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Design, synthesis, and antiproliferative activity of novel 1,2,4-triazole-chalcone compounds

  • Jinjing Li , Pingping Fan , Yuxiao Liu , Yan Zhao , Chengyang Shi , Shujing Zhou EMAIL logo and Hongbin Qiu EMAIL logo
Published/Copyright: October 27, 2023
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 29 Issue 1

Abstract

A series of novel 1,2,4-triazole-chalcone compounds 10a–10s were designed by molecular hybridization strategy and synthesized. The molecular structures of the novel chalcones were characterized by 1H-NMR, 13C-NMR, and HRMS. The anti-proliferative activities of the novel chalcones against four cancer cell lines in vitro were examined by MTT, four tumor cell lines including human colon cancer cell SW620, human non-small cell lung cancer cell A549, human cervical cancer cell HeLa, and human breast cancer cell MCF-7. Compound 10o showed certain selectivity to SW620 cell line, and its IC50 value was 21.55 μM. 10q had good anti-proliferative activity against A549 cells with an IC50 value of 25.58 μM.

Keywords: chalcone; triazol; molecular hybridization; anti-proliferative activity

1 Introduction

The classical structure of chalcone is mainly composed of α, β-unsaturated ketone structure [1]. Many reactive sites in chalcone structure can be modified by chemistry groups [2], such as the aryl, halogen, hydroxyl, carboxyl, and phenyl groups. Through structural modification, it can interact with different molecular targets, thus showing a wide range of biological activities, such as antitumor [3], antibacterial [4], antidiabetic [5], antitubercular [6], antioxidant [7], antimalarial [8], and so on. A series of chalcones with anticancer activity have been reported in recent years (Figure 1). Recently, studies show that chalcones can exert anticancer effects through promotion of apoptosis of tumor cells, microtubule polymerization, anti-angiogenesis, and inhibition of multidrug resistance [9]. This shows that the development of novel chalcones anticancer medicines has limitless potential.

Figure 1 Chalcones’ structure with anti-proliferative activity.
Figure 1

Chalcones’ structure with anti-proliferative activity.

The compounds with the triazole heterocyclic structures have a considerable therapeutic utility through interacting with some receptors and enzymes [10]. Triazole is a five-membered aromatic heterocyclic compound containing two double bonds and three nitrogen atoms, which has two isomeric forms, namely 1,2,3-triazole (1) and 1,2,4-triazole (2), depending on the position of the nitrogen atom in the ring [11], as shown in Figure 2. In recent years, 1,2,4-triazole compounds have attracted the attention of many scientists in the pharmaceutical field due to their unique structural features and biological activities. In the anticancer field, they have unlimited potential as aromatase inhibitors [12], protein kinase inhibitors [13], carbonic anhydrase inhibitors [14], angiogenesis inhibitors [15], and tubulin polymerization inhibitors [16]. Currently, a variety of anticancer drugs containing the 1,2,4-triazole fraction are available, including Anastrozole, Vorozole, and Letrozole, as shown in Figure 2.

Figure 2 Drug molecular structure with triazole structure.
Figure 2

Drug molecular structure with triazole structure.

Molecular hybridization is the combination of two different pharmacophores to form new hybrid molecules, and this method has become one of the important strategies for the design and synthesis of novel and efficient drugs [17]. In this article, two structures with broad-spectrum anticancer activity, chalcones and 1,2,4-triazoles, were combined by molecular hybridization to obtain a series of novel chalcones with potent biological activity. As shown in Figure 3, 19 novel chalcones were obtained by linking [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole and chalcone in the same molecular structure through C–O bond and structural modification by introducing different groups to the B-ring. These novel chalcones were evaluated in vitro against four human tumor cell lines: SW620 (human colon cancer cells), A549 (human non-small cell lung cancer cells), HeLa (human cervical cancer cells), and MCF-7 (human breast cancer cells).

Figure 3 Design principle of the novel chalcones.
Figure 3

Design principle of the novel chalcones.

