1,2,3-triazole-dithiocarbamate-naphthalimides: Synthesis,characterization,and biological evaluation

Abstract

Fifteen novel dithiocarbamate-derived naphthalimides as a type of potential anticancer and antimicrobial agents were synthesized and characterized by spectral and analytical techniques. The structures of 2b, 5a, and 7b were established by X-ray crystallography. Their in vitro antitumor activities were evaluated by the MTT method against MDA-MB-231, HepG-2, PC12, as well as A549. Based on the results of the MTT assay, compound 7c bearing a morpholinyl substituent displayed the highest activity and selectivity toward HepG-2 cancer cells with an IC₅₀ of 10.86 µM. All new compounds were screened for their antimicrobial activity against Candida albicans, Escherichia coli, Bacillus subtilis, and Staphylococcus aureus. The preliminary results showed that compound 7d (an N-methyl piperazine) showed high efficacy against B. subtilis with a minimum inhibitory concentration value of 7.6 µM, which was superior to that of the clinical drug, Cefuroxim. It is found that the anticancer and antibacterial activities of the dithiocarbamate-naphthalimide derivatives were significantly enhanced when bearing a 1,2,3-triazole group.

Keywords

1,2,3-triazole anticancer antimicrobial dithiocarbamates naphthalimide

Introduction

The design and synthesis of highly efficient antitumor agents had attracted a lot of attention over the years. The development of the naphthalimide class of compounds as anticancer agents started in 1973. Two leading members of this family, amonafide and mitonafide, have been studied in phase I and phase II clinical trials. Unfortunately, the use and development of this kind of drug have been limited due to their unexpected toxicity.¹

In the past few decades, optimization of anticancer drugs has been an ongoing process. One promising strategy is the combination of an active moiety with known anticancer groups aimed at the development of potent cytotoxic substances. Recently, the Liu group reported the biological activities of dithiocarbamate (DTC) derivatives achieved by the introduction of the 1,2,3-trizaole ring leading to several compounds that showed an excellent, broad spectrum of anticancer activities and good anti-LSD1 activities.^2–5 The Qian group investigated the anticancer activity of triazole-naphthalimides by introducing a 1,2,3-triazole ring to the 3 or 4 position of the naphthalimide and improved the anticancer cytotoxicity of the compounds over Amonafide.^6,7 Our group recently reported tethering the biologically active group DTC to ruthenium(II) and dppfM(II) (M = Pt and Pd) units.^8,9 These novel organometallic complexes-containing DTC exhibited good anticancer activity.

Inspired by the biological importance of naphthalimides as anticancer agents, it was necessary for us to attempt alternative structural modification of naphthalimides to find favorable or different biological activities. In this paper, the biologically active groups 1,2,3-triazole and DTC are tethered to a naphthalimide unit. The in vitro anticancer and antimicrobial activities of several novel 1,2,3-triazole-DTC-naphthalimides are described.

Results and discussion

Chemistry

The synthesis of the 1,2,3-triazole-dithiocarbamate-naphthalimides is shown in Scheme 1. Compound 1 reacted with CS₂ and various secondary amines in the presence of anhydrous K₃PO₄ in one pot to give compounds 2 in good yields. The synthesis of the 1,2,3-triazole-DTC-naphthalimides 5a–5e and 7a–7e was achieved by reacting appropriately substituted alkyne DTCs 4a–4e and 1,8-naphthalimide azides 3 and 6 by click reactions. The target compounds were characterized by NMR and electron ionization mass spectroscopy (EI-MS), which are given in the experimental. In addition, the crystal structures of 2b, 5a, and 7b were determined by X-ray diffraction analysis.

X-ray diffraction studies

The single-crystal X-ray structures of 2b, 5a, and 7b are shown in Figures 1 –3, respectively. The crystallographic details and selected bond distances and angles are presented in the Supplementary Material (Tables S1 and S2, respectively). The double C–O and C–N bond distances are within the range of those reported for naphthalimide compounds.¹⁰ The average C–S bond distance in 5a is longer than that in 2b and 7b. The S1–C–S2 bond angles of 2b and 7b are 121.51(8)° and 122.6(3)°, respectively, which are slightly smaller than that of compound 5a (124.4(2)°). The bond length and angles are within the range of those reported for dithiocarbamates.¹¹

Biological evaluation

The in vitro antiproliferative activities of the synthetic compounds 2a–2e, 5a–5e, and 7a–7e against four cancer cell lines, including MDA-MB-231 (mammary adenocarcinoma cell), Hep-2 (human hepatoma carcinoma cell), PC12 (rat pheochromocytoma cell), and A549 (human lung adenocarcinoma cell), were assayed by the classical MTT method, and the results, each expressed as an IC₅₀, are summarized in Table 1. Cisplatin (CDDP) was used as the reference drug.

