Synthesis and the biological activity of phosphonylated 1,2,3-triazolenaphthalimide conjugates

Article abstract of DOI:10.3390/molecules21111420

A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)- methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates designed as analogues of amonafide was synthesized. All phosphonates were assessed for antiviral activity against a broad range of DNA and RNA viruses and several of them showed potency against varicella-zoster virus (VZV) [EC₅₀ (50% effective concentration) = 27.6-91.5 μM]. Compound 16b exhibited the highest activity against a thymidine kinase-deficient (TK-) VZV strain (EC₅₀ = 27.59 μM), while 16d was the most potent towards TK+ VZV (EC₅₀ = 29.91 μM). Cytostatic properties of the compounds 14a-i-17a-i were studied on L1210, CEM, HeLa and HMEC-1 cell lines and most of them were slightly cytostatic for HeLa [IC50 (50% inhibitory concentration) = 29-130 μM] and L1210 cells [IC50 (50% inhibitory concentration) =14-142 μM].

Full text of DOI:10.3390/molecules21111420

molecules
Article
Synthesis and the Biological Activity of
Phosphonylated 1,2,3-Triazolenaphthalimide
Conjugates
Iwona E. Głowacka 1,*, Rafał Gulej 1, Piotr Grzonkowski 1, Graciela Andrei 2,
Dominique Schols 2, Robert Snoeck 2 and Dorota G. Piotrowska 1
1
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Muszyn´skiego 1,
90-151 Lodz, Poland; rafal.gulej@stud.umed.lodz.pl (R.G.); grzonkowskipiotr4@gmail.com (P.G.);
dorota.piotrowska@umed.lodz.pl (D.G.P.)
Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium;
2
Graciela.Andrei@rega.kleuven.be (G.A.); Dominique.Schols@rega.kleuven.be (D.S.);
Robert.Snoeck@rega.kleuven.be (R.S.)
*
Correspondence: iwona.glowacka@umed.lodz.pl; Tel.: +48-42-677-92-37; Fax: +48-42-678-83-98
Academic Editor: D. Hadjipavlou-Litina
Received: 3 October 2016; Accepted: 20 October 2016; Published: 26 October 2016
Abstract: A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-
methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates designed as analogues of amonafide was synthesized.
All phosphonates were assessed for antiviral activity against a broad range of DNA and RNA viruses
and several of them showed potency against varicella-zoster virus (VZV) [EC50 (50% effective
concentration) = 27.6–91.5
kinase-deficient (TK−) VZV strain (EC50 = 27.59
TK+ VZV (EC50 = 29.91
M). Cytostatic properties of the compounds 14a
L1210, CEM, HeLa and HMEC-1 cell lines and most of them were slightly cytostatic for HeLa [IC50
µ
M]. Compound 16b exhibited the highest activity against a thymidine
M), while 16d was the most potent towards
17a were studied on
µ
µ
–
i
–
–i
(50% inhibitory concentration) = 29–130 µM] and L1210 cells [IC50 (50% inhibitory concentration) =
14–142 µM].
Keywords: azidophosphonates; acyclonucleotides; naphthalimides; 1,2,3-triazoles; cycloaddition;
antiviral; cytostatic
1. Introduction
Pharmacologically important natural as well as synthetic compounds having various heterocyclic
systems including powerful pharmacophores such as triazoles and naphthalimides are of special
interest. Numerous compounds of the 1,2,3-triazole family have shown a broad spectrum of biological
activities, including antibacterial [
antiallergic effects [17]. Furthermore, substituted 1,2,3-triazoles have also been used as agrochemicals,
dyes, photostabilisers and corrosion inhibitors [18 20]. Various biological activities of substituted
1,2], antifungal [3–6], anticancer [7–11], antiviral [12–16] and
–
1,2,3-triazoles are closely related to their chemical reactivity since they are able to form hydrogen
bonds, could be protonated at the physiological pH and are resistant to oxidation and reduction as
well as to enzymatic hydrolysis to name the most important features.
Naphthalimide derivatives such as mitonafide [21
–23], amonafide [21
–
25], azonafide [26
–28],
DMP-840 [29] and elinafide (Lu-79553) [30 31] exhibit intercalating properties [21
,
,22]. However, the
clinical use of these compounds has been limited due to their low therapeutic indices as well as poor
water-solubility [32]. In order to improve therapeutic properties of naphthalimides, many efforts have
been undertaken towards synthesizing novel derivatives with higher activity and lower toxicity.
Molecules 2016, 21, 1420; doi:10.3390/molecules21111420
www.mdpi.com/journal/molecules

Molecules 2016, 21, 1420
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The concept of combining two pharmacophoric fragments of biologically active compounds into
a single molecule is commonly applied aiming at improvement of activities and eventually to avoid
serious side effects of the known candidates. Having this idea in mind several structural analogues of
amonafide have been synthesized over the years (Figure 1).
R = CH2CH2N(CH3)2
CH2CH2N(CH2CH3)2
CH2CH2CH2CH3
R
N
R
N
O
O
O
O
CH2CH2OH
CH2CH2N(CH2CH2)2NH
N
N
R1
N
N
1
2
N
N
R1 = H, Ph
N
N
N
N
N
n
N
N
n
Ar
O
N
O
O
N
O
Ar
Br
Br
X
N
n
N
Ar
Br
3
4
X = N, CH
Ar = substituted phenyl
n = 3, 5, 7
Ar = substituted phenyl
n = 1 - 4
Figure 1. Examples of naphthalimides containing triazole units.
Qian and Li reported the synthesis of 6-(1,2,3-triazole)-1,8-naphthalimides
cytotoxic activity [33]. Furthermore, 5-substituted analogues were also obtained and their cytotoxicity
against MCF-7, HeLa and 7721 cells was evaluated [34]. Among all tested compounds , derivatives
having a 2-(N,N-dimethylamino)ethyl group at the imide nitrogen and phenyl at C4 in the 1,2,3-triazole
ring or alternatively lacking this substituent were found the most active (IC50 in the 0.258–0.725
range) with inhibition abilities higher than that of amonafide, used as a control. On the other hand,
antifungal and antimicrobial properties of 1,2,4-triazole derivatives were examined and several
1 and proved their
2
2
µM
3
compounds exhibited even better activity against some tested strains than orbifloxacin, chloromycin
and fluconazole used as reference drugs [35]. Among bis(1,2,3-triazole)-conjugates of naphthalimides
4
, a derivative substituted with 3,4-dichlorophenyl groups exhibited better inhibitory activity toward
Escherichia coli than norfloxacin and chloromycin with a minimum inhibitory concentration (MIC)
value of 1 µg/mL [36].
These achievements prompted us to propose a new modification at the imide nitrogen of
amonafide 14–17 by installation of N1-substituted 1,2,3-triazoles decorated at the end of the alkyl
chain with phosphonoalkyl groups. We aimed to understand the influence of the phosphonate group
on the biological activity of the designed amonafide analogues. On the other hand, compounds
14
phosphonate moiety and a naphthalimide fragment serves as a modified nucleobase. Thus, in principle
compounds 14 17 may primarily act as intercalators (through a naphthalimide ring) but also by a
phosphonate activation and termination of DNA/RNA synthesis.
–17 resemble analogues of acyclic nucleotides in which the phosphate group is replaced with a
–

Molecules 2016, 21, 1420
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2. Results and Discussion
2.1. Chemistry
The synthetic strategy to the 1,2,3-triazole-containing naphthalimide derivatives 14a–i–17a–i
is presented in Schemes 1 and 2. The syntheses of alkynes
previously described. For the purpose of this project both
known procedure described for 41], although it appeared to be a new approach to the preparation of
a compound . The alkynes 11 and 12 were synthesized from commercially available 1,8-naphthalimic
anhydride as shown in Scheme 1. The nitration of the anhydride provided 43] which was
then reduced to give a compound 10 44]. The subsequent propargylation of and 10 afforded the
alkynes 11 and 12, respectively. Azidophosphonates 13a 45 50] were previously obtained and fully
characterized in our laboratory. The Cu(I)-catalyzed Hüisgen dipolar cycloaddition of N-propargyl
derivatives 11 12 and the respective azidoalkylphosphonates 13a 45 50] allowed to construct
naphthalimides 14a 17a having various phosphonoalkyl groups regioselectively installed at N-1
of the 1,2,3-triazole subunit (Scheme 2). The chromatographic purification or crystallization gave pure
14a 17a
in good to excellent yields. Their structures and purities were established by 1H-, 13C- and
31P-NMR and IR techniques as well as by elemental analyses.
7
[
37–
39] and
8 [40–42] have been
7
and
8
were obtained following the
8
[
7
5
5
9 [
[
9
–i
[
–
7–
8/
–
–i
[
–
–
i–
–i
–
i–
–i
Scheme 1. Synthesis of the alkynes 7, 8, 11 and 12. Reagents and Conditions: a. propargylamine, EtOH,
reflux (3 h for 7, 11 and 12; 20 h for 8); b. HNO3, H2SO4; c. SnCl2, HCl.
(EtO)2(O)P
X
N
N
N
O
N
O
O
N
O
CuSO4
sodium ascorbate
(EtO)2(O)P
X N3
EtOH-H2O (1:1, v/v)
MW 15 -20 min.
R
R
13a−i
7
8
R = H
a X = CH2,
b X = CH2CH2,
c X = CH2CH2CH2,
d X = CH2CH2CH2CH2,
e X = CH(OH)CH2,
14a−i R = H
R = 6-Br
15a−i R = 6−Br
16a−i R = 5−NO2
17a−i R = 5−NH2
11 R = 5−NO2
12 R = 5−NH2
f
X = CH2CH(OH)CH2,
g X = CH2OCH2CH2,
h X = CH2CH2OCH2CH2,
i X = CH2NHC(O)CH2
Scheme 2. Synthesis of 1,2,3-triazoles derivatives 14a–i–17a–i.

Molecules 2016, 21, 1420
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2.2. Antiviral Activity and Cytostatic/Cytotoxic Evaluation
Phosphonates 14a–i–17a–i were evaluated for their antiviral activities against a wide variety
of DNA and RNA viruses using the following cell-based assays: (a) human embryonic lung (HEL)
cell cultures: herpes simplex virus-1 (KOS strain), herpes simplex virus-2 (G strain), vaccinia virus,
vesicular stomatitis virus, thymidine kinase-deficient herpes simplex virus-1 (TK− KOS ACVr) and
adenovirus-2, cytomegalovirus (AD-169 stain and Davis stains) and varicella-zoster virus (TK+ VZV
stain and TK− VZV stain); (b) HeLa cell cultures: vesicular stomatitis virus, Coxsackie virus B4 and
respiratory syncytial virus; (c) Vero cell cultures: para-influenza-3 virus, reovirus-1, Sindbis virus,
Coxsackie virus B4, Punta Toro virus; (d) Crandell-Rees Feline Kidney (CRFK) cell cultures: feline
corona virus (FIPV) and feline herpes virus (FHV) and (e) Madin Darby Canine Kidney (MDCK)
cell cultures: influenza A virus H1N1 subtype, influenza A virus H3N2 subtype and influenza B
virus. Ganciclovir, cidofovir, acyclovir, brivudin, (S)-9-(2,3-dihydroxypropyl)adenine [(S)-DHPA],
Hippeastrum hybrid agglutinin (HHA), Urticadioica agglutinin (UDA), dextran sulfate (molecular weight
5000, DS-5000), ribavirin, oseltamivir carboxylate, amantadine and rimantadine were used as the
reference compounds. The antiviral activity was expressed as the EC50: the compound concentration
required to reduce virus-induced cytopathogenicity by 50% (other viruses).
Among the synthesized compounds, several phosphonates 14
,
15 and 16 slightly inhibited the
M range, however with
replication of both TK+ and TK− VZV strains with EC50 in the 27.6–91.5
µ
lower potency than that of acyclovir and brivudine, used as reference drugs (Table 1).
Table 1. The antiviral activity and cytotoxicity against varicella-zoster virus (VZV) in HEL cell cultures.
Antiviral Activity EC50 (µM) a
Cytotoxicity (µM)
Compound
TK+ VZV Strain
TK VZV Strain
Cell Growth (CC50)
−
c
Cell Morphology (MCC) b
11
48.9
>100
86.39
69.93
>100
34.2
40.44
86.39
37.14
39.11
>100
32.82
29.91
83.63
56.66
50.17
40.9
>100
64.47
56.66
>100
74.63
38.07
37.54
>100
70.83
64.47
27.59
47.82
53.85
>100
91.45
>100
64.47
7.82
100
>100
>100
>100
>100
>100
100
>100
>100
>100
100
>100
>100
>100
>100
>100
>100
20
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
1.15
3.25
>440
>440
>300
>300
14c
14d
14e
14h
15b
15d
15f
15h
16a
16b
16c
16d
16e
16f
16g
16h
5.36
3.18
1.51
1.15
0.013
0.0078
Amonafide
Acyclovir
6.48
20
47.51
29.35
24.95
13.72
>440
>440
>300
>300
Brivudin
a Effective concentration required to reduce virus plaque formation by 50%. Virus input was 100 plaque forming
units (PFU); b Minimum cytotoxic concentration that causes a microscopically detectable alternation of cell
morphology; c Cytotoxic concentration required to reduce cell growth by 50%, n.d.—not determined.
The cytotoxicity of the tested compounds toward the uninfected host cells was defined as the
minimum cytotoxic concentration (MCC) that causes a microscopically detectable alteration of normal
cell morphology. The 50% cytotoxic concentration (CC50), causing a 50% decrease in cell viability
was determined using a colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-
2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay system. None of the tested compounds affected cell
morphology of HEL, HeLa, Vero, MDCK and CRFK cells at concentrations up to 100 µM.