2 Results and discussion

2.1 Synthesis

The novel chalcones 10a–10s were synthesized according to known synthetic methods [18–22] and the synthetic route is shown in Scheme 1. Compound 3 was obtained by condensation reaction of thiocarbonyl dihydrazide (1) with glacial acetic acid (2). Compound (6) was obtained by nucleophilic substitution reaction of phenol (4) with chloroacetic acid (5). Then compound 7 was obtained by cyclization reaction of compound 3 with compound 6, and compound 8 was obtained by Friedel–Crafts acylation reaction of compound 7. Finally, the target compounds 10a–10s were obtained by condensation reaction of compound 8 with various aldehydes 9a–9s under acidic conditions.

Scheme 1 Synthetic routes to the novel chalcones 10a–10s.
Scheme 1

Synthetic routes to the novel chalcones 10a–10s.

2.2 Bioactivity studies

The anti-proliferative activity of this series of compounds was evaluated in SW620 (human colon cancer cells), A549 (human non-small cell lung cancer cells), HeLa (human cervical cancer cells), and MCF-7 (human breast cancer cells) using the MTT method with Cisplatin as the positive control drug. The results of the in vitro anti-proliferative activity of the novel chalcones against cancer cells are shown in Table 1.

Table 1

In vitro anti-proliferative activity of novel chalcones against SW620, A549, HeLa, and MCF-7 cancer cell lines

IC50 (μM) IC50 (μM)
Compd. SW620 A549 HeLa MCF-7 Compd. SW620 A549 HeLa MCF-7
10a ＞50 ＞50 ＞50 ＞50 10k ＞50 ＞50 ＞50 ＞50
10b ＞50 ＞50 ＞50 ＞50 10l ＞50 ＞50 36.25 ＞50
10c 28.26 32.05 ＞50 ＞50 10m ＞50 ＞50 ＞50 ＞50
10d 30.63 ＞50 ＞50 ＞50 10n ＞50 ＞50 ＞50 ＞50
10e ＞50 48.24 ＞50 ＞50 10o 21.55 35.60 ＞50 ＞50
10f ＞50 ＞50 34.72 29.45 10p ＞50 ＞50 ＞50 ＞50
10g 23.28 28.77 38.03 ＞50 10q 35.22 25.58 ＞50 ＞50
10h ＞50 ＞50 ＞50 ＞50 10r ＞50 ＞50 ＞50 31.66
10i ＞50 ＞50 ＞50 ＞50 10s 33.35 ＞50 32.83 ＞50
10j ＞50 ＞50 ＞50 ＞50 Cisplatin 7.09 5.60 6.73 15.38

The results showed that the anti-proliferative activity of the novel chalcones was related to the B-ring structure. For SW620 cells, compounds with benzene ring and halogen atoms in the B ring have better anti-proliferative activity. Among them, the anti-proliferative activity of compound 10g (IC50 = 23.28 μM) containing two halogen atoms is better than that of compound 10c (IC50 = 28.26 μM) or compound 10d (IC50 = 30.63 μM) which contains one halogen atom. The anti-proliferative activity of compound 10c containing F atom is better than that of compound 10d containing Br atom. In addition, the anti-proliferative activity of compound 10o (IC50 = 21.55 μM) containing dimethylamino group on SW620 cells was better than that of compounds containing electron-withdrawing group-halogen atoms. These seem to indicate that dimethylamino groups have special significance for the inhibitory activity of this novel chalcones on the proliferation of cancer cells in vitro. In addition, the S-containing heterocycle compound 10s and compound 10q also showed anti-proliferative activity against SW620 with IC50 value of 33.35 and 35.22 μM, respectively (Figure 4).

Figure 4 Anti-proliferative activity of novel chalcone derivatives against various cell lines.
Figure 4

Anti-proliferative activity of novel chalcone derivatives against various cell lines.