Table 1.

Antiproliferative activity of the 1,8-naphthalimide-dithiocarbamate derivatives.

Compound	Antiproliferative activity (IC₅₀^a, µM)
Compound	MDA-MB-231	HepG-2	PC12	A549
2a	>100	41.668	3.6711	5.4188
2b	>100	>100	>100	>100
2c	96.785	>100	8.7902	7.3063
2d	80.217	>100	11.125	3.2203
2e	>100	>100	>100	>100
5a	>100	55.616	19.35	>100
5b	21.052	>100	21.409	2.308
5c	>100	>100	>100	>100
5d	19.29	40.196	9.954	9.0323
5e	>100	>100	>100	9.0657
7a	>100	38.619	>100	23.714
7b	15.5	33.931	>100	4.3202
7c	>100	10.86	>100	14.375
7d	29.411	91.453	7.2778	2.2699
7e	>100	>100	4.8139	40.198
Cisplatin	3.162	9.803	3.012	1.1248

Antiproliferative activity was assayed by exposure for 24 h to substances and expressed as concentration required to inhibit tumor cell proliferation by 50% (IC₅₀). Data are presented as the mean vales from the dose–response curves of three independent experiments.

As shown in Table 1, the DTCs 2a–2e derived by modification of the N-atom of 1,8-naphthalimide show good in vitro anticancer activities against PC12 and A549. The pyrrole-substituted compound 2a, in particular, displayed an IC₅₀ value of 3.671 µM against PC12 in vitro, which is almost equal to the standard used. Among the 1,2,3-triazole-DTCs 5a–5e, only a few compounds exhibited good cytotoxicity, as shown by compound 5b. Compared to the corresponding DTCs 2a–2e, the antiproliferative activities of the 1,2,3-triazole-DTCs were significantly improved, as shown by compound 5d. Usually, the naphthalimides with substituents at the 4-position showed only very weak antitumor activity. However, in this work, the naphthalimides substituted by 1,2,3-triazoles containing the DTC group at the 4-position displayed remarkable antitumor activity. Based on the results of the MTT assays, in this series, compound 7c, bearing a morpholinyl substituent, displayed the highest activity and selectivity toward HepG-2 cancer cells with an IC₅₀ of 10.86 µM. The most active compound, 7d, against A549 showed an IC₅₀ value of 2.2699 µM, which nearly reached the level of cisplatin. It was found that the introduction of a triazole ring helps to improve the activities of DTC-naphthalimides. Some naphthalimides with substituents at the 4-position have higher activity.

Recently, the Zhou group found that triazole-naphthalimides displayed good antimicrobial activities,^12,13 and so, the antimicrobial activities of the 1,2,3-triazole-DTC-naphthalimides were also investigated. All the target compounds were evaluated for their antimicrobial activity in vitro against three bacteria (Escherichia coli, Bacillus subtilis, and Staphylococcus aureus) and one fungus (Candida albicans) (Table 2).

Table 2.

In vitro antibacterial and antifungal activities as MIC^a (µM) of 1,8-naphthalimide-dithiocarbamate derivatives.

Compds.	C. albicans	E. coli	B. subtilis	S. aureus
2a	−	−	−	−
2b	77.4	−	−	−
2c	−	−	−	−
2d	−	−	−	−
2e	−	−	−	−
5a	137	−	−	137
5b	−	133	−	133
5c	−	−	−	−
5d	129	129	647	259
5e	115	−	−	−
7a	129	−	32.3	64.6
7b	629	−	62.9	31.5
7c	125	−	15.7	31.3
7d	122	−	7.6	122
7e	109	−	109	−
Fluconazole	3.27	−	−	−
Streptomycin	−	6.88	−	−
Cefuroxim	−	−	9.4	−
Ampicillin	−	−	−	1.24

C. albicans: Candida albicans; E. coli: Escherichia coli; B. subtilis: Bacillus subtilis; S. aureus: Staphylococcus aureus.

Minimum inhibitory concentration against C. albicans, B. subtilis, S. aureus, and Staphylococcus aureus.