Molecules 2016, 21, 1420
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The cytostatic activity of the tested compounds was defined as the 50% cytostatic inhibitory
concentration (IC50) causing a 50% decrease in cell proliferation and was determined against murine
leukaemia L1210, human lymphocyte CEM, human cervix carcinoma HeLa and human dermal
microvascular endothelial HMEC-1 cells (Table 2).
Table 2. The inhibitory effect of the tested compounds against the proliferation of murine leukemia
(L1210), human T-lymphocyte (CEM) and human cervix carcinoma cells (HeLa).
a
IC50 (µM)
Compound
L1210
CEM
HeLa
HMEC-1
7
8
11
>250
≥250
206 ± 42
≥250
48 ± 8
138 ± 38
>250
>250
177 ± 16
229 ± 18
187 ± 25
148 ± 59
124 ± 19
119 ± 3
>250
109 ± 5
>250
>250
>250
>250
14a
14b
14c
14d
14e
14f
14g
14h
14i
15a
15b
15c
15d
15e
15f
15g
15h
15i
16a
16b
16c
16d
16e
16f
16g
16h
16i
17a
17b
17c
17d
17e
17f
17g
17h
17i
>250
>250
204 ± 65
172 ± 20
150 ± 11
≥250
≥250
≥250
156 ± 40
180 ± 54
≥250
>250
>250
>250
158 ± 4
168 ± 29
171 ± 25
≥250
168 ± 26
215 ± 49
154 ± 22
>250
>250
≥250
196 ± 32
222 ± 39
>250
>250
28 ± 1
14 ± 1
20 ± 3
17 ± 3
42 ± 15
23 ± 3
24 ± 3
26 ± 2
31 ± 2
66 ± 7
>250
34 ± 9
70 ± 52
111 ± 39
68 ± 11
71 ± 1
64 ± 11
>250
60 ± 27
56 ± 20
52 ± 34
22 ± 0
196 ± 60
60 ± 13
66 ± 20
29 ± 11
137 ± 72
69 ± 1
176 ± 37
55 ± 23
95 ± 4
127 ± 14
71 ± 21
79 ± 4
66 ± 0
>250
88 ± 5
185 ± 40
152 ± 1
152 ± 0
92 ± 43
>250
152 ± 1
152 ± 1
151 ± 0
>250
154 ± 1
118 ± 71
136 ± 22
126 ± 37
>250
155 ± 6
148 ± 3
152 ± 1
>250
62 ± 20
62 ± 1
55 ± 2
>250
87 ± 21
84 ± 16
61 ± 15
>250
44 ± 19
54 ± 21
29 ± 17
81 ± 4
132 ± 2
42 ± 21
76 ± 8
56 ± 16
86 ± 6
177 ± 76
214 ± 5
120 ± 7
≥250
101 ± 78
69 ± 12
≥250
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
>250
>250
>250
>250
>250
>250
116 ± 60
72 ± 58
130 ± 77
97 ± 42
66 ± 3
>250
>250
>250
>250
142 ± 2
109 ± 3
>250
>250
112 ± 58
n.d
Amonafide
1.0 ± 0.4
0.54 ± 0.50
2.0 ± 1.2
0.31 ± 0.00
a
50% Inhibitory concentration or compound concentration required to inhibit tumor cell proliferation by 50%,
n.d.—not determined.
Among all tested compounds 1,2,3-triazole-amonafide conjugates 15a–i having a bromine atom
at C6 of the naphthalimide unit were the most cystostatic toward the tested tumor cell lines at
concentrations as low as 14 M being especially effective for L1210 (IC50 = 14–42 M). Conjugates
16a containing the nitro group at C5 were slightly less active and showed moderate cytostatic effects
toward HeLa cells (IC50 = 29–132 M). The replacement of the nitro by an amino group at C5 of the
µ
µ
–
i
µ

Molecules 2016, 21, 1420
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naphthalimide skeleton resulted in the decrease or even loss of the inhibitory capacity of the respective
analogues (15a vs. 17a ). Similarly, negligible inhibitory properties against the proliferation of the
–
i
–i
tested cell lines were noticed for the series of naphthalimide phosphonates 14a–i (R = H).
The presence of the 1,2,3-triazole unit seems to be necessary for cytostatic activity of the tested
compounds since naphthalimides devoid of this moiety appeared inactive (11 vs. 16a
However, it was found that a compound moderately inhibited (IC50 = 48 M) the proliferation of
HeLa cells while naphthalimides 14a could be considered inactive (IC50 = 150–>250 M). Among the
–i and 8 vs. 15a–i).
7
µ
–
i
µ
1,2,3-triazoles with phosphonate linkers [compounds 16 (nitro) and 15 (bromo)], the compounds with
longer fragments are generally associated with the higher potency, e.g., 16c and 15c (trimethylene),
15d (tetramethylene) and 15h (CH2CH2OCH2CH2), the lowest activity being observed for 16e and 15e
[CH(OH)CH2] as well as for 16i and 15i [CH2NHC(O)CH2] with shorter fragments.
3. Experimental Section
3.1. General Information
1H-NMR spectra were taken in CDCl3 or DMSO-d6 on the following spectrometers: Mercury-200
(Varian NMR INSTRUMENT, Palo Alto, CA, USA) and Avance III (600 MHz) (Bruker Instruments,
Karlsruhe, Germany) with TMS as an internal standard; chemical shifts δ are given in ppm with respect
to TMS and coupling constants J in Hz. 13C-NMR spectra were recorded for CDCl3 or DMSO-d6
solutions on a Bruker Avance III (600 MHz) spectrometer at 151 MHz. 31P-NMR spectra were taken in
CDCl3 or DMSO-d6 on Varian Mercury-200 and Bruker Avance III at 81 and 243 MHz.
IR spectral data were measured on an Infinity MI-60 FT-IR spectrometer (ATI Instruments North
America—Mattson, Medison, WI, USA). Melting points were determined on a Boetius apparatus and
are uncorrected. Elemental analyses were performed by the Microanalytical Laboratory of the Faculty
of Pharmacy (Medical University of Lodz) on a PE 2400 CHNS analyser (Perkin Elmer Corp., Norwalk,
CT, USA).
The following adsorbents were used: column chromatography, silica gel 60 (70–230 mesh, Merck
KGaA, Darmstadt, Germany); analytical TLC, Merck TLC plastic sheets silica gel 60 F254. TLC plates
were developed in chloroform–methanol solvent systems. Visualization of spots was effected with
iodine vapors. All solvents were purified by methods described in the literature.
All microwave irradiation experiments were carried out in a RM 800 microwave reactor
(Plazmatronika, Wrocław, Poland).
3.2. Synthesis of 2-(Prop-2-yn-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (7)
A suspension of a compound
5 (1.00 mmol), propargyl amine (1.05 mmol) in ethanol (15 mL) was
◦
stirred at 78 C for 3 h. The reaction mixture was cooled to room temperature and filtered to give pure
7
as a white powder. Yield 90%; m.p. 239–240 ◦C; IR (KBr):
ν
= 3244, 3001, 2996, 1734, 1689, 1331,
1
780 cm−1; H-NMR (200 MHz, CDCl3):
δ = 8.65 (dd, J = 7.3 Hz, J = 1.2 Hz, 2H, Haromat.), 8.24 (dd,
J = 8.1 Hz, J = 1.2 Hz, 2H, Haromat.), 7.78 (dd, J = 8.1 Hz, J = 7.3 Hz, 2H, Haromat.), 4.97 (d, J = 2.5 Hz, 1H,
HC≡CCH2), 2.20 (t, J = 2.5 Hz, 2H, HC≡CCH2).
3.3. Synthesis of 5-Nitro-2-(prop-2-yn-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (11)
A suspension of compound
stirred at 78 C for 4 h. The reaction mixture was cooled to room temperature then filtered to give 11 as
9 (1.00 mmol), propargyl amine (1.05 mmol) in ethanol (15 mL) was
◦
an orange powder which was pure to be used in the next step without further purification. Yield 90%;
◦
m.p. = 213–214 C; IR (KBr):
CDCl3): = 9.30 (d, J = 2.2 Hz, 1H, Haromat.), 9.11 (d, J = 2.2 Hz, 1H, Haromat.), 8.78 (dd, J = 7.3 Hz,
J = 1.2 Hz, 1H, Haromat.), 8.40 (dd, J = 8.3 Hz, J = 1.2 Hz, 1H, Haromat.), 7.91 (dd, J = 8.3 Hz, J = 7.3 Hz, 1H,
Haromat.), 4.97 (d, J = 2.5 Hz, 1H, HC CCH2), 2.20 (t, J = 2.5 Hz, 2H, HC
CCH2); 13C-NMR (151 MHz,
DMSO-d6): = 162.45, 161.99, 146.30, 137.18, 134.69, 131.38, 130.52, 129.99, 129.76, 124.03, 123.66, 122.61,
ν
= 3257, 3082, 3064, 2992, 1711, 1672, 1344, 789 cm−1; 1H-NMR (200 MHz,
δ
≡
≡
δ