For A549 cells, compound 10o (IC50 = 35.60 μM) containing dimethylamino group, compound 10c (IC50 = 32.05 μM), compound 10e (IC50 = 48.24 μM), and compound 10g (IC50 = 28.77 μM) containing halogen atoms have good anti-proliferative activity against these cells. Compound 10q containing S heterocycle-thiophene ring has the best anti-proliferative activity with IC50 value of 25.58 μM, which is similar to the structure found in previous studies. However, after changing the position of the S atom on the thiophene ring, the anti-proliferative activity of the compound changed greatly. For example, when the S atom site changed from compound 10q at the ortho position to compound 10r at the meta position (IC50 > 50 μM), compound 10r was not sensitive to A549.

The results of anti-proliferative activity showed that this series of novel chalcone compounds were not sensitive to HeLa cells and MCF-7 cells.

3 Conclusion

A series of novel chalcone compounds were designed by molecular hybridization strategy. It was found that the compounds with B ring structure containing benzene ring and halogen atom showed good anti-proliferative activity for cancer cells in vitro. Among them, compound 10o has good anti-proliferative activity against SW620 cells in vitro, which can be used for further development as an anti-tumor lead. Compound 10q has good anti-proliferative activity against A549 cells, but it is not sensitive to A549 cells when the position of S atom on compound 10q is changed. So, we can further explore the effect of the position of the S atom on the novel chalcones for the anti-proliferative activity against A549 cells.

4 Experimental

4.1 Experimental details

The experimental materials were purchased from Shanghai Xian Ding Company and were used directly without any purification. The melting points of the new chalcones were determined using an X-6 microscopic melting point tester. The 1H-NMR spectra and 13C-NMR spectra were obtained on the Bruker Avance spectrometer using CDCl3 as solvent. The mass spectral information of the compounds was obtained using ESI+ mode.

4.2 Synthesis of 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol (3)

Thiocarbazide (94.21 mmol) was added to acetic acid (612.36 mmol) and stirred for 4 h at reflux temperature. The reaction process was monitored by TLC. After the reaction, the reaction system was cooled to room temperature and filtered to obtain the crude product, and then the pure product was obtained by recrystallization from distilled water. Yield: 74.78%, purple needle-like solid, and 1H-NMR (500 MHz, DMSO-d6) δ13.40 (s, 1H), 5.51 (s, 2H), 2.24 (s, 3H).

4.3 Synthesis of 2-phenoxyacetic acid (6)

To a mixed solution of 20% sodium hydroxide (43 mL) and phenol (106.26 mmol) was added chloroacetic acid (127.51 mmol) and stirred at reflux for 4 h. The reaction process was monitored by TLC. After the reaction, the pH was adjusted to 1–2 with concentrated hydrochloric acid, then filtration and drying. Yield: 89.75%, white flake solid, and 1H-NMR (400 MHz, CDCl3) δ 7.32 (t, J = 8.0 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 4.69 (s, 2H).

4.4 Synthesis of 3-methyl-6-(phenoxymethyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadia-zole (7)

2-Phenoxyacetic acid (65.73 mmol) was added to the phosphorus trichloride (50 mL) at room temperature, then 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol (65.73 mmol) was added under stirring. Sequentially, reflux reaction for 6 h. The reaction process was monitored by TLC. After the reaction, the reaction solution was quenched with ice water, pH was adjusted to 7–8 with 30% NaOH aqueous solution, then filtration and drying. Yield: 85.50%, yellowish solid, 1H-NMR (400 MHz, CDCl3) δ 7.34 (t, J = 8.0 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.01–6.93 (m, 2H), 5.32 (s, 2H), 2.73 (s, 3H).

4.5 1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)et-han-1-one (8)

Aluminum trichloride (142.11 mmol) and acetic anhydride (44.66 mmol) were added to the mixed solution of dichloromethane (150 mL) and compound 7 (40.60 mmol) in order, the system temperature was maintained at 0°C during feeding and stirred for 20 min. Then, the reaction was raised to room temperature for 4 h. The reaction process was monitored by TLC. After the reaction, the reaction solution was quenched with ice water, then filtration and drying. Product was obtained by column chromatography purification. Yield: 93.02%, yellowish solid, 1H-NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.5 Hz, 2H), 7.05 (d, J = 7.7 Hz, 2H), 5.32 (d, J = 55.5 Hz, 2H), 2.77 (s, 3H), 2.57 (s, 3H).