As shown in Table 2, most of compounds 2a–2e were weak or inactive to the tested strains, except that compound 2b displayed certain antifungal activity for Candida albicans. Some of 1,2,3-triazole-DTCs 5a–5e showed some antibacterial activities. Some of naphthalimides with substituents at the 4-position displayed good activity against Bacillus subtilis. Especially, compound 7d (an N-methylpiperazine) showed high efficacy against B. subtilis with a minimum inhibitory concentration (MIC) value of 7.6 µM, which was superior to that of the clinical drug Cefuroxim. It was found that the antibacterial activity of the corresponding DTC-naphthalimide derivatives was significantly enhanced when bearing a 1,2,3-triazole group, and the antibacterial activity of the naphthalimides with substituents at the 4-position was significantly higher than those of derivatives derived from N-atom of 1,8-naphthalimide. However, the enhanced antibacterial activity is mainly toward Gram-positive bacteria, such as B. subtilis and S. aureus, not Gram-negative pathogen (i.e. E. coli).

Conclusion

In summary, a series of novel naphthalimide derivatives with DTC or 1,2,3-triazole-DTC moieties were designed and synthesized, and their antitumor and antibacterial activities were evaluated in vitro. It was found that the introduction of a triazole ring helps to improve the activities of the DTC-naphthalimides and that some naphthalimides with substituents at the 4-position have the higher activities. This work demonstrates that incorporating the biological active naphthalimide and DTC units, or a 1,2,3-triazole-DTC moiety, might result in novel classes of lead compounds with potential antitumor and antimicrobial activities.

Experimental section

General procedures

All manipulations were carried out at room temperature under a nitrogen atmosphere using standard Schlenk techniques, unless otherwise stated. All reagents were purchased from commercial sources and were used without further purification. ¹H and ¹³C NMR spectra were obtained using a Bruker 500 MHz magnetic resonance spectrometer. ¹H and ¹³C NMR chemical shifts are relative to tetramethylsilane (TMS). Mass spectrometry was recorded with a Bruker amaZon SL spectrometer. The starting materials 2-(3-bromopropyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (1),¹⁴ 4a–e,⁴ and 6-azido-2-(2-(dimethylamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6)⁷ were prepared by the procedures described in the literature.

General procedure for synthesis of DTC-naphthalimides 2a–e

To a solution of amine (1.1 mmol) in dimethylformamide (DMF) (5 mL) was added dropwise carbon disulfide (0.17 g, 2.2 mmol) and anhydrous potassium phosphate (0.23 g, 1.1 mmol). The resulting mixture was stirred at room temperature for 30 min. Then, the naphthalimide compound 1 (0.32 g, 1.0 mmol) was added in one portion, and the stirring was continued for another 12 h. After completion of the reaction, the mixture was diluted with ice-cold water and the precipitate was filtered and recrystallized from ethanol to give the target compounds 2a–e.

2a: White solid, 0.35 g (Yield: 90%). m.p.: 178–180 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J = 10.0 Hz, 2H, -PhH), 8.21 (d, J = 10.0 Hz, 2H, -PhH), 7.75 (t, J = 7.5 Hz, 2H, -PhH), 4.33 (t, J = 7.5 Hz, 2H, -NCH₂CH₂-), 3.90 (t, J = 7.5 Hz, 2H, -NCH₂CH₂-), 3.65 (t, J = 7.5 Hz, 2H, -NCH₂CH₂-), 3.44 (t, J = 7.5 Hz, 2H, -SCH₂CH₂-), 2.24–2.14 (m, 2H -NCH₂CH₂-), 2.11–2.01 (m, 2H, -NCH₂CH₂-), 1.96 (p, J = 6.8 Hz, 2H, -NCH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃) δ 206.92, 195.49, 164.20, 133.90, 131.56, 131.23, 128.15, 126.89, 122.62, 49.35, 46.58, 39.36, 34.65, 30.89, 27.58. ESI-MS(+): m/z found 385.1021 [M+H]⁺, 407.0842 [M+Na]⁺, calcd for C₂₀H₂₀N₂O₂S₂: 384.0966.

2b: White solid, 0.33 g (Yield: 82%). m.p.: 174–175 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J = 10.0 Hz, 2H, -PhH), 8.21 (d, J = 10.0 Hz, 2H, -PhH), 7.75 (t, J = 7.5 Hz, 2H, -PhH), 4.33 (t, J = 7.5 Hz, 2H, -NCH₂CH₂CH₂S-), 4.26 (brs, 2H, -NCH₂CH₂-) 3.89 (brs, 2H, -NCH₂CH₂-), 3.44 (t, J = 7.5 Hz, 2H, -SCH₂CH₂-), 2.21–2.16 (m, 2H, -SCH₂CH₂-), 1.68–1.60 (m, 6H, -CH₂CH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃) δ 195.60, 164.25, 133.93, 131.58, 131.28, 128.18, 126.92, 122.65, 45.70, 39.36, 34.70, 27.64, 24.32, 8.58. ESI-MS(+): m/z found 399.1168 [M+H]⁺, 421.0992 [M+Na]⁺, calcd for C₂₁H₂₂N₂O₂S₂: 398.1123.