Molecules 2016, 21, 1420
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79.37, 73.81, 29.90. Anal. Calcd. for C15H8N2O4: C, 64.29; H, 2.88; N, 10.00. Found: C, 64.33; H, 3.02;
N, 9.95.
3.4. Synthesis of 5-Amino-2-(prop-2-yn-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (12)
A suspension of compound 10 (1.00 mmol), propargyl amine (1.05 mmol) in ethanol (15 mL) was
◦
stirred at 78 C for 3 h. The reaction mixture was cooled to room temperature and filtered to give 12 as
orange needles which were pure to be used in the next step without further purification. Yield 92%;
m.p. >250 ◦C; IR (KBr):
DMSO-d6):
1H, Haromat.), 7.63 (dd, J = 8.2 Hz, J = 7.2 Hz, 1H, Haromat.), 7.31 (d, J = 2.2 Hz, 1H, Haromat.), 6.04 (s, 2H,
NH2), 4.75 (d, J = 2.2 Hz, 1H, HC CCH2), 3.13 (t, J = 2.2 Hz, 2H, HC
CCH2); 13C-NMR (151 MHz,
DMSO-d6): = 163.48, 163.31, 148.42, 134.09, 132.41, 127.49, 126.20, 122.65, 122.38, 121.86, 120.97, 112.65,
ν
= 3406, 3373, 3209, 2999, 1730, 1693, 1445, 782 cm−1; 1H-NMR (200 MHz,
δ
= 8.11 (d, J = 7.2 Hz, 1H, Haromat.), 8.06 (d, J = 8.2 Hz, 1H, Haromat.), 7.99 (d, J = 2.2 Hz,
≡
≡
δ
80.00, 73.26, 29.47. Anal. Calcd. for C15H10N2O2: C, 71.99; H, 4.03; N, 11.19. Found: C, 71.74; H, 3.98;
N, 10.96.
3.5. General Procedure for Copper(I)-Catalyzed Cycloaddition Reactions
To a solution of azidoalkylphosphonate 13a
CuSO4 5H2O (0.10 mmol), sodium ascorbate (0.20 mmol) and the respective N-propargyl
naphthalimides 7/8 11/12 (1.00 mmol) were added. The reaction mixture was microwave irradiated
–i (1.00 mmol) in EtOH (1.0 mL) and H2O (1.0 mL),
×
–
at 35–40 ◦C for 15 min. After removal of solvents the residue was suspended in chloroform (5 mL),
filtered through a layer of Celite and concentrated in vacuo. Crude products were purified on silica gel
columns with chloroform–methanol mixtures (100:1 or 50:1, v/v) or crystallized from the appropriate
solvents to give the 1,2,3-triazoles 14a–i–17a–i.
Diethyl {4-[1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}methylphosphonate
(
14a): Yield ◦81% (after crystallization from an ethyl acetate–hexane mixture). A white solid;
m.p. 110–111 C; IR (KBr):
ν
= 3446, 3245, 3234, 2983, 2931, 1700, 1659, 1236, 1023, 782, cm−1; 1H-NMR
(200 MHz, CDCl3):
Haromat.), 7.86 (s, 1H, HC50), 7.70 (dd, J = 8.1 Hz, J = 7.3 Hz, 2H, Haromat.), 5.49 (s, 2H, CH2), 4.71 (d,
J = 13.0 Hz, 2H, PCH2), 4.15–4.00 (m, 4H, 2 POCH2CH3), 1.24 (t, J = 7.0 Hz, 6H, 2 POCH2CH3);
13C-NMR (151 MHz, CDCl3):
= 163.81, 144.18, 134.14, 131.63, 131.46, 128.24, 126.92, 124.27, 122.51,
63.46 (d, J = 6.6 Hz, POC), 45.83 (d, J = 155.3 Hz, PC), 35.18, 16.24 (d, J = 5.7 Hz, POCC); 31P-NMR
(81 MHz, CDCl3): = 16.57 ppm. Anal. Calcd. for C20H21N4O5P: C, 56.08; H, 4.94; N, 13.08. Found: C,
δ = 8.54 (dd, J = 7.3 Hz, J = 1.2 Hz, 2H, Haromat.), 8.16 (dd, J = 8.1 Hz, J = 1.2 Hz, 2H,
×
×
δ
δ
56.21; H, 4.76; N, 12.84.
Diethyl 2-{4-[(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethylphosphonate
(
14b): Yield 79% (after crystallization from an ethyl acetate–hexane mixture). A white solid;
m.p. 63–64 ◦C; IR (KBr): = 3422, 3245, 2981, 2927, 1701, 1659, 1588, 1237, 1026, 780 cm−1; 1H-NMR
(200 MHz, CDCl3): = 8.62 (dd, J = 7.3 Hz, J = 1.2 Hz, 2H, Haromat.), 8.22 (dd, J = 8.3 Hz, J = 1.2 Hz, 2H,
Haromat.), 7.75 (dd, J = 8.3 Hz, J = 7.3 Hz, 2H, Haromat.), 7.69 (s, 1H, HC50), 5.51 (s, 2H, CH2), 4.62–4.48
(m, 2H, PCH2CH2), 4.12–3.98 (m, 4H, 2 POCH2CH3), 2.46–2.29 (m, 2H, PCH2), 1.26 (t, J = 7.0 Hz,
6H, 2 = 163.85, 143.77, 134.78, 131.63, 131.49, 128.23,
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
126.95, 123.52, 122.51, 62.10 (d, J = 6.5 Hz, POC), 44.47 (PCC), 35.23, 27.29 (d, J = 143.0 Hz, PC), 16.32
(d, J = 5.9 Hz, POCC); 31P-NMR (81 MHz, CDCl3):
= 26.30 ppm. Anal. Calcd. for C21H23N4O5P
0.5H2O: C, 55.87; H, 5.36; N, 12.41. Found: C, 55.93; H, 5.15; N, 12.38.
ν
δ
×
×
δ
δ
×
Diethyl 3-{4-[(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}propylphosphonate
14c): Yield 78% (after crystallization from an ethyl acetate–hexane mixture). A white solid;
m.p. 131–132 ◦C; IR (KBr): = 3440, 3143, 2984, 1703, 1662, 1590, 1236, 1050, 785, 755 cm−1; 1H-NMR
(600 MHz, CDCl3): = 8.64 (d, J = 7.3 Hz, 2H, Haromat.), 8.22 (d, J = 8.3 Hz, 2H, Haromat.), 7.77 (dd,
J = 8.3 Hz, J = 7.3 Hz, 2H, Haromat.), 7.69 (s, 1H, HC50), 5.53 (s, 2H, CH2), 4.41 (t, J = 6.9 Hz, 2H,
PCH2CH2CH2), 4.12–4.03 (m, 4H, 2 POCH2CH3), 2.20 (dqu, J = 21.7 Hz, J = 6.9 Hz, 2H, PCH2CH2),
(
ν
δ
×

Molecules 2016, 21, 1420
8 of 20
1.72 (dt, J = 18.6 Hz, J = 8.0 Hz, 2H, PCH2), 1.30 (t, J = 7.1 Hz, 6H, 2
×
POCH2CH3); 13C-NMR (151 MHz,
CDCl3):
POC), 50.02 (d, J = 15.5 Hz, PCCC), 35.25, 23.65 (d, J = 4.5 Hz, PCC), 22.66 (d, J = 143.5 Hz, PC), 16.39
(d, J = 6.2 Hz, POCC); 31P-NMR (243 MHz, CDCl3):
= 29.99 ppm. Anal. Calcd. for C22H25N4O5P: C,
δ = 163.84, 143.52, 134.12, 131.64, 131.48, 128.25, 126.92, 123.40, 122.55, 61.74 (d, J = 6.5 Hz,
δ
57.89; H, 5.52; N, 12.27. Found: C, 57.73; H, 5.23; N, 12.26.
Diethyl 4-{4-[(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}butylphosphonate
(
14d): Yield ◦85% (after crystallization from an ethyl acetate–hexane mixture). A white sol−id1;
m.p. 131–132 C; IR (KBr):
ν
= 3399, 3142, 3073, 2982, 2875, 1702, 1663, 1626, 1590, 1236, 1031, 786 cm
;
1H-NMR (200 MHz, CDCl3):
J = 1.0 Hz, 2H, Haromat.), 7.74 (dd, J = 8.3 Hz, J = 7.3 Hz, 2H, Haromat.), 7.63 (s, 1H, HC50), 5.50 (s, 2H,
CH2), 4.30 (t, J = 7.2 Hz, 2H, PCCCCH2), 4.13–3.95 (m, 4H, 2 POCH2CH3), 2.00 (qu, J = 6.9 Hz, 2H,
PCCCH2), 1.80–1.49 (m, 4H, PCCH2 and PCH2), 1.30 (t, J = 7.1 Hz, 6H, 2
POCH2CH3); 13C-NMR
(151 MHz, CDCl3): = 163.88, 143.73, 134.11, 131.63, 131.46, 128.25, 126.92, 123.13 122.56, 61.54 (d,
J = 6.0 Hz, 2 POC), 49.63, 35.27, 30.76 (d, J = 15.9 Hz, PCCC), 25.00 (d, J = 141.9 Hz, PC), 19.72 (d,
J = 4.5 Hz, PCC), 16.41 (d, J = 6.0 Hz, POCC); 31P-NMR (81 MHz, CDCl3):
= 31.78 ppm. Anal. Calcd.
δ = 8.61 (dd, J = 7.3 Hz, J = 1.0 Hz, 2H, Haromat.), 8.20 (d, J = 8.3 Hz,
×
×
δ
×
δ
for C23H27N4O5P: C, 58.72; H, 5.78; N, 11.91. Found: C, 58.66; H, 5.64; N, 11.86.
Diethyl 2-{4-[(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-1-hydroxyethylphosphonate
(
14e): Yield 80% (after crystallization from a methanol–diethyl ether mixture). A white solid; m.p.
186–188 ◦C; IR (KBr): = 3300, 3192, 2983, 1704, 1690, 1221, 1040, 1024, 787 cm−1; 1H-NMR (600 MHz,
ν
CDCl3):
δ
= 8.59 (dd, J = 7.3 Hz, J = 0.8 Hz, 2H, Haromat.), 8.19 (dd, J = 8.2 Hz, J = 0.8 Hz, 2H, Haromat.),
0
7.85 (s, 1H, HC5 ), 7.75 (dd, J = 8.2 Hz, J = 7.3 Hz, 2H, Haromat.), 5.51 (AB, J = 14.5 Hz, 1H, CHaHb), 5.49
(AB, J = 14.5 Hz, 1H, CHaHb), 4.78 (ddd, J = 14.3 Hz, J = 6.2 Hz, J = 2.5 Hz, 1H, PCCHaHb), 4.38 (ddd,
J = 14.3 Hz, J = 9.6 Hz, J = 5.5 Hz, 1H, PCCHaHb), 4.35 (dt, J = 9.6 Hz, J = 2.5 Hz, 1H, PCH), 4.22–4.11
(m, 4H, 2
13C-NMR (151 MHz, CDCl3):
67.19 (d, J = 164.6 Hz, PC), 63.58 and 63.24 (2
35.20, 16.42 and 16.38 (2 d, J = 6.0 Hz, 2 δ
POCC); 31P-NMR (243 MHz, CDCl3):
×
POCH2CH3), 1.35 (t, J = 7.0 Hz, 3H, POCH2CH3), 1.32 (t, J = 7.0 Hz, 3H, POCH2CH3);
= 163.74, 143.38, 134.04, 131.50, 131.35, 128.07, 126.87, 124.98, 122.2,
d, J = 7.6 Hz, 2 POC), 51.57 (d, J = 9.1 Hz, PCC),
= 19.89 ppm. Anal.
δ
×
×
×
×
Calcd. for C21H23N4O6P: C, 55.02; H, 5.06; N, 12.22. Found: C, 55.10; H, 4.88; N, 12.22.
Diethyl 3-{4-[(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-2-hydroxypropylphosphonate
(
14f): Yie◦ld 90% (after crystallization from a methanol–diethyl ether mixture). A white solid;
m.p. >260 C; IR (KBr):
ν
= 3430, 3148, 2986, 2930, 1776, 1740, 1237, 1029, 755 cm−1; 1H-NMR (200 MHz,
CDCl3):
7.82 (s, 1H, HC50), 7.73 (dd, J = 7.9 Hz, J = 8.3 Hz, 2H, Haromat.), 5.51 (s, 2H, CH2), 4.55–4.27 (m, 3H,
PCCCH2, OH), 4.19–3.96 (m, 5H, PCCH, 2 POCH2CH3), 2.06–1.67 (m, 2H, PCH2), 1.32 and 1.26 (t,
J = 7.0 Hz, 3H, POCH2CH3); 13C-NMR (151 MHz, CDCl3):
= 163.83, 143.63, 134.07, 131.59, 131.44,
128.21, 126.90, 124.85, 122.53, 65.62 (d, J = 3.0 Hz, PCC), 62.21 (d, J = 6.4 Hz, POC), 62.18 (d, J = 6.4 Hz,
POC), 55.72 (d, J = 16.6 Hz, PCCC), 35.26, 30.59 (d, J = 139.8 Hz, PC), 16.30 (d, J = 6.0 Hz, 2 POCC);
31P-NMR (81 MHz, CDCl3):
= 29.28 ppm. Anal. Calcd. for C22H25N4O6P: C, 55.93; H, 5.33; N, 11.86.
Found: C, 55.79; H, 5.14; N, 11.86.
δ = 8.60 (dd, J = 7.9 Hz, J = 0.9 Hz, 2H, Haromat.), 8.20 (dd, J = 8.3 Hz, J = 0.9 Hz, 2H, Haromat.),
×
δ
×
δ
Diethyl 2-{4-[(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethoxy-methylphosphonate
14g): Yield 82% (after crystallization from a methanol–diethyl ether mixture). A white solid; m.p.
(
◦
−1
;
154–155 C; IR (KBr):
1H-NMR (200 MHz, CDCl3):
J = 1.0 Hz, 2H, Haromat.), 7.77 (s, 1H, HC50), 7.74 (dd, J = 8.3 Hz, J = 7.3 Hz, 2H, Haromat.), 5.50 (s, 2H,
CH2), 4.50 (t, J = 4.9 Hz, 2H, PCH2OCH2CH2), 4.15–4.00 (m, 4H, 2 POCH2CH3) 3.95 (t, J = 4.9 Hz,
2H, PCOCH2CH2), 3.74 (d, J = 8.2 Hz, 2H, PCH2O), 1.28 (t, J = 7.1 Hz, 6H, 2
POCH2CH3); 13C-NMR
(151 MHz, CDCl3): = 163.82, 143.76, 134.09, 131.63, 131.43, 128.24, 126.92, 123.90, 122.57, 71.35
(d, J = 10.1 Hz, PCOC), 65.36 (d, J = 166.3 Hz, PC), 62.40 (d, J = 6.5 Hz, POC), 50.02, 35.25, 16.42 (d,
ν
= 3319, 3148, 3068, 3988, 2980, 2908, 1704, 1662, 1590, 1237, 1029, 784, 756 cm
δ
= 8.60 (dd, J = 7.3 Hz, J = 1.0 Hz, 2H, Haromat.), 8.19 (dd, J = 8.3 Hz,
×
×
δ