4.6 General procedure for synthesis of (E)-chalcones (10a–10s)

Concentrated hydrochloric acid (2 mL) was added to the mixed solution of compound 8 (6.94 mmol), aldehyde (20.81 mmol), and anhydrous ethanol (25 mL), and the reaction was stirred at reflux for 18–20 h. The reaction process was monitored by TLC. After the reaction, the reaction solution was quenched with ice water, then filtration and drying. Compounds 10a–10s were obtained by column chromatography purification.

(E)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)-3-phenylprop-2-en-1-one (10a): yield 76.98%, pale yellow powder, m.p.: 258–259°C. 1H-NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 15.6 Hz, 1H), 7.48 (d, J = 15.6 Hz, 1H), 7.31 (dd, J = 16.2, 8.2 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.16–7.02 (m, 3H), 6.96 (d, J = 7.9 Hz, 1H), 5.40 (s, 2H), 3.85 (s, 3H), 2.72 (s, 3H). HRMS (ESI) m/z [M + H]+ calcd for C20H16N5O2S: 377.10722, found: 377.10574.

(E)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)-3-(naphthalen-2-yl)prop-2-en-1-one (10b): yield 66.59%, pale yellow powder, m.p.: 234.5–235.5°C. 1H-NMR (400 MHz, CDCl3) δ 8.12 (d, J = 6.9 Hz, 2H), 8.07–7.94 (m, 2H), 7.83 (d, J = 24.9 Hz, 3H), 7.67–7.47 (m, 3H), 7.26 (s, 1H), 7.13 (s, 2H), 5.42 (s, 2H), 2.75 (s, 3H). HRMS (ESI) m/z [M + H]+ calcd for C24H18N4O2S: 427.12287, found: 427.12158.

(E)-3-(2-fluorophenyl)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)prop-2-en-1-one (10c): yield 80.41%, pale yellow powder, m.p.: 203–204°C. 1H-NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.9 Hz, 2H), 7.89 (d, J = 15.9 Hz, 1H), 7.67–7.57 (m, 2H), 7.43–7.31 (m, 1H), 7.19 (dd, J = 11.0, 4.2 Hz, 1H), 7.14 (dd, J = 5.9, 5.0 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 5.41 (s, 2H), 2.74 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.54, 165.47, 163.03, 160.50, 137.41, 132.86, 131.85, 131.76, 131.06, 129.91, 129.89, 124.54, 124.50, 124.38, 124.30, 123.09, 122.98, 116.41, 116.19, 114.74, 65.13, 10.29. HRMS (ESI) m/z [M + H]+ calcd for C20H15FN4O2S: 395.09780, found: 395.09628.

(E)-3-(2-bromophenyl)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)prop-2-en-1-one (10d): yield 74.40%, pale yellow powder, m.p.: 187–188°C. 1H-NMR (400 MHz, CDCl3) δ 8.12 (s, 3H), 8.10–8.01 (m, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.37 (dd, J = 22.0, 11.7 Hz, 1H), 7.25 (dd, J = 15.8, 8.1 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 5.42 (s, 4H), 2.72 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.43, 165.44, 160.54, 153.08, 144.62, 142.92, 135.06, 133.55, 132.65, 131.30, 131.11, 127.88, 127.72, 125.79, 124.71, 114.76, 65.13, 10.28. HRMS (ESI) m/z [M + H]+ calcd for C20H15BrN4O2S: 455.01773, found: 455.01614.

(E)-3-(4-chlorophenyl)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)prop-2-en-1-one (10e): yield 63.86%, pale yellow powder, m.p.: 208–209°C. 1H-NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 15.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 5.29 (s, 2H), 2.73 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.23, 165.41, 160.51, 153.07, 144.65, 143.12, 136.48, 133.41, 132.89, 130.99, 129.53, 129.26, 122.09, 114.77, 65.14, 10.29. HRMS (ESI) m/z [M + H]+ calcd for C20H15ClN4O2S: 411.06825, found: 411.06720.

