH-H), 8.42 (d, 1H, J = 7.8 Hz, NAPH-H), 8.05 (d, 1H,
J = 7.8 Hz, NAPH-H), 7.86 (t, 1H, J = 8.0 Hz, NAPH-H), 7.50 (s, 1H, Im 2-H), 7.06
(s, 1H, Im 5-H), 6.92 (s, 1H, Im 4-H), 4.16 (t, 2H, J = 7.4 Hz, Im-CH2), 3.94 (t, 2H,
J = 7.1 Hz, naphthalimide-CH2), 1.72À1.76 (m, 4H, naphthalimide-CH2CH2, Im-
CH2CH2), 1.40À1.45 (m, 4H, Im-CH2CH2CH2CH2) ppm; ESI–MS (m/z): 426 [M]+;
HR-MS (TOF) calcd for C21H20BrN3O2 [M+H]+, 426.0817; found, 426.0808.
Synthesis of 1-(3-(4-bromo-1,8-naphthalimide-2-yl)propyl)-3-(2,4-dichlorob-
enzyl)-1H-1,3-imidazol-3-ium bromide (7a).
A mixture of compound 6a
(0.80 g, 2.0 mmol) and 2,4- difluorobenzyl bromide (0.52 g, 2.5 mmol) in
acetonitrile (15 mL) was stirred at 83 °C. After the reaction came to the end, the
solvent was evaporated under reduced pressure. The residue was washed three
times with petroleum ether (30À60 °C) and dried to give compound 7a (0.79 g)
as white solid. Yield 71%; mp 228À230 °C; IR (KBr)
m
: 3135, 3071, 2969, 2854,
1660, 1506, 1365, 1277, 1232, 1153, 883, 780, 688 cmÀ1
;
1H NMR (300 MHz,
internal standard. Chemical shifts were given in
d ppm and signals are
DMSO-d6) d: 9.23 (s, 1H, Im 2-H), 8.55 (d, 2H, J = 8.4 Hz, NAPH-H), 8.31 (d, 1H,
J = 7.6 Hz, NAPH-H), 8.27 (d, 1H, J = 8.1 Hz, NAPH-H), 8.01 (t, 1H, J = 8.0 Hz,
NAPH-H), 7.84 (s, 1H, Im 4-H), 7.79 (s, 1H, Im 5-H), 7.56À7.64 (m, 1H, 2,4-F2Ph
6-H), 7.34À7.41 (m, 1H, 2,4-F2Ph 5-H), 7.16À7.21 (m, 1H, 2,4-F2Ph 3-H), 5.47 (s,
2H, Im N3-CH2), 4.27 (t, 2H, J = 8.0 Hz, Im N1-CH2), 4.06 (t, 2H, J = 8.0 Hz,
naphthalimide-CH2), 2.19À2.24 (m, 2H, Im N1-CH2CH2) ppm; ESI–MS (m/z):
described as singlet (s), doublet (d), triplet (t), quartet (q), broad (br) and
multiplet (m). The mass spectra were recorded on LCMS-2010A and HR-MS.
Column chromatographies were performed on silica gel (300–400 mesh)
column. TLC analyses were done using pre-coated silica gel plates and
visualization was done using UV lamp at 254 nm. All the solvents used were
analytical grade only.
511 [MÀBr]+; HR-MS (TOF) calcd for C25H19BrF2N3O2 [M+H]+, 511.0701;
+
Synthesis of 2-(3-(1H-1,2,4-triazol-1-yl)propyl)-4-bromo-1,8-naphthalimide (4a).
found, 511.0709.
A
mixture of 1H-1,2,4-triazole (0.50 g, 7.0 mmol), 4-bromo-2-(3-
17. National Committee for Clinical Laboratory Standards Approved standard
Document. M27-A2, Reference Method for Broth Dilution Antifungal
Susceptibility Testing of Yeasts, National Committee for Clinical Laboratory
Standards, wayne, PA, 2002.
18. (a) Karthikeyan, M. S.; Holla, B. S.; Kumari, N. S. Eur. J. Med. Chem. 2008, 43, 309;
(b) Karegoudar, P.; Prasad, D. J.; Ashok, M.; Mahalinga, M. Eur. J. Med. Chem.
2008, 43, 808; (c) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (d)
Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
bromopropyl)-1,8-naphthalimide (3a, 1.98 g, 5.0 mmol), potassium carbonate
(1.04 g, 7.5 mmol) and TBAB (tetrabutyl ammonium bromide, 5 mg) in
acetonitrile (30 mL) was stirred at 55 °C. After the reaction came to the end
(monitored by TLC, eluent, chloroform/methanol, 10/1, V/V), the solvent was
evaporated and then water (30 mL) was added. The resulting mixture was
extracted with CH2Cl2 (3 Â 30 mL), the combined organic phases were dried
over anhydrous Na2SO4 and then the solvent was evaporated under reduced
pressure. The resulting residue was purified via silica gel column
chromatography (chloroform/methanol, 10/1, V/V) to give compound 4a
19. Fang, B.; Zhou, C. H.; Rao, X. C. Eur. J. Med. Chem. 2010, 45, 4388.