2c: White solid, 0.37 g (Yield: 94%). m.p.: 186–188 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J = 5.0 Hz, 2H, -PhH), 8.21 (d, J = 5.0 Hz, 2H, -PhH), 7.76 (t, J = 7.5 Hz, 2H, -PhH), 4.33 (t, J = 7.5 Hz, 4H, -NCH₂CH₂CH₂S-), 3.99 (s, 2H, -NCH₂CH₂-), 3.74 (s, 4H, -OCH₂CH₂-), 3.46 (t, J = 5.0 Hz, 2H, -SCH₂CH₂-), 2.2–2.13 (m, 4H, -SCH₂CH₂-, -NCH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃) δ 206.86, 197.51, 164.18, 133.93, 131.53, 131.22, 128.10, 126.89, 122.54, 66.19, 39.23, 34.49, 30.86, 27.50. ESI-MS(+): m/z found 401.0963 [M+H]⁺, calcd for C₂₀H₂₀N₂O₃S₂: 400.0915.

2d: Light yellow solid, 0.33 g (Yield: 81%). m.p.: 194–195 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J = 5.0 Hz, 2H, -PhH), 8.21 (d, J = 10.0 Hz, 2H, -PhH), 7.75 (t, J = 10.0 Hz, 2H, -PhH), 4.32 (t, J = 7.5 Hz, 2H, -SCH₂CH₂-) 3.96 (br, 2H, -NCH₂CH₂-), 3.44 (t, J = 7.5 Hz, 2H, -SCH₂CH₂-), 2.46 (s, 4H, CH₃NCH₂-), 2.31 (s, 3H, CH₃N-), 2.21–2.16 (m, 4H, -SCH₂CH₂-, -NCH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃) δ 206.90, 196.92, 164.19, 133.92, 131.54, 131.23, 128.12, 126.89, 122.57, 54.35, 45.58, 39.27, 34.64, 30.88, 27.54. ESI-MS(+): m/z found 414.1281 [M+H]⁺, calcd for C₂₁H₂₃N₃O₂S₂: 413.1232.

2e: Light yellow solid, 0.42 g (Yield: 88%). m.p.: 184–185 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.61 (d, J = 5.0 Hz, 2H, -PhH), 8.21 (d, J = 10.0 Hz, 2H, -PhH), 7.75 (t, J = 7.5 Hz, 2H, -PhH), 7.29 (t, J = 7.5 Hz, 2H, -PhH), 6.91 (t, J = 5.0 Hz, 3H, -PhH), 4.46 (br, 2H, -NCH₂CH₂-), 4.34 (t, J = 5.0 Hz, 2H, -NCH₂CH₂CH₂S-), 4.12 (br, 2H, -NCH₂CH₂-), 3.47 (t, J = 7.5 Hz, 2H, -SCH₂CH₂-), 3.27 (t, J = 5.0 Hz, 4H, PhNCH₂-), 2.23–2.11 (m, 2H, -SCH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃) δ 206.91, 197.12, 164.21, 150.28, 133.94, 131.55, 131.25, 129.25, 128.13, 126.91, 122.57, 120.41, 116.23, 48.65, 39.27, 34.64, 30.88, 27.53. ESI-MS(+): m/z found 476.1411 [M+H]⁺, calcd for C₂₆H₂₅N₃O₂S₂: 475.1388.

Synthesis of the azide naphthalimide compound 3

The naphthalimide 1 (1.60 g, 5 mmol) and NaN₃ (0.65 g, 10 mmol) were dissolved in anhydrous DMF (50 mL) under nitrogen. The reaction mixture was stirred at 60 °C and monitored by thin layer chromatography (TLC) until conversion of the starting materials was satisfactory. After the reaction, cold water was added and the reaction mixture was extracted with CH₂Cl₂ (3 × 40 mL). The combined organic layer was dried over anhydrous Na₂SO₄, and concentrated under vacuum to afford 1.15 g (82%) of a yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.58–8.55 (m, 2H, -PhH), 8.20–8.18 (m, 2H, -PhH), 7.75–7.70 (m, 2H, -PhH), 4.27–4.23 (m, 2H, -NCH₂CH₂CH₂N-), 3.41–3.37 (m, 2H, -NCH₂CH₂CH₂N-), 2.04–1.97 (m, 2H, -NCH₂CH₂CH₂N-). ¹³C NMR (250 MHz, CDCl₃) δ 164.10, 162.44, 134.03, 131.52, 131.22, 126.87, 122.38, 53.35, 36.39, 31.32.