(E)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (10f): yield 62.28%, pale yellow powder, m.p.: 201–202°C. 1H-NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 15.7 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 15.7 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 5.50–5.28 (m, 2H), 2.73 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.03, 165.36, 160.66, 153.06, 144.66, 142.54, 138.31, 132.64, 131.07, 128.46, 125.93, 125.89, 123.89, 114.83, 65.15, 10.28. HRMS (ESI) m/z [M + H]+ calcd for C21H15F3N4O2S: 445.09461, found: 445.09360.

(E)-3-(5-bromo-2-chlorophenyl)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)prop-2-en-1-one(10g): yield 66.23%, pale yellow powder, m.p. 210–211°C. 1H-NMR (600 MHz, CDCl3) δ 8.13–7.98 (m, 3H), 7.84 (s, 1H), 7.44 (t, J = 10.9 Hz, 2H), 7.30 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 5.41 (s, 2H), 2.73 (s, 3H). 13C-NMR (126 MHz, CDCl3) δ 187.91, 165.45, 160.65, 138.95, 135.10, 134.31, 133.88, 132.39, 131.69, 131.22, 130.40, 125.21, 120.77, 114.78, 65.07, 10.40. HRMS (ESI) m/z [M + H]+ calcd for C20H14BrClN4O2S: 488.97876, found: 488.97943.

(E)-3-(2-methoxyphenyl)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)prop-2-en-1-one(10h): yield 80.51%, pale yellow powder, m.p.: 211–212°C. 1H-NMR (400 MHz, CDCl3) δ 8.06 (s, 3H), 7.61 (s, 2H), 7.37 (s, 1H), 7.03 (d, J = 42.5 Hz, 4H), 5.39 (s, 2H), 3.91 (s, 3H), 2.72 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 189.14, 165.58, 160.24, 158.83, 153.10, 144.60, 140.22, 133.32, 131.74, 130.94, 129.22, 123.96, 122.46, 120.77, 114.63, 111.33, 65.11, 55.57, 10.27. HRMS (ESI) m/z [M + H]+ calcd for C21H18N4O3S: 407.11779, found: 407.11630.

(E)-3-(3-methoxyphenyl)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)prop-2-en-1-one(10i): yield 82.29%, pale yellow powder, m.p.: 153–154°C. 1H-NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 15.6 Hz, 1H), 7.48 (d, J = 15.6 Hz, 1H), 7.31 (dd, J = 16.2, 8.2 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.16–7.05 (m, 3H), 6.96 (d, J = 7.9 Hz, 1H), 5.40 (s, 2H), 3.85 (s, 3H), 2.72 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.49, 165.50, 160.43, 160.02, 144.52, 136.25, 132.94, 130.96, 129.94, 121.95, 121.02, 116.23, 114.71, 113.59, 65.12, 55.36, 10.28. HRMS (ESI) m/z [M + H]+ calcd for C21H18N4O3S: 407.11779, found: 407.11664.

(E)-3-(4-methoxyphenyl)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)prop-2-en-1-one(10j): yield 90.80%, pale yellow powder, m.p.: 212–214°C.1H-NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 15.5 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 15.5 Hz, 1H), 7.08 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 7.8 Hz, 2H), 5.39 (s, 2H), 3.84 (s, 3H), 2.72 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.55, 165.55, 161.76, 160.25, 153.09, 144.62, 144.50, 133.32, 130.84, 130.17, 127.63, 119.32, 114.66, 114.47, 65.13, 55.41, 10.28. HRMS (ESI) m/z [M + H]+ calcd for C21H18N4O3S: 407.11779, found: 407.11658.