Molecules 2016, 21, 1420
9 of 20
J = 6.0 Hz, 2
×
POCC); 31P-NMR (81 MHz, CDCl3):
δ
= 21.16 ppm. Anal. Calcd. for C22H25N4O6P: C,
55.93; H, 5.33; N, 11.86. Found: C, 55.90; H, 5.28; N, 11.84.
Diethyl 2-(2-{4-[(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethoxy)ethylphosphonate
(
14h): Yield 79% (after crystallization from a methanol–diethyl ether mixture). A white solid; m.p.
156–158 ◦C; IR (KBr): = 3352, 3144, 2985, 2932, 2906, 1703, 1662, 1237, 1028, 785, 754 cm−1; 1H-NMR
(200 MHz, CDCl3): = 8.60 (dd, J = 7.2 Hz, J = 0.9 Hz, 2H, Haromat.), 8.22 (dd, J = 7.9 Hz, J = 0.9 Hz,
2H, Haromat.), 7.78 (s, 1H, HC50), 7.74 (dd, J = 7.9 Hz, J = 7.2 Hz, 1H, Haromat.), 5.59 (s, 2H, CH2), 4.47
(t, J = 5.3 Hz, 2H, PCH2CH2OCH2CH2), 4.11–3.97 (m, 4H, 2 POCH2CH3), 3.77 (t, J = 5.3 Hz, 2H,
PCCOCH2CH2), 3.64 (dt, J = 11.8 Hz, J = 7.6 Hz, 2H, PCH2CH2O), 2.03 (dt, J = 18.7 Hz, J = 7.6 Hz,
2H, PCH2CH2O), 1.28 (t, J = 7.1 Hz, 6H, 2 = 163.86,
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
ν
δ
×
×
δ
143.56, 134.07, 131.63, 131.44, 128.25, 126.92, 124.28, 122.60, 68.90, 65.23 (PCCO), 61.65 (d, J = 6.0 Hz,
POC), 50.06, 35.27, 26.33 (d, J = 138.9 Hz, PC), 16.39 (d, J = 6.1 Hz, POCC); 31P-NMR (81 MHz, CDCl3):
δ
= 28.75 ppm. Anal. Calcd. for C23H27N4O6P: C, 56.79; H, 5.59; N, 11.52. Found: C, 56.72; H, 5.42;
N, 11.70.
Diethyl 2-{4-[(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}acetamido-methylphosphonate
(
14i): Yield 91% (after column chromato◦graphy with chloroform–methanol mixtures (100:1 or 50:1,
v/v)). A white powder; m.p. 170–171 C; IR (KBr):
782 cm−1; H-NMR (200 MHz, CDCl3):
ν = 3355, 2974, 2930, 1660, 1626, 1237, 1050,
1
δ = 8.51 (dd, J = 7.3 Hz, J = 1.1 Hz, 2H, Haromat.), 8.12 (dd,
J = 8.2 Hz, J = 1.1 Hz, 2H, Haromat.), 7.80 (s, 1H, HC50), 7.66 (dd, J = 8.2 Hz, J = 7.3 Hz, 2H, Haromat.),
7.49 (t, J = 5.9 Hz, 1H, NHCO), 5.44 (s, 2H, CH2), 5.01 (s, 2H), 4.06–3.92 (m, 4H, 2 POCH2CH3),
3.62 (dd, J = 12.2 Hz, J = 5.9 Hz, 2H, PCH2NH), 1.17 (t, J = 7.1 Hz, 6H, 2
POCH2CH3); 13C-NMR
(151 MHz, CDCl3): = 165.24 (d, J = 5.5 Hz, C=O), 163.82, 144.09, 134.15, 131.60, 131.48, 128.20, 126.93,
124.93, 122.47, 62.84 (d, J = 6.5 Hz, POC), 52.56, 35.17, 34.97 (d, J = 156.5 Hz, PC), 16.28 (d, J = 5.6 Hz,
POCC); 31P-NMR (81 MHz, CDCl3):
= 22.21 ppm. Anal. Calcd. for C22H24N5O6P: C, 54.43; H, 4.98;
×
×
δ
δ
N, 14.43. Found: C, 54.38; H, 4.82; N, 14.35.
Diethyl {4-[(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}methylphosphonate
(
15a): Yield 82% (after column chromatography with chloroform–methanol mixtures (100:1 and 50:1,
v/v)). A white powder; m.p. 158–159 ◦C; IR (KBr):
ν
= 3334, 3052, 3008, 2989, 2967, 1711, 1670, 1222,
1032, 757 cm−1; 1H-NMR (600 MHz, CDCl3):
1H, Haromat.), 8.46 (d, J = 7.8 Hz, 1H, Haromat.), 8.05 (d, J = 7.8 Hz, 1H, Haromat.), 7.88 (s, 1H, HC5 ), 7.86
(dd, J = 8.5 Hz, J = 7.8 Hz, 1H, Haromat.), 5.53 (s, 2H, CH2), 4.74 (d, J = 13.0 Hz, 2H, PCH2), 4.15–4.00 (m,
δ
= 8.67 (d, J = 7.8 Hz, 1H, Haromat.), 8.59 (d, J = 8.5 Hz,
0
4H, 2
×
POCH2CH3), 1.29 (t, J = 7.0 Hz, 6H, 2
×
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
δ = 163.24,
163.21, 143.87, 133.49, 132.28, 131.46, 131.13, 130.68, 130.52, 129.07, 128.08, 124.30, 122.94, 122.07, 63.45
(d, J = 6.4 Hz, POC), 45.63 (d, J = 156.4 Hz, PC), 35.26, 16.25 (d, J = 6.8 Hz, POCC); 31P-NMR (243 MHz,
CDCl3): δ = 16.65 ppm. Anal. Calcd. for C20H20BrN4O5P: C, 47.35; H, 3.97; N, 11.04. Found: C, 47.31;
H, 3.73; N, 10.99.
Diethyl 2-{4-(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl)-1H-1,2,3-triazol-1-yl}ethylphosphonate
(
ν
15b): Yield 80% (after crystallization from ethyl acetate). A white solid; m.p. 132–134 ◦C; IR (KBr):
= 3400, 3352, 3308, 2985, 2932, 1703, 1666, 1232, 1026, 779, 750 cm−1; 1H-NMR (200 MHz, CDCl3):
= 8.61 (dd, J = 7.3 Hz, J = 1.2 Hz, 1H, Haromat.), 8.50 (dd, J = 7.3 Hz J = 1.2 Hz, 1H, Haromat.), 8.37 (d,
δ
,
J = 8.3 Hz, 1H, Haromat.), 7.98 (d, J = 7.9 Hz, 1H, Haromat.), 7.78 (dd, J = 8.3 Hz, J = 7.3 Hz, 1H, Haromat.),
7.64 (s, 1H, HC50), 5.48 (s, 2H, CH2), 4.57–4.43 (m, 2H, PCH2CH2), 4.07–3.93 (m, 4H, 2
POCH2CH3),
2.41–2.29 (m, 2H, PCH2), 1.21 (t, J = 7.1 Hz, 6H, 2
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
= 163.15, 163.14, 143.43, 133.42, 132.22, 131.38, 131.09, 130.58, 130.48, 128.94, 128.06, 123.58, 122.85,
121.98, 62.09 (d, J = 6.5 Hz, POC), 44.48 (PCC), 35.28, 27.26 (d, J = 141.0 Hz, PC), 16.32 (d, J = 5.8 Hz,
POCC); 31P-NMR (243 MHz, CDCl3):
= 26.28 ppm. Anal. Calcd. for C21H22BrN4O5P: C, 48.38; H,
4.25; N, 10.75. Found: C, 48.07; H, 4.10; N, 10.62.
×
×
δ
δ

Molecules 2016, 21, 1420
10 of 20
Diethyl 3-{4-[(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}propylphosphonate
(
15c): Yi◦eld 76% (after crystallization from an ethyl acetate–hexane mixture). A white solid; m.p.
118–120 C; IR (KBr):
ν
= 3404, 2990, 2942, 2829, 1705, 1666, 1590, 1234, 1047, 1029, 752 cm−1; 1H-NMR
(200 MHz, CDCl3):
δ = 8.68 (dd, J = 7.3 Hz, J = 1.2 Hz, 1H, Haromat.), 8.56 (dd, J = 8.3 Hz, J = 1.2 Hz,
1H, Haromat.), 8.42 (d, J = 7.9 Hz, 1H, Haromat.), 8.04 (d, J = 7.9 Hz, 1H, Haromat.), 7.84 (dd, J = 8.3 Hz,
J = 7.3 Hz, 1H, Haromat.), 7.67 (s, 1H, HC50), 5.49 (s, 2H, CH2), 4.40 (t, J = 7.0 Hz, 2H, PCH2CH2CH2),
4.15–3.96 (m, 4H, 2
J = 18.9 Hz, J = 8.0 Hz, 2H, PCH2), 1.28 (t, J = 7.1 Hz, 6H, 2
CDCl3): = 163.29, 163.26, 143.50, 133.49, 132.31, 131.47, 131.12, 130.68, 130.51, 129.09, 128.08, 123.48,
122.97, 122.10, 61.76 (d, J = 6.5 Hz, POC), 50.02 (d, J = 15.1 Hz, PCCC), 35.32, 23.64 (d, J = 4.5 Hz, PCC),
22.66 (d, J = 143.5 Hz, PC), 16.40 (d, J = 5.7 Hz, POCC); 31P-NMR (243 MHz, CDCl3):
= 30.85 ppm.
×
POCH2CH3), 2.18 (dqu, J = 21.0 Hz, J = 7.0 Hz, 2H, PCH2CH2), 1.72 (dt,
×
POCH2CH3); 13C-NMR (151 MHz,
δ
δ
Anal. Calcd. for C22H24BrN4O5P: C, 49.36; H, 4.52; N, 10.47. Found: C, 49.25; H, 4.44; N, 10.45.
Diethyl 4-{4-[(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}butylphosphonate
(
15d): Yield 88% (after crystallization from an ethyl acetate–hexane mixture). A white solid; m.p.
110–112 ◦C; IR (KBr): = 3357, 2982, 2938, 2909, 2875, 1794, 1703, 1024, 962 cm−1; 1H-NMR (200 MHz,
CDCl3): = 8.67 (dd, J = 7.3 Hz, J = 1.2 Hz, 1H, Haromat.), 8.57 (d, J = 8.3 Hz J = 1.2 Hz, 1H, Haromat.),
ν
δ
,
8.42 (d, J = 7.9 Hz, 1H, Haromat.), 8.04 (d, J = 7.9 Hz, 1H, Haromat.), 7.84 (dd, J = 8.3 Hz, J = 7.3 Hz, 1H,
0
Haromat.), 7.63 (s, 1H, HC5 ), 5.48 (s, 2H, CH2), 4.31 (t, J = 7.2 Hz, 2H, PCCCCH2), 4.12–3.97 (m, 4H, 2
×
POCH2CH3), 2.12–1.90 (m, 2H, PCCCH2), 1.84–1.49 (m, 4H, PCCH2 and PCH2), 1.30 (t, J = 7.2 Hz, 6H,
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
= 163.25, 163.22, 143.41, 133.43, 132.26, 131.43, 131.09,
130.65, 130.50, 129.05, 128.06, 123.17, 122.96, 122.08, 61.54 (d, J = 7.6 Hz, 2 POC), 49.64, 35.33, 30.74 (d,
J = 13.6 Hz, PCCC), 24.95 (d, J = 143.5 Hz, PC), 19.71 (d, J = 4.5 Hz, PCC), 16.40 (d, J = 6.0 Hz, POCC);
31P-NMR (81 MHz, CDCl3):
= 31.77 ppm. Anal. Calcd. for C23H26BrN4O5P: C, 50.29; H, 4.77; N,
10.20. Found: C, 50.11; H, 4.62; N, 10.00.
2
×
δ
×
δ
Diethyl
2-{4-[(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-1-
hydroxyethylphosphonate (15e):◦Yield 80% (after crystallization from an ethyl acetate–hexane mixture).
A white solid; m.p. 198–200 C; IR (KBr):
ν = 3261, 2987, 2933, 2909, 1704, 1665, 1234, 1046, 1023,
1
753 cm−1; H-NMR (200 MHz, CDCl3):
δ = 8.50 (dd, J = 7.3 Hz, J = 1.1 Hz, 1H, Haromat.), 8.44 (d,
J = 8.3 Hz, J = 1.1 Hz, 1H, Haromat.), 8.26 (d, J = 7.9 Hz, 1H, Haromat.), 7.94 (d, J = 7.9 Hz, 1H, Haromat.),
0
7.88 (s, 1H, HC5 ), 7.75 (dd, J = 8.3 Hz, J = 7.3 Hz, 1H, Haromat.), 5.41 (s, 2H, CH2), 4.79 (ddd, J = 11.3 Hz,
J = 6.3 Hz, J = 2.3 Hz, 1H, PCCHaHb), 4.46 (dt, J = 9.9 Hz, J = 2.3 Hz, 1H, PCH), 4.38 (ddd, J = 11.3 Hz,
J = 9.9 Hz, J = 5.0 Hz, 1H, PCCHaHb), 4.21–4.06 (m, 4H, 2
×
POCH2CH3), 1.31 (t, J = 6.9 Hz, 3H,
= 163.09, 163.00,
POCH2CH3), 1.29 (t, J = 6.9 Hz, 3H, POCH2CH3); 13C-NMR (151 MHz, CDCl3):
δ
143.05, 133.36, 132.15, 131.31, 131.07, 130.45, 128.78, 128.02, 126.87, 125.10, 122.73, 121.87, 67.20 (d,
J = 164.6 Hz, PC), 63.40 (d, J = 7.6 Hz, POC), 63.25 (d, J = 7.6 Hz, POC), 51.64 (d, J = 9.1 Hz, PCC), 35.27,
16.44 (d, J = 6.0 Hz, POCC), 16.40 (d, J = 6.0 Hz, POCC); 31P-NMR (81 MHz, CDCl3):
δ
= 20.91 ppm.
Anal. Calcd. for C21H22BrN4O6P: C, 46.94; H, 4.13; N, 10.43. Found: C, 47.07; H, 3.91; N, 10.48.
Diethyl 3-{4-[(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-2-
hydroxypropylphosphonate (15f): Yield 85% (after crystallization from a methanol–diethyl ether mixture).
A white solid; m.p. 152–153 ◦C; IR (KBr): = 3330, 3155, 2986, 2909, 1704, 1664, 1234, 1027, 752 cm−1
1H-NMR (200 MHz, CDCl3):
= 8.54 (dd, J = 7.5 Hz, J = 1.0 Hz, 1H, Haromat.), 8.48 (d, J = 8.5 Hz,
ν
;
δ
J = 10.0 Hz, 1H, Haromat.), 8.29 (d, J = 7.9 Hz, 1H, Haromat.), 7.96 (d, J = 7.9 Hz, 1H, Haromat.), 7.90 (s, 1H,
HC5 ), 7.65 (dd, J = 8.5 Hz, J = 7.5 Hz, 1H, Haromat.), 5.49 (s, 2H, CH2), 4.52–4.17 (m, 3H, PCCCH2, OH),
4.16–3.95 (m, 5H, PCCH, 2
×
POCH2CH3), 2.10–1.60 (m, 2H, PCH2), 1.33 and 1.29 (t, J = 7.0 Hz, 3H,
= 163.30, 163.28, 143.33, 133.47, 132.31, 131.47, 131.12,
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
δ
130.64, 130.50, 129.05, 128.07, 124.95, 122.94, 122.07, 65.61 (d, J = 4.4 Hz, PCC), 62.30 (d, J = 6.0 Hz,
POC), 62.20 (d, J = 6.0 Hz, POC), 55.75 (d, J = 17.6 Hz, PCCC), 35.34, 30.59 (d, J = 141.8 Hz, PC), 16.30 (d,
J = 6.0 Hz, 2
×
POCC); 31P-NMR (81 MHz, CDCl3):
δ = 29.21 ppm. Anal. Calcd. for C22H24BrN4O6P:
C, 47.93; H, 4.39; N, 10.16. Found: C, 47.94; H, 4.50; N, 10.16.