General procedure for synthesis of 1,2,3-triazole-DTC naphthalimides 5a–e and 7a–e

The azide naphthalimide derivatives 3 or 6 (1.1 mmol), CuSO₄·5H₂O (37 mg, 0.15 mmol), and sodium ascorbate (60 mg, 0.3 mmol) were dissolved in THF (5 mL) and H₂O (5 mL). Then, the alkyne DTC derivatives 4 (1 mmol) were added and the resulting mixture was stirred at room temperature for 15 h. After the reaction, the reaction mixture was poured into the ice-cold water and extracted with CH₂Cl₂. The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na₂SO₄. The crude products were purified by column chromatography on silica gel (eluent: CH₂Cl₂/CH₃OH, 50:1, V/V) to give compounds 5a–d and 7a–d.

5a: Light yellow solid, 0.13 g (Yield: 29%). m.p.: 175–177 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.61 (d, J = 5.0 Hz, 2H, -PhH), 8.25 (d, J = 10.0 Hz, 2H, -PhH), 7.84 (s, 1H, -NCH=C-), 7.78 (t, J = 7.5 Hz, 2H, -PhH), 4.65 (s, 2H, -SCH₂-), 4.45 (d, J = 7.5 Hz, 2H, -NCH₂CH₂CH₂N-), 4.30 (s, 2H, -NCH₂CH₂CH₂N-), 3.93 (t, J = 5.0 Hz, 2H, -NCH₂CH₂-), 3.63 (t, J = 7.5 Hz, 2H, -NCH₂CH₂-), 2.43–2.37 (m, 2H, -NCH₂CH₂CH₂N-), 2.10–2.04 (m, 2H, -NCH₂CH₂-), 2.00–1.95 (m, 2H, -NCH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃) δ 192.24, 164.76, 134.73, 131.95, 128.64, 127.50, 122.85, 55.64, 51.06, 38.06, 31.56, 29.49, 26.53, 24.75. ESI-MS(+): m/z found 466.1303 [M+H]⁺, calcd for C₂₃H₂₃N₅O₂S₂: 465.1293.

5b: Light yellow solid, 0.18 g (Yield: 37%). m.p.: 168–170 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.61 (d, J = 10.0 Hz, 2H, -PhH), 8.24 (d, J = 10.0 Hz, 2H, -PhH), 7.82 (s, 1H, -NCH=C-), 7.78 (t, J = 7.5 Hz, 2H, -PhH), 4.65 (s, 2H, -SCH₂-), 4.45 (t, J = 7.5 Hz, 2H, -NCH₂CH₂CH₂N-), 4.30 (t, J = 7.5 Hz, 4H, -NCH₂CH₂CH₂N-, -NCH₂CH₂-), 3.85 (brs, 2H, -NCH₂CH₂-), 2.42–2.37 (m, 2H, -NCH₂CH₂CH₂N-), 1.69–1.64 (m, 6H, -CH₂CH₂CH₂_–). ¹³C NMR (125 MHz, CDCl₃) δ 194.72, 164.74, 134.73, 132.06, 131.93, 128.61, 127.49, 122.80, 53.81, 52.03, 49.09, 38.01, 32.18, 29.41, 26.47, 25.97, 24.66. MS calcd for C₂₄H₂₅N₅O₂S₂Na [M+Na]⁺: 502.14, found: 502.1. ESI-MS(+): m/z found 480.1452 [M+H]⁺, calcd for C₂₄H₂₅N₅O₂S₂: 479.1450.

5c: Light yellow solid, 0.15 g (Yield: 30%). m.p.: 162–164 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.61 (d, J = 5.0 Hz, 2H, -PhH), 8.24 (d, J = 10.0 Hz, 2H, -PhH), 7.82 (s, 1H, -NCH=C-), 7.78 (t, J = 7.5 Hz, 2H, -PhH), 4.67 (s, 2H, -SCH₂-), 4.45 (t, J = 7.5 Hz, 2H, -NCH₂CH₂CH₂N-), 4.29 (t, J = 5.0 Hz, 4H, -NCH₂CH₂CH₂N-, -NCH₂CH₂O-), 3.93 (brs, 2H, -NCH₂CH₂O-), 3.75 (brs, 4H, -NCH₂CH₂O-), 2.42–2.37 (m, 2H, -NCH₂CH₂CH₂N-). ¹³C NMR (125 MHz, CDCl₃) δ 196.56, 164.26, 143.51, 134.25, 131.44, 128.13, 127.01, 122.98, 122.32, 66.17, 51.36, 50.57, 48.34, 37.53, 31.63, 28.96. ESI-MS(+): m/z found 482.1248 [M+H]⁺, calcd for C₂₃H₂₃N₅O₃S₂: 481.1242. MS calcd for C₂₃H₂₃N₅O₃S₂ [M+Na]⁺: 504.12, found: 504.1.