(E)-3-(2-ethoxyphenyl)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)prop-2-en-1-one(10k): yield 74.74%, pale yellow powder, m.p.: 202–203°C. 1H-NMR (400 MHz, CDCl3) δ 8.13–7.90 (m, 3H), 7.66 (d, J = 15.8 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 8.5 Hz, 2H), 7.01–6.85 (m, 2H), 5.38 (s, 2H), 4.12 (q, J = 6.8 Hz, 2H), 2.71 (s, 3H), 1.49 (t, J = 6.9 Hz, 3H). 13C-NMR (101 MHz, CDCl3) δ 189.13, 165.59, 160.24, 158.33, 144.63, 140.58, 133.38, 131.68, 130.89, 129.73, 123.96, 122.45, 120.66, 114.63, 112.22, 100.00, 65.12, 64.05, 14.86, 10.28. HRMS (ESI) m/z [M + H]+ calcd for C22H20N4O3S: 421.13344, found: 421.13168.

(E)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)-3-(2,3,4-trimethoxyphenyl)prop-2-en-1-one(10l): yield 71.69%, pale yellow powder, m.p.: 181–182°C. 1H-NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 15.7 Hz, 1H), 7.51 (d, J = 15.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.7 Hz, 1H), 5.38 (s, 2H), 3.99–3.82 (m, 9H), 2.70 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.99, 165.65, 160.27, 155.92, 153.86, 153.15, 144.66, 142.62, 140.07, 133.42, 130.91, 123.95, 122.03, 120.99, 114.68, 107.78, 65.17, 61.41, 60.93, 56.16, 10.32. HRMS (ESI) m/z [M + H]+ calcd for C23H22N4O5S: 467.13892, found: 467.13748.

(E)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)-3-(o-tolyl)prop-2-en-1-one(10m): yield 70.52%, pale yellow powder, m.p.: 208–209°C. 1H-NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 14.9, 12.2 Hz, 3H), 7.70 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 15.5 Hz, 1H), 7.33 (t, J = 6.9 Hz, 1H), 7.26 (t, J = 8.8 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 5.43 (s, 2H), 2.76 (s, 3H), 2.49 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.49, 165.50, 160.41, 142.33, 138.32, 133.94, 133.07, 130.98, 130.94, 130.26, 126.41, 126.34, 122.74, 114.72, 65.13, 19.81, 10.29. HRMS (ESI) m/z [M + H]+ calcd for C21H18N4O2S: 391.12287, found: 391.12143.

(E)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)-3-(p-tolyl)prop-2-en-1-one(10n): yield 75.32%, pale yellow powder, m.p.: 224–225°C. 1H-NMR (400 MHz, CDCl3) δ 8.06 (s, 2H), 7.78 (d, J = 13.8 Hz, 1H), 7.53 (s, 3H), 7.16 (d, J = 50.9 Hz, 4H), 5.40 (s, 2H), 2.73 (s, 3H), 2.39 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.49, 165.50, 160.43, 160.02, 144.52, 136.25, 132.94, 130.96, 129.94, 121.95, 121.02, 116.23, 114.71, 113.59, 65.12, 55.36, 10.28. HRMS (ESI) m/z [M + H]+ calcd for C21H18N4O2S: 391.12287, found: 391.12161.

(E)-3-(4-(dimethylamino)phenyl)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)prop-2-en-1-one(10o): yield 83.51%, pale yellow powder, m.p.: 198–199°C. 1H-NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 15.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.36–7.19 (m, 1H), 7.07 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 5.38 (s, 2H), 3.00 (d, J = 28.9 Hz, 5H), 2.73 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.49, 165.50, 160.43, 160.02, 144.52, 136.25, 132.94, 130.96, 129.94, 121.95, 121.02, 116.23, 114.71, 113.59, 65.12, 55.36, 10.28. HRMS (ESI) m/z [M + H]+ calcd for C22H21N5O2S: 420.14942, found: 420.14804.