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Diethyl 2-{4-[(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethoxy-
methylphosphonate (15g): Yield 90% (after crystallization from an ethyl acetate–hexane mixture). A white
◦
−1
;
solid; m.p. 127–128 C; IR (KBr):
ν
= 3441, 3148, 3087, 2985, 2935, 2908, 1704, 1665, 1234, 1027, 751 cm
1H-NMR (200 MHz, CDCl3):
δ
= 8.51 (dd, J = 7.3 Hz, J = 1.2 Hz, 1H, Haromat.), 8.47 (d, J = 8.3 Hz,
J = 1.2 Hz, 1H, Haromat.), 8.45 (d, J = 7.9 Hz, 1H, Haromat.), 7.99 (d, J = 7.9 Hz, 1H, Haromat.), 7.74 (dd,
J = 8.3 Hz, J = 7.3 Hz, 1H, Haromat.), 7.70 (s, 1H, HC50), 5.49 (s, 2H, CH2), 4.49 (t, J = 5.1 Hz, 2H,
PCH2OCH2CH2), 4.18–3.98 (m, 4H, 2
(d, J = 8.1 Hz, 2H, PCH2O), 1.30 (t, J = 7.2 Hz, 6H, 2
= 163.25, 163.23, 143.32, 133.44, 132.26, 131.43, 131.19, 130.67, 130.45, 129.08, 128.08, 124.21, 123.00,
122.13, 71.32 (d, J = 9.1 Hz, PCOC), 65.16 (d, J = 166.1 Hz, PC), 62.47 (d, J = 6.3 Hz, POC), 50.03,
35.32, 16.44 (d, J = 5.4 Hz, 2 = 21.17 ppm. Anal. Calcd. for
POCC); 31P-NMR (81 MHz, CDCl3):
×
POCH2CH3), 3.94 (t, J = 5.1 Hz, 2H, PCOCH2CH2), 3.70
×
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
δ
×
δ
C22H24BrN4O6P: C, 47.93; H, 4.39; N, 10.16. Found: C, 48.07; H, 4.10; N, 9.97.
Diethyl 2-(2-{4-[(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethoxy)
ethylphosphonate (15h): Yield 86% (after crystallization from an ethyl acetate–hexane mixture). A white
solid; m.p. 92–93 ◦C; IR (KBr):
1H-NMR (200 MHz, CDCl3):
ν
= 3145, 3086, 2984, 2930, 2907, 2876, 1704, 1666, 1234, 1047, 751 cm−1
;
= 8.72 (dd, J = 7.3 Hz, J = 1.0 Hz, 1H, Haromat.), 8.55 (d, J = 8.3 Hz,
δ
J = 1.0 Hz, 1H, Haromat.), 8.49 (d, J = 7.9 Hz, 1H, Haromat.), 8.10 (d, J = 7.9 Hz, 1H, Haromat.), 7.84 (dd,
J = 8.3 Hz, J = 7.3 Hz, 1H, Haromat.), 7.76 (s, 1H, HC50), 5.52 (s, 2H, CH2), 4.49 (t, J = 5.3 Hz, 2H,
PCH2CH2OCH2CH2), 4.18–3.95 (m, 4H, 2
(dt, J = 12.0 Hz, J = 7.5 Hz, 2H, PCH2CH2O), 2.03 (dt, J = 18.4 Hz, J = 7.5 Hz, 2H, PCH2CH2O), 1.25
(t, J = 6.9 Hz, 6H, 2 = 163.27, 163.25, 143.28, 133.40,
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
×
POCH2CH3), 3.79 (t, J = 5.3 Hz, 2H, PCCOCH2CH2), 3.56
×
δ
132.26, 131.43, 131.11, 130.66, 130.42, 129.09, 128.07, 124.31, 123.03, 122.16, 68.97, 65.24 (PCCO), 61.63
(d, J = 5.7 Hz, POC), 50.08, 35.36, 26.10 (d, J = 140.1 Hz, PC), 16.40 (d, J = 6.0 Hz, POCC); 31P-NMR
(81 MHz, CDCl3):
δ = 28.76 ppm. Anal. Calcd. for C23H26BrN4O6P: C, 48.86; H, 4.64; N, 9.91. Found:
C, 48.83; H, 4.56; N, 10.10.
Diethyl 2-{4-[(6-Bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}acetamido-
methylphosphonate (15i): Yield 88% (after column chromatography with chloroform–methanol mixtures
(100:1 or 50:1, v/v)). A white solid; m.p. 173–174 ◦C; IR (KBr):
ν
= 3240, 3148, 3071, 2987, 2932, 1703,
1
1665, 1234, 1025, 752 cm−1; H-NMR (200 MHz, CDCl3):
δ = 8.52 (dd, J = 7.3 Hz, J = 0.8 Hz, 1H,
Haromat.), 8.42 (d, J = 8.3 Hz, J = 0.8 Hz, 1H, Haromat.), 8.39 (d, J = 7.9 Hz, 1H, Haromat.), 8.00 (d, J = 7.9 Hz,
1H, Haromat.), 7.84 (s, 1H, HC50), 7.80 (dd, J = 8.3 Hz, J = 7.3 Hz, 1H, Haromat.), 7.40 (brt, J = 5.9 Hz,
1H, NHCO), 5.56 (s, 2H, CH2), 5.01 (s, 2H), 4.16–3.98 (m, 4H, 2
J = 6.0 Hz, 2H, PCH2NH), 1.12 (t, J = 7.2 Hz, 6H, 2
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
= 165.26 (d, J = 5.5 Hz, C=O), 163.25, 163.24, 143.76, 133.49, 132.29, 131.45, 131.12, 130.62, 130.54,
128.99, 128.07, 125.02, 122.85, 121.98, 62.87 (d, J = 6.6 Hz, POC), 52.57, 35.25, 35.00 (d, J = 155.4 Hz,
PC), 16.30 (d, J = 5.4 Hz, POCC); 31P-NMR (81 MHz, CDCl3):
= 22.29 ppm. Anal. Calcd. for
×
POCH2CH3), 3.62 (dd, J = 12.4 Hz,
×
δ
δ
C22H23BrN5O6P: C, 46.82; H, 4.11; N, 12.41. Found: C, 46.62; H, 3.90; N, 12.11.
Diethyl {4-[(5-Nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}methylphosphonate
(
16a): Yield 71% (after crystallization from an ethyl acetate–hexane mixture). A white solid; m.p.
◦
1
147–148 C; IR (KBr):
(200 MHz, CDCl3):
ν
= 3335, 2988, 2939, 1698, 1711, 1670, 1244, 1110, 790, 757 cm−1; H-NMR
δ
= 9.24 (d, J = 2.2 Hz, 1H, Haromat.), 9.07 (d, J = 2.2 Hz, 1H, Haromat.), 8.73 (dd,
J = 7.4 Hz, J = 1.2 Hz, 1H, Haromat.), 8.36 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H, Haromat.), 7.88 (dd, J = 8.4 Hz,
0
J = 7.4 Hz, 1H, Haromat.), 7.84 ( s, 1H, HC5 ), 5.47 (s, 2H, CH2), 4.66 (d, J = 13.1 Hz, 2H, PCH2), 4.13–3.98
(m, 4H, 2
×
POCH2CH3), 1.22 (2
×
t, J = 7.0 Hz, 6H, 2
×
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
δ
= 162.70, 162.17, 146.36, 143.43, 135.78, 134.68, 131.05, 130.23, 129.12, 129.11, 124.52, 124.39, 124.35,
123.04, 63.50 (d, J = 6.6 Hz, POC), 45.36 (d, J = 155.6 Hz, PC), 35.47, 16.27 (d, J = 5.6 Hz, POCC);
31P-NMR (81 MHz, CDCl3):
δ
= 16.50 ppm. Anal. Calcd. for C20H20N5O7P: C, 50.74; H, 4.26; N, 14.79.
Found: C, 50.73; H, 3.99; N, 14.93.