5d: Brown yellow solid, 0.12 g (Yield: 24%). m.p.: 176–178 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.61 (d, J = 5.0 Hz, 2H, -PhH)), 8.24 (d, J = 10.0 Hz, 2H, -PhH)), 7.81 (s, 1H, -NCH=C-), 7.77 (t, J = 7.5 Hz, 2H, -PhH)), 4.65 (s, 2H, -SCH₂-), 4.44 (t, J = 7.5 Hz, 2H, -NCH₂CH₂CH₂N-), 4.34–4.27 (m, 4H, -NCH₂CH₂CH₂N-, -NCH₂CH₂N-), 3.91 (brs, 2H, -NCH₂CH₂N-), 2.47 (brs, 4H, -NCH₂CH₂N-), 2.42–2.36 (m, 2H, -NCH₂CH₂CH₂N-), 2.31 (s, 3H,-NCH₃). ¹³C NMR (125 MHz, CDCl₃) δ 195.93, 164.24, 134.22, 131.57, 131.43, 128.12, 126.99, 122.32, 54.25, 51.21, 49.75, 48.40, 45.43, 37.52, 31.80, 28.95. MS calcd for C₂₄H₂₆N₆O₂S₂Na [M+Na]⁺: 517.16, found: 517.1. ESI-MS(+): m/z found 495.1571 [M+H]⁺, calcd for C₂₄H₂₆N₆O₂S₂: 494.1559.

5e: Brown yellow solid, 0.32 g (Yield: 57%). m.p.: 178–179 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J = 10.0 Hz, 2H, -PhH), 8.23 (d, J = 5.0 Hz, 2H, -PhH), 7.83 (s, 1H, -NCH=C-), 7.77 (t, J = 7.5 Hz, 2H, -PhH), 7.29–7.26 (m, 2H, -PhH), 6.91–6.89 (m, 3H, -PhH), 4.68 (s, 2H, -SCH₂-), 4.45 (t, J = 7.5 Hz, 4H, -NCH₂CH₂CH₂N-, -NCH₂CH₂N-), 4.29 (t, J = 7.5 Hz, 2H, -NCH₂CH₂CH₂N-), 4.14–4.07 (m, 2H, -NCH₂CH₂N-), 3.29 (brs, 4H, -NCH₂CH₂N-), 2.42–2.37 (m, 2H, -NCH₂CH₂CH₂N-). ¹³C NMR (125 MHz, CDCl₃) δ 195.91, 164.25, 150.16, 134.23, 131.58, 131.44, 129.28, 128.13, 127.00, 122.32, 120.51, 116.24, 60.94, 60.35, 48.66, 48.46, 37.50, 31.64, 28.92, 25.58, 21.01, 14.17. ESI-MS(+): m/z found 557.1663 [M+H]⁺, calcd for C₂₉H₂₈N₆O₂S₂: 556.1715.

7a: Yellow solid, 0.19 g (Yield: 39%). m.p.: 142–144 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.69–8.67 (m, 2H, -PhH), 8.29 (d, J = 10.0 Hz, 1H, -PhH), 8.25 (s, 1H, -NCH=C-), 7.84 (t, J = 7.5 Hz, 2H, -PhH), 4.85 (s, 2H, -SCH₂-), 4.36 (t, J = 5.0 Hz, 2H, -NCH₂CH₂N-), 3.94 (t, J = 5.0 Hz, 2H, -NCH₂CH₂-), 3.68 (t, J = 7.5 Hz, 2H, -NCH₂CH₂-), 2.71 (t, J = 5.0 Hz, 2H, -NCH₂CH₂N-), 2.38 (s, 6H, -N(CH₃)₂), 2.13–2.08 (m, 2H, -NCH₂CH₂-), 2.03–1.99 (m, 3H, -NCH₂CH₂-).¹³C NMR (125 MHz, CDCl₃) δ 191.29, 163.70, 163.18, 145.44, 138.16, 132.21, 130.68, 129.64, 129.08, 128.50, 126.30, 125.33, 123.71, 123.43, 122.86, 56.76, 55.32, 50.67, 45.57, 38.21, 30.64, 26.05, 24.24. ESI-MS(+): m/z found 495.1559 [M+H]⁺, calcd for C₂₄H₂₆N₆O₂S₂: 494.1559.