(E)-3-(4-isopropylphenyl)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)prop-2-en-1-one(10p): yield 87.15%, pale yellow powder, m.p.: 167–168°C. 1H-NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.5 Hz, 2H), 7.79 (d, J = 15.6 Hz, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 15.6 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 7.4 Hz, 2H), 5.41 (s, 2H), 3.02–2.84 (m, 1H), 2.74 (s, 3H), 1.27 (d, J = 6.9 Hz, 6H). 13C-NMR (101 MHz, CDCl3) δ 188.61, 165.66, 160.35, 152.01, 144.72, 133.10, 132.51, 130.90, 128.57, 127.09, 120.73, 114.70, 65.19, 34.10, 23.72, 10.35. HRMS (ESI) m/z [M + H]+ calcd for C23H22N4O2S: 419.15417, found: 419.15262.

(E)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)-3-(thiophen-2-yl)prop-2-en-1-one(10q): yield 73.13%, pale yellow powder, m.p.: 196–197°C. 1H-NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.3 Hz, 2H), 8.00–7.89 (m, 1H), 7.42 (d, J = 4.4 Hz, 1H), 7.31 (dd, J = 24.8, 9.5 Hz, 2H), 7.10 (d, J = 7.3 Hz, 3H), 5.40 (s, 2H), 2.74 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 187.89, 165.49, 160.40, 153.08, 144.63, 140.38, 137.03, 132.97, 131.96, 130.87, 128.75, 128.36, 120.37, 114.71, 65.13, 10.29. HRMS (ESI) m/z [M + H]+ calcd for C18H14N4O2S2:383.06364, found: 383.06210.

(E)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)-3-(thiophen-3-yl)prop-2-en-1-one(10r): yield 93.48%, pale yellow powder, m.p.: 230–231°C. 1H-NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 25.9, 7.6 Hz, 2H), 7.80 (d, J = 15.5 Hz, 1H), 7.61 (s, 1H), 7.47–7.32 (m, 2H), 7.28 (d, J = 17.5 Hz, 1H), 7.10 (d, J = 7.6 Hz, 2H), 5.40 (s, 2H), 2.74 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 188.76, 165.49, 160.35, 144.64, 138.09, 133.13, 130.90, 129.91, 129.00, 127.05, 125.23, 123.54, 121.41, 114.70, 77.31, 76.99, 76.67, 65.14, 10.29. HRMS (ESI) m/z [M + H]+ calcd for C18H14N4O2S2: 383.06364, found: 383.06204.

(E)-1-(4-((3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)methoxy)phenyl)-3-(3-methylthiophen-2-yl)prop-2-en-1-one(10’s): yield 77.08%, pale yellow powder, m.p.: 208–209°C. 1H-NMR (400 MHz, CDCl3) δ 8.15–7.93 (m, 3H), 7.28 (dd, J = 18.7, 10.4 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 4.9 Hz, 1H), 5.40 (s, 2H), 2.73 (s, 3H), 2.39 (s, 3H). 13C-NMR (101 MHz, CDCl3) δ 187.83, 165.55, 160.34, 153.11, 144.63, 142.75, 135.43, 134.51, 133.11, 131.47, 130.79, 127.27, 119.34, 114.68, 65.13, 14.26, 10.28. HRMS (ESI) m/z [M + H]+ calcd for C19H16N4O2S2: 397.07929, found: 397.07809.

4.7 Cytotoxic activity

The in vitro anti-proliferative activity of the novel chalcones 10a–10s was performed by MTT assay using cisplatin as a positive control drug. The tumor cells selected were log phase human colon cancer cells SW620, human breast cancer cells MCF-7, human non-small cell lung cancer cells A549, and human cervical cancer cells HeLa.