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Diethyl 2-{4-[(5-Nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethylphosphonate
(
16b): Yi◦eld 88% (after crystallization from an ethyl acetate–hexane mixture). White needles; m.p.
1
170–171 C; IR (KBr):
ν
= 3284, 3142, 3079, 2934, 2910, 1713, 1667, 1244, 790, 703 cm−1; H-NMR
(200 MHz, CDCl3):
δ = 9.26 (d, J = 2.2 Hz, 1H, Haromat.), 9.08 (d, J = 2.2 Hz, 1H, Haromat.), 8.74 (dd,
J = 7.3 Hz, J = 1.1 Hz, 1H, Haromat.), 8.38 (dd, J = 8.3 Hz, J = 1.1 Hz, 1H, Haromat.), 7.89 (dd, J = 8.3 Hz,
J = 7.3 Hz, 1H, Haromat.), 7.68 (s, 1H, HC50), 5.46 (s, 2H, CH2), 4.58–4.45 (m, 2H, PCH2CH2), 4.09–3.94
(m, 4H, 2
(151 MHz, CDCl3):
124.54, 124.46, 123.61, 123.07, 62.14 (d, J = 6.0 Hz, POC), 44.55 (PCC), 35.50, 27.30 (d, J = 140.4 Hz, PC),
16.34 (d, J = 5.7 Hz, POCC); 31P-NMR (81 MHz, CDCl3):
= 26.23 ppm. Anal. Calcd. for C21H22N4O7P:
×
POCH2CH3), 2.42-2.24 (m, 2H, PCH2), 1.23 (t, J = 7.1 Hz, 6H, 2
×
POCH2CH3); 13C-NMR
δ
= 162.74, 162.23, 146.40, 143.04, 135.77, 134.72, 131.06, 130.25, 129.13, 129.13,
δ
C, 51.75; H, 4.55; N, 14.37. Found: C, 51.54; H, 4.43; N, 14.17.
Diethyl 3-{4-[(5-Nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}propylphosphonate
(
ν
16c): Yield 80% (after crystallization from ethyl acetate). A white solid; m.p. 113–114 ◦C; IR (KBr):
1
= 3404, 3084, 2982, 2943, 1712, 1671, 1597, 1244, 1112, 1029, 791, 758 cm−1; H-NMR (200 MHz,
CDCl3):
δ = 9.32 (d, J = 2.1 Hz, 1H, Haromat.), 9.13 (d, J = 2.1 Hz, 1H, Haromat.), 8.80 (dd, J = 7.3 Hz,
J = 1.1 Hz, 1H, Haromat.), 8.43 (dd, J = 8.3 Hz, J = 1.1 Hz, 1H, Haromat.), 7.94 (dd, J = 8.3 Hz, J = 7.3 Hz,
0
1H, Haromat.), 7.71 (s, 1H, HC5 ), 5.52 (s, 2H, CH2), 4.41 (t, J = 7.0 Hz, 2H, PCH2CH2CH2), 4.15–3.97 (m,
4H, 2
×
POCH2CH3), 2.30–2.08 (m, 2H, PCH2CH2), ), 1.80–1.60 (m, 2H, PCH2), 1.29 (t, J = 7.0 Hz, 6H,
= 162.76, 162.25, 146.37, 143.06, 135.77, 134.74, 131.07,
2
×
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
δ
130.26, 129.11, 129.11, 124.56, 124.43, 123.39, 123.08, 61.79 (d, J = 6.0 Hz, POC), 50.00 (d, J = 15.1 Hz,
PCCC), 35.50, 23.64 (d, J = 4.4 Hz, PCC), 22.46 (d, J = 143.5 Hz, PC), 16.40 (d, J = 5.4 Hz, POCC);
31P-NMR (81 MHz, CDCl3):
δ = 30.84 ppm. Anal. Calcd. for C22H24N5O7P: C, 52.70; H, 4.82; N, 13.97.
Found: C, 52.75; H, 4.93; N, 14.01.
Diethyl 4-{4-[(5-Nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}butylphosphonate
(
16d): Yi◦eld 82% (after crystallization from ethyl an acetate–hexane mixture). White needles; m.p.
1
150–151 C; IR (KBr):
ν
= 3369, 3145, 3082, 2987, 1711, 1670, 1243, 1027, 791, 754 cm−1; H-NMR
(200 MHz, CDCl3):
δ = 9.31 (d, J = 2.1 Hz, 1H, Haromat.), 9.13 (d, J = 2.1 Hz, 1H, Haromat.), 8.79 (dd,
J = 7.4 Hz, J = 1.1 Hz, 1H, Haromat.), 8.42 (dd, J = 8.3 Hz, J = 1.1 Hz, 1H, Haromat.), 7.94 (dd, J = 8.3 Hz,
J = 7.4 Hz, 1H, Haromat.), 7.67 (s, 1H, HC50), 5.52 (s, 2H, CH2), 4.30 (t, J = 7.1 Hz, 2H, PCCCCH2),
4.13–3.95 (m, 4H, 2
1.28 (t, J = 7.1 Hz, 6H, 2
135.73, 134.72, 131.06, 130.27, 129.11, 129.09, 124.59, 124.44, 123.28, 123.11, 61.59 (d, J = 6.6 Hz, 2
POC), 49.71, 35.52, 30.76 (d, J = 15.8 Hz, PCCC), 25.00 (d, J = 141.9 Hz, PC), 19.72 (d, J = 4.9 Hz, PCC),
16.41 (d, J = 6.0 Hz, POCC); 31P-NMR (81 MHz, CDCl3):
= 31.73 ppm. Anal. Calcd. for C23H26N5O7P:
C, 53.59; H, 5.08; N, 13.59. Found: C, 53.56; H, 4.92; N, 13.55.
×
POCH2CH3), 2.07–1.92 (m, 2H, PCCCH2), 1.82–1.53 (m, 4H, PCCH2 and PCH2),
×
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
δ
= 162.75, 162.25, 146.38, 142.99,
×
δ
Diethyl 2-{4-[(5-Nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-1-
hydroxyethylphosphonate (16e): ◦Yield 83% (after crystallization from an ethyl acetate–hexane mixture).
A white solid; m.p. 212–213 C; IR (KBr):
ν ;
= 3302, 3130, 2973, 1710, 1694, 1228, 1027, 789 cm−1
1H-NMR (200 MHz, CDCl3):
δ = 9.30 (d, J = 2.2 Hz, 1H, Haromat.), 9.13 (d, J = 2.2 Hz, 1H, Haromat.),
8.79 (dd, J = 7.3 Hz, J = 1.2 Hz, 1H, Haromat.), 8.42 (dd, J = 8.3 Hz, J = 1.2 Hz, 1H, Haromat.), 7.94 (dd,
J = 8.3 Hz, J = 7.3 Hz, 1H, Haromat.), 7.85 (s, 1H, HC50), 5.52 (AB, J = 14.2 Hz, 1H, CHaHb), 5.49 (AB,
J = 14.2 Hz, 1H, CHaHb), 4.76 (ddd, J = 13.8 Hz, J = 6.8 Hz, J = 2.6 Hz, 1H, PCCHaHb), 4.52–4.27 (m,
2H, PCCHaHb, PCH), 4.26–4.08 (m, 4H, 2
×
POCH2CH3), 1.34 (t, J = 7.0 Hz, 3H, POCH2CH3), 1.32 (t,
= 162.74, 162.21, 146.38, 142.78, 135.73,
J = 7.0 Hz, 3H, POCH2CH3); 13C-NMR (151 MHz, CDCl3):
δ
134.70, 131.04, 130.23, 129.12, 129.08, 124.98, 124.55, 124.41, 123.08, 67.15 (d, J = 164.6 Hz, PC), 63.46
(d, J = 6.6 Hz, POC), 63.24 (d, J = 6.6 Hz, POC), 51.55 (d, J = 9.1 Hz, PCC), 35.51, 16.44 (d, J = 6.0 Hz,
POCC), 16.40 (d, J = 6.0 Hz, POCC); 31P-NMR (81 MHz, CDCl3):
δ
= 20.63 ppm. Anal. Calcd. for
C21H22N5O8P: C, 50.10; H, 4.40; N, 13.91. Found: C, 55.02; H, 4.14; N, 13.86.

Molecules 2016, 21, 1420
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Diethyl
hydroxypropylphosphonate (16f): Yield 86% (after crystallization from an ethyl acetate–hexane mixture).
A white solid; m.p. 176–177 ◦C; IR (KBr):
= 3279, 3135, 3080, 2986, 2931, 2830, 1709, 1667, 1232, 1033,
799, 755 cm−1; 1H-NMR (200 MHz, CDCl3):
= 9.31 (d, J = 2.2 Hz, 1H, Haromat.), 9.13 (d, J = 2.2 Hz, 1H,
3-{4-[(5-Nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-2-
ν
δ
Haromat.), 8.79 (dd, J = 7.4 Hz, J = 1.2 Hz, 1H, Haromat.), 8.43 (dd, J = 8.2 Hz, J = 1.2 Hz, 1H, Haromat.),
7.94 (dd, J = 8.2 Hz, J = 7.4 Hz, 1H, Haromat.), 7.86 (s, 1H, HC50), 5.53 (s, 2H, CH2), 4.56–4.31 (m,
3H, PCCCH2, OH), 4.18–4.00 (m, 5H, PCCH, 2
×
POCH2CH3), 2.06–1.74 (m, 2H, PCH2), 1.31 and
= 162.75, 162.22, 146.39, 142.92,
1.30 (t, J = 7.0 Hz, 3H, POCH2CH3); 13C-NMR (151 MHz, CDCl3):
δ
135.70, 134.70, 131.06, 130.27, 129.09, 129.06, 124.96, 124.60, 124.44, 123.12, 65.59 (d, J = 3.0 Hz, PCC),
62.32 (d, J = 6.4 Hz, POC), 62.26 (d, J = 6.4 Hz, POC), 55.75 (d, J = 16.6 Hz, PCCC), 35.55, 30.56 (d,
J = 140.4 Hz, PC), 16.36 (d, J = 6.0 Hz, POCC), 16.32 (d, J = 6.0 Hz, POCC); 31P-NMR (81 MHz, CDCl3):
δ
= 29.28 ppm. Anal. Calcd. for C22H24N5O8P: C, 51.07; H, 4.68; N, 13.53. Found: C, 51.18; H, 4.43;
N, 13.77.
Diethyl 2-{4-[(5-Nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethoxy-
methylphosphonate (16g): Yield 82% (after crystallization from an ethyl acetate–hexane mixture).
A yellow powder; m.p. 89–90 ◦C; IR (KBr):
ν
= 3397, 3019, 1712, 1672, 1215, 1048, 757 cm−1; 1H-NMR
(200 MHz, CDCl3):
δ = 9.30 (d, J = 2.2 Hz, 1H, Haromat.), 9.12 (d, J = 2.2 Hz, 1H, Haromat.), 8.78 (dd,
J = 7.3 Hz, J = 1.2 Hz, 1H, Haromat.), 8.44 (dd, J = 8.3 Hz, J = 1.2 Hz, 1H, Haromat.), 7.94 (dd, J = 8.3 Hz,
J = 7.3 Hz, 1H, Haromat.), 7.82 (s, 1H, HC50), 5.51 (s, 2H, CH2), 4.52 (t, J = 4.8 Hz, 2H, PCH2OCH2CH2),
4.18–4.04 (m, 4H, 2
PCH2O), 1.31 (t, J = 7.1 Hz, 6H, 2
146.36, 142.92, 135.72, 134.67, 131.04, 130.26, 129.10, 129.07, 124.60, 124.37, 124.31, 123.11, 71.32 (d,
×
POCH2CH3) 3.95 (t, J = 4.8 Hz, 2H, PCOCH2CH2), 3.75 (d, J = 8.2 Hz, 2H,
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
= 162.72, 162.21,
×
δ
J = 10.6 Hz, PCOC), 65.34 (d, J = 166.1 Hz, PC), 62.50 (d, J = 6.5 Hz, POC), 50.04, 35.52, 16.46 (d,
J = 6.0 Hz, 2
×
POCC); 31P-NMR (81 MHz, CDCl3):
δ = 21.15 ppm. Anal. Calcd. for C22H24N5O8P: C,
51.07; H, 4.68; N, 13.53. Found: C, 51.10; H, 4.39; N, 13.62.
Diethyl 2-(2-{4-[(5-Nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethoxy)
ethylphosphonate (16h): Yield 89%; (after column chromatography with chloroform–methanol mixtures
(100:1 or 50:1, v/v)). A yellow oil; IR (film):
ν ;
= 3363, 3018, 2992, 1711, 1670, 1216, 1053, 755 cm−1
1H-NMR (200 MHz, CDCl3):
δ
= 9.30 (d, J = 2.2 Hz, 1H, Haromat.), 9.12 (d, J = 2.2 Hz, 1H, Haromat.),
8.78 (dd, J = 7.3 Hz, J = 1.2 Hz, 1H, Haromat.), 8.42 (dd, J = 8.3 Hz, J = 1.2 Hz, 1H, Haromat.), 7.93 (dd,
J = 8.3 Hz, J = 7.3 Hz, 1H, Haromat.), 7.82 (s, 1H, HC50), 5.52 (s, 2H, CH2), 4.48 (t, J = 5.3 Hz, 2H,
PCH2CH2OCH2CH2), 4.12–3.98 (m, 4H, 2
(dt, J = 12.1 Hz, J = 7.6 Hz, 2H, PCH2CH2O), 2.05 (dt, J = 18.9 Hz, J = 7.6 Hz, 2H, PCH2CH2O), 1.29
(t, J = 7.1 Hz, 6H, 2 = 162.76, 162.25, 146.40, 142.86,
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
×
POCH2CH3), 3.78 (t, J = 5.3 Hz, 2H, PCCOCH2CH2), 3.66
×
δ
135.67, 134.68, 131.06, 130.29, 129.10, 129.03, 124.65, 124.40, 124.37, 123.17, 68.96, 65.25 (PCCO), 61.68
(d, J = 6.0 Hz, POC), 50.13, 35.57, 26.87 (d, J = 140.4 Hz, PC), 16.41 (d, J = 6.1 Hz, POCC); 31P-NMR
(81 MHz, CDCl3):
δ = 28.70 ppm. Anal. Calcd. for C23H26N5O8P: C, 51.98; H, 4.93; N, 13.18. Found: C,
51.70; H, 4.67; N, 13.15.
Diethyl 2-{4-[(5-Nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}acetamido-
methylphosphonate (16i): Yield 91%. A white powder; m.p. 217–219 ◦C; IR (KBr):
ν
= 3287, 3075, 2986,
1
2854, 1709, 1687, 1229, 1031, 758 cm−1; H-NMR (200 MHz, DMSO-d6):
δ = 9.51 (d, J = 2.2 Hz, 1H,
Haromat.), 9.00 (d, J = 2.2 Hz, 1H, Haromat.), 8.82 (dd, J = 7.5 Hz, J = 0.6 Hz, 1H, Haromat.), 8.72 (dd,
J = 8.2 Hz, J = 0.6 Hz, 1H, Haromat.), 8.70 (brt, J = 2.8 Hz, 1H, NH), 8.09 (dd, J = 8.2 Hz, J = 7.5 Hz, 1H,
Haromat.), 8.03 (s, 1H, HC50), 5.36 (s, 2H, CH2), 5.10 (s, 2H), 4.19–3.97 (m, 4H, 2
×
POCH2CH3), 3.59
POCH2CH3); 13C-NMR (151
= 165.93 (d, J = 5.2 Hz, C=O), 162.97, 162.51, 146.36, 142.85, 137.00, 134.60, 131.39,
130.37, 130.04, 129.76, 125.41, 124.35, 123.57, 122.91, 62.30 (d, J = 6.5 Hz, POC), 51.87, 35.97, 34.65 (d,
J = 155.5 Hz, PC), 16.65 (d, J = 5.6 Hz, POCC); 31P-NMR (81 MHz, DMSO-d6):
= 22.27 ppm. Anal.
Calcd. for C22H23N6O8P: C, 49.82; H, 4.37; N, 15.84. Found: C, 49.88; H, 4.07; N, 15.64.
(dd, J = 11.8 Hz, J = 6.0 Hz, 2H, PCH2NH), 1.19 (t, J = 7.1 Hz, 6H, 2
MHz, DMSO-d6):
×
δ
δ