7b: Brown yellow solid, 0.41 g (Yield: 81%). m.p.: 166–168 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.70–8.68 (m, 2H, -PhH), 8.29 (d, J = 10.0 Hz, 1H, -PhH), 8.23 (s, 1H, -NCH=C-), 7.86–7.82 (m, 2H, -PhH), 4.88 (s, 2H, -SCH₂-), 4.37–4.31 (m, 4H, -NCH₂CH₂N-, -NCH₂CH₂-), 3.90 (s, 2H, -NCH₂CH₂-), 2.69 (t, J = 5.0 Hz, 2H, -NCH₂CH₂N-), 2.37 (s, 6H, -N(CH₃)₂), 1.73 (brs, 6H, -NCH₂CH₂- -CH₂CH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃) δ 194.15, 163.74, 163.22, 145.45, 138.21, 132.26, 130.73, 129.66, 129.14, 128.55, 126.37, 125.41, 123.79, 123.49, 122.93, 56.89, 53.39, 51.57, 45.72, 38.39, 31.44, 26.05, 25.46, 24.21. ESI-MS(+): m/z found 509.1711 [M+H]⁺, calcd for C₂₅H₂₈N₆O₂S₂: 508.1715.

7c: Yellow solid, 0.25 g (Yield: 50%). m.p.: 146–148 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.71–8.68 (m, 2H, -PhH), 8.26 (d, J = 5.0 Hz, 1H, -PhH), 8.20 (s, 1H, -NCH=C-), 7.86–7.82 (m, 2H, -PhH), 4.88 (s, 2H, -SCH₂-), 4.35 (t, J = 7.5 Hz, 4H, -NCH₂CH₂O-), 3.97 (brs, 2H, -NCH₂CH₂N-), 3.78 (brs, 4H, -OCH₂CH₂N-), 2.68 (t, J = 7.5 Hz, 2H, -NCH₂CH₂N-), 2.36 (s, 6H, -N(CH₃)₂). ¹³C NMR (125 MHz, CDCl₃) δ 196.07, 163.66, 163.14, 144.87, 138.06, 132.23, 130.66, 129.51, 129.09, 128.54, 126.31, 125.34, 123.82, 123.44, 122.92, 56.86, 51.64, 50.54, 45.70, 38.37, 31.16, 29.65, 28.78. ESI-MS(+): m/z found 511.1534 [M+H]⁺, calcd for C₂₄H₂₆N₆O₃S₂: 510.1508.

7d: Brown yellow solid, 0.40 g (Yield: 77%). m.p.: 168–170 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.69–8.67 (m, 2H, -PhH), 8.27 (d, J = 5.0 Hz, 1H, -PhH), 8.21 (s, 1H, -NCH=C-), 7.84 (t, J = 7.5 Hz, 2H, -PhH), 4.87 (s, 2H, -SCH₂-), 4.35 (t, J = 5.0 Hz, 4H, -NCH₂CH₂N-), 3.97 (brs, 2H, -NCH₂CH₂N-), 2.69 (t, J = 7.5 Hz, 2H, -NCH₂CH₂N-), 2.51 (brs, 4H, -NCH₂CH₂N-), 2.36 (s, 6H, -N(CH₃)₂), 2.33 (s, 3H, -NCH₃). ¹³C NMR (125 MHz, CDCl₃) δ 195.49, 163.71, 163.19, 145.12, 138.14, 132.25, 130.71, 129.60, 129.12, 128.56, 126.35, 125.39, 123.81, 123.49, 122.93, 56.90, 54.36, 53.46, 51.50, 49.95, 45.74, 45.61, 38.41, 31.37. ESI-MS(+): m/z found 524.1824 [M]⁺, calcd for C₂₅H₃₀N₇O₂S₂: 524.1902.