Cancer cells in logarithmic growth phase were inoculated in 96-well plates at 100 μL per well (approximately 4,000 cells), and the cell suspension was continuously mixed during inoculation to maintain a consistent cell density. The 96-well plates were edged without cell suspension, and PBS buffer was used instead. The plates were then incubated at 37°C in a 5% CO2 thermostat, and after 24 h of incubation, the cells were ready for dosing when they recovered their morphology. The novel chalcone stock solution was diluted with culture medium into different concentrations with gradient concentrations of 40, 20, 10, 5, and 2.5 μM. The culture medium in the 96-well plate was removed by aspiration with a draining gun, and six sub-wells were set up according to each concentration, and 200 μL of culture medium with different concentrations of derivatives was added to each well and incubated in a 37°C, 5% CO2 thermostat for 48 h. The culture medium was discarded, 20 μL MTT solution (5 mg mL−1) was added to each well, incubated for 4 h at 37°C, the supernatant was discarded, 150 μL DMSO was added to each well to dissolve the formazan pellet, and shaken at low speed for 10 min. The absorbance value (OD) was measured at 490 nm with an enzyme marker, and the cell growth inhibition rate and IC50 value were calculated from the OD value. The experiments were repeated three times and the mean values were taken.

  1. Funding information: This work was supported by Natural Science Foundation of Heilongjiang Province of China (LH2022H094).

  2. Author contributions: Among the authors in the list, Professor Hongbin Qiu provided technical guidance for the biological activity experiments of the derivatives in the article, and Professor Shujing Zhou contributed to the design of the synthetic route of the derivatives in the article and the funding of the article fund project. Dr. Jinjing Li contributed to the overall research idea and the revision of the article. Pingping Fan contributed to the synthesis, the biological activity of the derivatives and the analysis of the results, and also wrote the manuscript. Yuxiao Liu contributed to the design, synthesis of the derivatives, purification of the derivatives and the analysis of the results. Dr. Yan Zhao and Chengyang Shi contributed to the biological activity experiments of the derivatives.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2023-07-08
Revised: 2023-08-29
Accepted: 2023-09-18
Published Online: 2023-10-27

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/hc-2022-0165
Keywords for this article
chalcone; triazol; molecular hybridization; anti-proliferative activity
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Synthesis, characterization, and antibacterial activity of a new poly azo compound containing N-arylsuccinimid and dibenzobarrelene moieties
  3. Design, synthesis, and antiviral activities evaluation of novel quinazoline derivatives containing sulfonamide moiety
  4. Design, synthesis, and anticancer activity of novel 4,6-dimorpholinyl-1,3,5-triazine compounds
  5. Design, synthesis, biological evaluation, and bio-computational modeling of imidazo, thieno, pyrimidopyrimidine, pyrimidodiazepene, and motifs as antimicrobial agents
  6. Synthesis of a novel phosphate-containing ligand rhodium catalyst and exploration of its optimal reaction conditions and mechanism for the polymerization of phenylacetylene
  7. Design, synthesis, and antiproliferative activity of novel 1,2,4-triazole-chalcone compounds
  8. Synthesis of metal–organic nanofiber/rGO nanocomposite as the sensing element for electrochemical determination of hypoxanthine
  9. Design and synthesis of various 1,3,4-oxadiazoles as AChE and LOX enzyme inhibitors
  10. Bis(2-cyanoacetohydrazide) as precursors for synthesis of novel azoles/azines and their biological evaluation
  11. Synthesis, characterization, and biological target prediction of novel 1,3-dithiolo[4,5-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives
  12. Sustainable conversion of carbon dioxide into novel 5-aryldiazenyl-1,2,4-triazol-3-ones using Fe3O4@SP-vanillin-TGA nanocomposite
  13. Erratum
  14. Erratum to “Design, synthesis and study of antibacterial and antitubercular activity of quinoline hydrazone hybrids”
  15. SI: Undergraduate Research in the Synthesis of Biologically Active Small Molecules and Their Applications
  16. Preparation of novel acyl pyrazoles and triazoles by means of oxidative functionalization reactions
  17. Synthesis and conformational analysis of N-BOC-protected-3,5-bis(arylidene)-4-piperidone EF-24 analogs as anti-cancer agents
  18. SI: Development of Heterocycles for Biomedical and Bioanalytical Applications
  19. Influence of octreotide on apoptosis and metabolome expression in lipopolysaccharide-induced A549 cells
  20. Crude extract of J1 fermentation promotes apoptosis of cervical cancer cells
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