Molecules 2016, 21, 1420
14 of 20
Diethyl {4-[(5-Amino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}methylphosphonate
17a): Yield 75% (after column chromatography with chloroform–methanol mixtures (100:1 and 50:1,
(
v/v)). A yellow oil; IR (film):
ν = 3430, 3352, 3234, 2983, 2932, 1698, 1660, 1623, 1236, 1020, 784,
1
748 cm−1; H-NMR (600 MHz, DMSO-d6):
δ = 8.10 (d, J = 7.2 Hz, 1H, Haromat.), 8.07 (d, J = 8.2 Hz,
1H, Haromat.), 8.00 (d, J = 2.2 Hz, 1H, Haromat.), 7.95 ( s, 1H, HC50), 7.64 (dd, J = 8.2 Hz, J = 7.2 Hz, 1H,
Haromat.), 7.32 (d, J = 2.2 Hz, 1H, Haromat.), 6.01 (s, 2H, NH2), 5.30 (s, 2H, CH2), 5.01 (d, J = 12.9 Hz,
2H, PCH2), 4.05–3.98 (m, 4H, 2
(151 MHz, DMSO-d6): = 164.00, 163.82, 148.41, 143.74, 134.10, 132.23, 127.46, 126.08, 124.85, 122.91,
122.35, 122.11, 121.11, 112.45, 63.02 (d, J = 6.3 Hz, POC), 45.10 (d, J = 150.3 Hz, PC), 35.51, 16.47 (d,
J = 5.8 Hz, POCC); 31P-NMR (243 MHz, DMSO-d6):
= 17.22 ppm. Anal. Calcd. for C20H22N5O5P: C,
×
POCH2CH3), 1.19 (t, J = 7.0 Hz, 6H, 2
×
POCH2CH3); 13C-NMR
δ
δ
54.18; H, 5.00; N, 15.80. Found: C, 54.36; H, 4.83; N, 15.84.
Diethyl 2-{4-[(5-Amino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethylphosphonate
(17b): Yield 75% (after column chromatography with chloroform–methanol mixtures (100:1 and 50:1,
v/v)). A yellow oil; IR (film):
ν = 3443, 3356, 3233, 3147, 3063, 2986, 1698, 1661, 1626, 1220, 1027,
1
784, 752 cm−1; H-NMR (200 MHz, CDCl3):
δ = 8.26 (dd, J = 7.2 Hz, J = 1.1 Hz, 1H, Haromat.), 7.98
(d, J = 2.4 Hz, 1H, Haromat.), 7.86 (dd, J = 8.3 Hz, J = 1.1 Hz, 1H, Haromat.), 7.70 (s, 1H, HC50), 7.54 (dd,
J = 8.3 Hz, J = 7.2 Hz, 1H, Haromat.), 7.22 (d, J = 2.4 Hz, 1H, Haromat.), 5.46 (s, 2H, CH2), 4.62–4.49 (m,
2H, PCH2CH2), 4.30 (s, 2H, NH2), 4.12–3.97 (m, 4H, 2
×
POCH2CH3), 2.47–2.30 (m, 2H, PCH2), 1.26
= 164.13, 163.84, 145.81, 143.92,
(t, J = 7.2 Hz, 6H, 2
×
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
δ
133.37, 131.85, 127.25, 126.92, 123.70, 123.02, 122.26, 122.19, 122.02, 113.90, 62.12 (d, J = 6.4 Hz, POC),
44.49 (PCC), 35.15, 27.23 (d, J = 141.4 Hz, PC), 16.32 (d, J = 5.7 Hz, POCC); 31P-NMR (81 MHz, CDCl3):
δ
= 26.33 ppm. Anal. Calcd. for C21H24N5O5P: C, 55.14; H, 5.29; N, 15.31. Found: C, 55.36; H, 5.06;
N, 15.25.
Diethyl 3-{4-[(5-Amino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}propylphosphonate
(
17c): Yield 79% (after column chromatography with chloroform–methanol mixtures (100:1 and 50:1,
v/v)). A white powder; m.p. 180–182 ◦C; IR (KBr):
= 3451, 3343, 3235, 3148, 3067, 2986, 1700, 1652,
1619, 1222, 1029, 794, 759 cm−1; 1H-NMR (600 MHz, CDCl3):
= 8.28 (dd, J = 7.3 Hz, J = 0.8 Hz, 1H,
ν
δ
Haromat.), 8.00 (d, J = 2.3 Hz, 1H, Haromat.), 7.87 (dd, J = 8.2 Hz, J = 0.8 Hz, 1H, Haromat.), 7.70 (s, 1H,
HC50), 7.56 (dd, J = 8.2 Hz, J = 7.3 Hz, 1H, Haromat.), 7.23 (d, J = 2.3 Hz, 1H, Haromat.), 5.49 (s, 2H,
CH2), 4.42 (t, J = 6.9 Hz, 2H, PCH2CH2CH2), 4.33 (s, 2H, NH2), 4.11–4.04 (m, 4H, 2
2.21 (dqu, J = 18.6 Hz, J = 6.9 Hz, 2H, PCH2CH2), 1.73 (dt, J = 18.6 Hz, J = 7.7 Hz, 2H, PCH2), 1.30 (t,
J = 7.1 Hz, 6H, 2 = 164.01, 163.83, 148.37, 143.72, 134.07,
POCH2CH3); 13C-NMR (151 MHz, CDCl3):
×
POCH2CH3),
×
δ
132.14, 127.43, 126.05, 123.71, 122.96, 122.33, 122.16, 122.15, 112.40, 61.52 (d, J = 6.7 Hz, POC), 49.77 (d,
J = 15.2 Hz, PCCC), 35.68, 23.83 (d, J = 3.5 Hz, PCC), 22.32 (d, J = 143.2 Hz, PC), 16.65 (d, J = 5.5 Hz,
POCC); 31P-NMR (243 MHz, CDCl3):
δ = 30.01 ppm. Anal. Calcd. for C22H26N5O5P: C, 56.05; H, 5.56;
N, 14.86. Found: C, 55.80; H, 5.41; N, 14.60.
Diethyl 4-{4-[(5-Amino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}butylphosphonate
(
17d): Yield 70% (after column chromatography with chloroform–methanol mixtures (100:1 and 50:1,
◦
v/v)). A yellow powder; m.p. 218–220 C; IR (KBr):
ν
= 3451, 3343, 3235, 3148, 3067, 2986, 1700,
= 8.28 (dd, J = 7.3 Hz, J = 0.8 Hz
1652, 1619, 1222, 1029, 794, 759 cm−1; 1H-NMR (600 MHz, CDCl3):
δ
,
1H, Haromat.), 8.00 (d, J = 2.3 Hz, 1H, Haromat.), 7.87 (dd, J = 8.2 Hz, J = 0.8 Hz, 1H, Haromat.), 7.70 (s,
1H, HC50), 7.56 (dd, J = 8.2 Hz, J = 7.3 Hz, 1H, Haromat.), 7.23 (d, J = 2.3 Hz, 1H, Haromat.), 5.49 (s,
2H, CH2), 4.42 (t, J = 6.9 Hz, 2H, PCCCCH2),4.33 (s, 2H, NH2), 4.20–4.00 (m, 4H, 2
2.02 (qu, J = 6.9 Hz, 2H, PCCCH2), 1.80–1.60 (m, 4H, PCCH2 and PCH2), 1.30 (t, J = 7.0 Hz, 6H, 2
POCH2CH3); 13C-NMR (151 MHz, DMSO-d6):
= 163.99, 163.81, 148.39, 143.61, 134.08, 132.15, 127.42,
126.04, 123.55, 122.97, 122.34, 122.17, 121.14, 112.38, 61.26 (d, J = 6.0 Hz, 2 POC), 49.16, 35.67, 30.64 (d,
J = 16.0 Hz, PCCC), 24.28 (d, J = 138.9 Hz, PC), 19.62 (d, J = 4.7 Hz, PCC), 16.69 (d, J = 5.7 Hz, POCC);
31P-NMR (243 MHz, CDCl3):
= 30.91 ppm. Anal. Calcd. for C23H28N5O5P: C, 56.90; H, 5.81; N, 14.43.
Found: C, 56.95; H, 5.75; N, 14.69.
×
POCH2CH3),
×
δ
×
δ