7e: Brown yellow solid, 0.49 g (Yield: 83%). m.p.: 140–142 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.69–8.67 (m, 2H, -PhH), 8.27 (d, J = 10.0 Hz, 1H, -PhH), 8.22 (s, 1H, -NCH=C-), 7.84–7.81 (m, 2H, -PhH), 7.29 (d, J = 7.5 Hz, 2H, -PhH), 6.93–6.87 (m, 3H, -PhH), 4.89 (s, 2H, -SCH₂-), 4.50 (brs, 2H, -NCH₂CH₂N-), 4.35 (t, J = 5.0 Hz, 2H, -NCH₂CH₂N-), 4.11 (brs, 2H, -NCH₂CH₂N-), 3.36–3.27 (m, 4H, -NCH₂CH₂N-), 2.69 (t, J = 7.5 Hz, 2H, -NCH₂CH₂N-), 2.36 (s, 6H, -N(CH₃)₂).¹³C NMR (125 MHz, CDCl₃) δ 195.71, 163.73, 163.21, 150.15, 145.04, 138.14, 132.28, 130.72, 129.59, 129.37, 129.15, 128.59, 126.37, 125.40, 123.86, 123.51, 122.97, 120.71, 116.34, 56.92, 51.36, 49.83, 48.77, 45.74, 38.41, 31.37. ESI-MS(+): m/z found 586.1945 [M]⁺, calcd for C₃₀H₃₂N₇O₂S₂: 586.2059.

Crystal structures determination for 2b, 5a, and 7b

Single crystals of compounds 2b, 5a, and 7b suitable for X-ray analysis were obtained by slow diffusion of hexane into solutions in dichloromethane. Diffraction intensity data were obtained using a Nonius Kappa CCD diffractometer with Mo Kα radiation (0.71073 Å) at room temperature (292 K). The structure was solved by direct methods (SHELXS-97) and refined by full matrix least squares on F² (SHELXL-97).^15,16 All non-H atoms were refined anisotropically. The hydrogen atoms were placed in the ideal positions and refined as riding atoms.

Cytotoxicity assay in vitro

Cytotoxic activities were evaluated by the MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] method in the MDA-MB-231, HepG-2, PC12, and A549 cell lines. Briefly, the cell suspensions (198 μL) were plated in 96-well microtiter plates at a density of 5 × 10⁴ cells mL⁻¹ and incubated for 12 h at 37 °C in a humidified incubator with 5% CO₂. The test compounds with different concentrations were added to each well and further incubated for 24 h under the same conditions. Then, 20 μL of the MTT solution was added to each well and incubated for 4 h. The old medium (200 μL) containing MTT was then gently replaced by dimethyl sulfoxide (DMSO) and pipetted to dissolve any formazan crystals formed. Absorbance was then determined on a Spectra Max Plus plate reader at 570 nm. Dose–response curves were generated, and the IC₅₀ values were determined. CDDP, a commonly approved agent for the treatment of many tumors, was used as the positive control.

Antibacterial assays

A total of four microbial strains were used in the study. Staphylococcus aureus (ATCC 27217), Escherichia coli (ATCC 15597), Bacillus subtilis (ATCC 63501), and Monilia albican (ATCC 10231), which were taken from the microbiology laboratory of Yunnan Minzu University, were used in the study. For experiments, bacteria were inoculated onto Colombia agar (Merck, Germany) plates supplemented with hemine (5 µg mL⁻¹), menadione (1 µg mL⁻¹), and 5% horse blood. Incubation was performed at 37 °C under anaerobic conditions for 5–7 d in an automated anaerobic chamber (Electrotek, UK) with 5% CO₂. After harvesting the bacteria, bacterial suspensions prepared in the sterilized test tubes containing Colombia broth supplemented with hemine (5 µg mL⁻¹), menadione (1 µg mL⁻¹), and the inoculum were adjusted according to the turbidity of the 0.5 McFarland standard. For the determination of the MIC, 100 µL of chemicals was added into the first wells of the U-bottom-polistiren microplates and serially diluted in the range of 0.125–256 µg mL⁻¹. Then, 100 µL of bacterial suspensions was added onto them, except the negative control well. Polistiren microplates were incubated for 48 h in an anaerobic cabin, and after the incubation time, wells which contained minimum concentration of the extracts where no visible growth can be seen were expressed as MIC, the minimum concentration which completely inhibited bacterial growth. All experiments were performed in duplicates.

Supplemental Material

sj-pdf-1-chl-10.1177_1747519820966971 – Supplemental material for 1,2,3-triazole-dithiocarbamate-naphthalimides: Synthesis, characterization, and biological evaluation

Supplemental material, sj-pdf-1-chl-10.1177_1747519820966971 for 1,2,3-triazole-dithiocarbamate-naphthalimides: Synthesis, characterization, and biological evaluation by Qiu Mei Chen, Zhen Li, Guang Xun Tian, Yi Chen and Xiang Hua Wu in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors acknowledge financial support from National Natural Science Foundation of China (No. 21002086) and the Natural Science Foundation of Yunnan Province (No. 2010ZC071).

ORCID iD

Xiang Hua Wu

Supplemental material

Supplemental material for this article is available online.

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