Molecules 2016, 21, 1420
15 of 20
Diethyl
hydroxyethylphosphonate (17e): Yield 80% (after crystallization from a methanol–diethyl ether mixture).
A white powder; m.p. 170–172 ◦C; IR (KBr):
= 3420, 3330, 3233, 3154, 2982, 1700, 1650, 1620, 1228,
1049, 1016, 797, 757 cm−1; 1H-NMR (600 MHz, DMSO-d6):
= 8.10 (d, J = 7.3 Hz, 1H, Haromat.), 8.05
2-{4-[(5-Amino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-1-
ν
δ
(d, J = 8.2 Hz, 1H, Haromat.), 8.00 (s, 1H, HC50), 7.99 (d, J = 2.3 Hz, 1H, Haromat.), 7.63 (dd, J = 8.2 Hz,
J = 7.3 Hz, 1H, Haromat.), 7.30 (d, J = 2.3 Hz, 1H, Haromat.), 6.00 (s, 2H, NH2), 5.28 (s, 2H, CH2), 4.52 (dt,
J = 14.2 Hz, J = 3.7 Hz, 1H, PCCHaHb), 4.38 (ddd, J = 14.2 Hz, J = 10.1 Hz, J = 7.0 Hz, 1H, PCCHaHb),
4.23–4.18 (m, 1H, PCH), 4.07–4.00 (m, 4H, 2
13C-NMR (151 MHz, DMSO-d6):
= 163.35, 163.30, 143.25, 137.05, 134.17, 131.67, 129.82, 127.07, 126.51,
123.20, 122.98, 122.19, 122.04, 121.04, 120.83, 120.51, 67.57 (d, J = 168.4 Hz, PC), 63.36 (d, J = 6.8 Hz,
POC), 63.24 (d, J = 6.8 Hz, POC), 52.46 (d, J = 11.7 Hz, PCC), 34.41, 16.60 (d, J = 4.7 Hz, 2 POCC);
31P-NMR (243 MHz, DMSO-d6):
= 25.85 ppm. Anal. Calcd. for C21H24N5O6P: C, 53.28; H, 5.11; N,
14.79. Found: C, 53.55; H, 5.35; N, 14.59.
×
POCH2CH3), 1.21 (t, J = 7.0 Hz, 6H, 2
×
POCH2CH3);
δ
×
δ
Diethyl 3-{4-[(5-Amino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-2-
hydroxypropylphosphonate (17f): Yield 75%. (after crystallization from a methanol–diethyl ether mixture).
An orange powder; m.p. 222–224 ◦C; IR (KBr):
= 3437, 3333, 3234, 3140, 3068, 3034, 2922, 1653, 1616,
1223, 1049, 778, 744 cm−1; 1H-NMR (600 MHz, DMSO-d6):
= 8.10 (d, J = 6.9 Hz, 1H, Haromat.), 8.06
ν
δ
(d, J = 8.1 Hz, 1H, Haromat.), 8.00 (d, J = 2.2 Hz, 1H, Haromat.), 7.93 (s, 1H, HC50), 7.63 (dd, J = 8.1 Hz,
J = 6.9 Hz, 1H, Haromat.), 7.31 (t, J = 2.2 Hz, 1H, Haromat.), 6.00 (brs, 2H, NH2), 5.35 (brs, 1H, OH), 5.29
(s, 2H, CH2), 4.45 (dd, J = 13.8 Hz, J = 3.6 Hz, 1H, PCCCHaHb), 4.26 (dd, J = 13.8 Hz, J = 7.7 Hz, 1H,
PCCCHaHb), 4.15–4.09 (m, 1H, PCCH), 4.02–3.93 (m, 4H, 2
×
POCH2CH3), 1.97 (ddd, J = 18.0 Hz,
J = 15.4 Hz, J = 5.3 Hz, 1H, PCHaHb), 1.88 (ddd, J = 18.0 Hz, J = 15.4 Hz, J = 7.1 Hz, 1H, PCHaHb), 1.21
(t, J = 7.0 Hz, 3H, POCH2CH3), 1.20 (t, J = 7.0 Hz, 3H, POCH2CH3); 13C-NMR (151 MHz, DMSO-d6):
δ
= 164.02, 163.84, 148.39, 143.29, 134.09, 132.16, 127.45, 126.05, 124.65, 122.98,122.34, 122.18, 121.14,
112.39, 65.45 (d, J = 1.8 Hz, PCC), 61.62 (d, J = 6.4 Hz, POC), 61.42 (d, J = 6.4 Hz, POC), 55.92 (d,
J = 13.0 Hz, PCCC), 35.62, 31.47 (d, J = 137.0 Hz, PC), 16.66 (d, J = 5.9 Hz, 2
POCC); 31P-NMR
(243 MHz, DMSO-d6): = 27.89 ppm. Anal. Calcd. for C22H26N5O6P: C, 54.21; H, 5.38; N, 14.37.
×
δ
Found: C, 53.92; H, 5.29; N, 14.15.
Diethyl 2-{4-[(5-Amino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethoxy-
methylphosphonate (17g): Yield 77% (after column chromatography with chloroform–methanol mixtures
◦
(100:1 or 50:1, v/v)). A yellow powder; m.p. 221–223 C; IR (KBr):
ν = 3438, 3339, 3233, 3145, 2980, 2890,
1701, 1651, 1620, 1222, 1048, 1024, 791, 743 cm−1; 1H-NMR (600 MHz, DMSO-d6):
1H, Haromat.), 8.05 (d, J = 8.2 Hz, 1H, Haromat.), 8.00 (d, J = 2.2 Hz, 1H, Haromat.), 7.96 (s, 1H, HC5 ), 7.63
(dd, J = 8.2 Hz, J = 7.2 Hz, 1H, Haromat.), 7.31 (t, J = 2.2 Hz, 1H, Haromat.), 6.00 (brs, 2H, NH2), 5.29 (s, 2H,
δ
= 8.10 (d, J = 7.2 Hz,
0
CH2), 4.50 (t, J = 5.0 Hz, 2H, PCH2OCH2CH2), 3.92–3.88 (m, 6H, 2
(d, J = 8.3 Hz, 2H, PCH2O), 1.12 (t, J = 7.1 Hz, 6H, 2
POCH2CH3); 13C-NMR (151 MHz, DMSO-d6):
= 164.04, 163.80, 148.40, 143.56, 134.09, 132.17, 127.44, 126.06, 123.97, 122.97, 122.35, 122.17, 121.15,
112.40, 71.00 (d, J = 11.6 Hz, PCOC), 64.31 (d, J = 163.1 Hz, PC), 62.16 (d, J = 6.3 Hz, POC), 49.47, 35.63,
16.63 (d, J = 5.3 Hz, 2 = 20.69 ppm. Anal. Calcd. for
POCC); 31P-NMR (243 MHz, DMSO-d6):
×
POCH2CH3, PCOCH2CH2), 3.80
×
δ
×
δ
C22H26N5O6P: C, 54.21; H, 5.38; N, 14.37. Found: C, 54.38; H, 5.46; N, 14.54.
Diethyl 2-(2-{4-[(5-Amino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-1H-1,2,3-triazol-1-yl}ethoxy)
ethylphosphonate (17h): Yield 77% (after column chromatography with chloroform–methanol mixtures
(100:1 or 50:1, v/v)). An orange powder; m.p. 180–183 ◦C; IR (KBr):
ν
= 3434, 3353, 3230, 2981, 2927,
= 8.33 (d, J = 7.2 Hz, 1H,
1698, 1659, 1623, 1222, 1025, 787, 748 cm−1; 1H-NMR (600 MHz, CDCl3):
δ
Haromat.), 8.06 (d, J = 2.2 Hz, 1H, Haromat.), 7.82 (d, J = 8.2 Hz, 1H, Haromat.), 7.78 (s, 1H, HC50), 7.54
(dd, J = 8.2 Hz, J = 7.2 Hz,1H, Haromat.), 7.18 (d, J = 2.2 Hz, 1H, Haromat.), 6.00 (brs, 2H, NH2), 5.49 (s,
2H, CH2), 4.59 (t, J = 5.1 Hz, 2H, PCH2CH2OCH2CH2), 4.19–4.02 (m, 4H, 2
J = 5.1 Hz, 2H, PCCOCH2CH2), 3.65 (dt, J = 15.4 Hz, J = 6.9 Hz, 2H, PCH2CH2O), 2.16 (dt, J = 18.6 Hz,
J = 6.9 Hz, 2H, PCH2CH2O), 1.35 (t, J = 7.1 Hz, 6H, 2
POCH2CH3); 13C-NMR (151 MHz, DMSO-d6):
×
POCH2CH3), 3.78 (t,
×

Molecules 2016, 21, 1420
16 of 20
δ
= 164.02, 163.84, 148.38, 143.56, 134.08, 132.13, 127.41, 126.03, 124.00, 123.00, 122.33, 122.20, 121.16,
112.37, 68.69, 64.73(PCCO), 61.36 (d, J = 6.4 Hz, POC), 49.71, 35.68, 26.28 (d, J = 137.2 Hz, PC), 16.64 (d,
J = 5.6 Hz, POCC); 31P-NMR (243 MHz, CDCl3):
= 27.84 ppm. Anal. Calcd. for C23H28N5O6P: C,
δ
55.09; H, 5.63; N, 13.97. Found: C, 55.12; H, 5.36; N, 13.70.
Diethyl 2-{4-[(5-Amino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl]-◦1H-1,2,3-triazol-1-yl}acetamido-
methylphosphonate (17i): Yield 96%. A yellow powder; m.p. 222–224 C; IR (KBr):
ν = 3447, 3374,
3225, 3146, 2991, 2927, 1695, 1649, 1619, 1223, 1021, 779, 744 cm−1; 1H-NMR (600 MHz, DMSO-d6):
δ
= 8.73 (t, J = 5.5 Hz, 1H, NHCO), 8.10 (d, J = 7.2 Hz, 1H, Haromat.), 8.05 (d, J = 8.1 Hz, 1H, Haromat.),
8.00 (d, J = 2.2 Hz, 1H, Haromat.), 7.95 (s, 1H, HC50), 7.63 (dd, J = 8.1 Hz, J = 7.2 Hz, 1H, Haromat.),
7.31 (t, J = 2.2 Hz, 1H, Haromat.), 6.00 (brs, 2H, NH2), 5.30 (s, 2H, CH2), 5.09 (s, 2H), 4.02–3.97 (m, 4H,
2
×
POCH2CH3), 3.60 (dd, J = 11.8 Hz, J = 5.9 Hz, 2H, PCH2NH), 1.19 (t, J = 6.9 Hz, 6H, 2
×
POCH2CH3);
13C-NMR (151 MHz, DMSO-d6):
δ
= 165.97 (d, J = 4.5 Hz, C=O), 164.00, 163.82, 148.39, 143.40, 134.08,
132.19, 127.45, 126.08, 125.18, 122.93, 122.35, 122.13, 121.12, 112.43, 62.32 (d, J = 6.2 Hz, POC), 51.83,
35.58, 34.62 (d, J = 155.2 Hz, PC), 16.64 (d, J = 5.7 Hz, POCC); 31P-NMR (121.5 MHz, DMSO-d6):
δ
= 22.29 ppm. Anal. Calcd. for C22H25N6O6P: C, 52.80; H, 5.04; N, 16.79. Found: C, 52.71; H, 4.86;
N, 16.53.
3.6. Antiviral Activity Assays
The compounds were evaluated against the following viruses: herpes simplex virus type 1
(HSV-1) strain KOS, thymidine kinase-deficient (TK−) HSV-1 KOS strain resistant to ACV (ACVr−),
herpes simplex virus type 2 (HSV-2) strains Lyons and G, varicella-zoster virus (VZV) strain Oka, TK
VZV strain 07 1, human cytomegalovirus (HCMV) strains AD-169 and Davis, vaccinia virus Lederle
−
strain, respiratory syncytial virus (RSV) strain Long, vesicular stomatitis virus (VSV), Coxsackie
B4, Parainfluenza 3, Influenza virus A (subtypes H1N1, H3N2), influenza virus B, Reovirus-1,
Sindbis, Reovirus-1, Punta Toro, human immunodeficiency virus type 1 strain IIIB and human
immunodeficiency virus type 2 strain ROD. The antiviral, other than anti-HIV, assays were based
on inhibition of virus-induced cytopathicity or plaque formation in human embryonic lung (HEL)
fibroblasts, African green monkey cells (Vero), human epithelial cells (HeLa) or Madin-Darby canine
kidney cells (MDCK). Confluent cell cultures in microtiter 96-well plates were inoculated with
100 CCID50 of virus (1 CCID50 being the virus dose to infect 50% of the cell cultures) or with
20 plaque forming units (PFU) (VZV) in the presence of varying concentrations of the test compounds.
Viral cytopathicity or plaque formation was recorded as soon as it reached completion in the control
virus-infected cell cultures that were not treated with the test compounds. Antiviral activity was
expressed as the EC50 or compound concentration required to reduce virus-induced cytopathogenicity
or viral plaque formation by 50%.
3.7. Cytostatic Activity Assays
All assays were performed in 96-well microtiter plates. To each well were added (5–7.5)
×
104
tumor cells and a given amount of the test compound. The cells were allowed to proliferate for 48 h
(murine leukemia L1210 cells) or 72 h (human lymphocytic CEM and human cervix carcinoma HeLa
cells) at 37 ◦C in a humidified CO2-controlled atmosphere. At the end of the incubation period, the
cells were counted in a Coulter counter. The IC50 (50% inhibitory concentration) was defined as the
concentration of the compound that inhibited cell proliferation by 50%.
4. Conclusions
A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-methyl]-
1H-1,2,3-triazol-1-yl}alkylphosphonates has been synthesized in good to excellent yields via
Cu(I)-catalyzed Hüisgen dipolar cycloaddition of N-propargyl naphthalimides 7/8 and 11/12 with the
respective azidoalkylphosphonates 13a–i under microwave irradiation.

Molecules 2016, 21, 1420
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The synthesized phosphonates 14a
–i
–17a
–i
were evaluated against a variety of DNA and RNA
viruses and several of them appeared slightly active against VZV (EC50 = 27.6–91.5 µM). Among
them, the compound−16b, which showed no potency toward the TK+ VZV strain, was found the most
active against the TK VZV strain (EC50 = 27.59 µM), with EC50 values comparable to reference drugs.
On the other hand, compound 16d exhibited the highest activity against TK+ VZV (EC50 = 29.91
µM),
athough lower than that of reference compounds.
Cytostatic properties of compounds 14a
cell lines and most of them were only slightly cytostatic for HeLa (IC50 = 29–130
cells (IC50 = 14–142 M). Among all tested compounds 14a 17a derivatives substituted with a
–
i–
17a
–
i
were studied on L1210, CEM, HeLa and HMEC-1
µM) and L1210
µ
–
i
–
–i
bromine atom at C6 (15b and 15d) were the most active. Based on a preliminary SAR analysis it was
established that the presence of the 1,2,3-triazole unit is essential for the cytostatic activity. Furthermore,
compounds with longer linkers [(CH2)3, (CH2)4 and CH2CH2OCH2CH2)] showed the higher cytostatic
potency than those having shorter fragments [CH(OH)CH2 and CH2NHC(O)CH2].
Acknowledgments: The authors wish to express their gratitude to Małgorzata Pluskota, Leentje Persoons,
Lies Van Den Heurck, Ellen De Waegenaere and Lizette van Berckelaer for excellent technical assistance. The
synthetic part of this work was supported by the Medical University of Lodz internal fund (503/3-014-1/503-01).
The virological part of this work was supported by the KU Leuven (GOA 15/19 TBA).
Author Contributions: Research group from Medical University of Lodz (Iwona E. Głowacka, Rafał Gulej,
Piotr Grzonkowski and Dorota G. Piotrowska) conceived the research project, participated in all steps of the
research, interpreted the results, discussed the experimental data and prepared the manuscript. Research group
from KU Leuven (Graciela Andrei, Dominique Schols and Robert Snoeck) conducted the biological assays and
provided the experimental procedures and results. All authors read, commented and approved the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).