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Synthesis of newer substituted chalcone linked 1,2,3-triazole analogs and evaluation of their cytotoxic activities

  • Matta Raghavender , Bhookya Shankar , Nalla Umapathi and Pochampally Jalapathi EMAIL logo
Published/Copyright: October 6, 2022
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 28 Issue 1

Abstract

An innovative heterocyclic biologically active chalcone 1,2,3-triazole analogs (6a–j) were prepared to extract excellent yields by coupling the substituted aryl azides (5a–5j) and 5-ethynyl-1,2,3-trimethoxybenzene, by using the method of Huisgen azide–alkyne cycloaddition. The typically synthesized analogs were elucidated by IR, 1H-nuclear magnetic resonance (NMR), 13C-NMR, and Electron spray ionization (ESI)-mass spectroscopy and tested for their cytotoxicity effectiveness in MTT assays against the A549 lung cancer cells. The cytotoxic studies suggested that a few analogs showed moderate to good activities. The compounds 6i and 6c showed low cytotoxicity against the A549 cell line among 12 analogs, the values of IC50 were displayed in the range of 65.05 ± 1.12 and 71.56 ± 1.29 µM, respectively. The compound 6j showed slightly less cytotoxicity but showed good selectivity against A549 cell lines.

Keywords: chalcone; 1,2,3-triazole analogs; cytotoxicity

1 Introduction

The death rate due to cancer has been rising since its initial diagnosis and becoming a burden to human lives globally. It remained challenging to develop continuous efforts toward the treatment and the prevention of cancer in extracting successful results to treat several types of cancer [1]. Hence, it is a prime area of research for the identification of innovative anticancer agents with a broader spectrum of cytotoxicity toward tumor cells [2]. It has been acknowledged that the organic compounds such as chalcone and other classes of flavones, isoflavonoids framework as a core unit to prove the pharmaceutical and biological actions [3,4]. Their structural motifs play an important role for the combinatorial assembly of heterocyclic skeletons and their biologically active functions [5,6,7]. Majority of edible portions in plants are rich in chalcones and are considered to be the precursors of isoflavonoids and flavonoids [8]. These compounds constitute an important group of natural and synthetic products by having a vast range of pharmacological functions as anti-tumor, antibacterial, antioxidant, anti-inflammatory, and antifungal agents [9,10]. Biological function of the substituted heterocyclic compounds proved as the substituent groups of chalcone, which showed cytotoxic activity toward MCF-7 cell line with IC50 of 6.88 μg/mL [11]. Similarly, the combretastatin-based chalcones showed the inhibitory function of microtubule polymerization, with excellent cytotoxic activity toward K562 cells with IC50 of 1.1 μM as shown in Figure 1 [12].

Figure 1 Structures of chalcone (a, b) and 1,2,3-triazole (c, d) derivatives as cancer agents.
Figure 1

Structures of chalcone (a, b) and 1,2,3-triazole (c, d) derivatives as cancer agents.

The discovery and the development of 1,2,3-triazole resulted in a wide range of products with biologically active functions, for instance anti-HIV, antibacterial, antifungal, anti-inflammatory, antiallergic, and antitubercular agents [13,14,15,16,17,18]. The recent developments in pharmacological research have become a promising success in designing anticancer agents. The hybrid of 1,2,3-triazol-naphthalimide has shown IC50 value of 0.348 μM against MCF-7 and 0.258 μM against K562 lines [19]. Whereas Stefely et al. have demonstrated the anti-tumor activity of heterocyclic N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl) aryl amide. Similarly, compound of 1,2,3-triazole has proved itself as active against MCF-7 cancer cells (IC50 of 46 nM) [20] Figure 1. All these research outcomes have led to finding more potent derivatives, which in turn to the molecular hybridization specially with chalcone-based 1,2,3-trizole along with other azoles. These studies helped in developing the new hybrid 1,2,3-trizole to explore the biological activity of such products for modifying anticancer agents [21]. Further, it was aimed to improve the cytotoxicity by incorporation of chalcone and triazole moieties within the same molecular system. The scaffold designed includes two fragments of the central backbone molecule, 1,2,3-trizole attachment of chalcone unit to enrich the desired pharmacophoric behavior with drug-like properties. Based on the above findings, chalcone-based 1,2,3-triazole hybrid has not only been synthesized but also evaluated for the new class of cytotoxic activities.

2 Results and discussions

2.1 Chemistry

The general approach to the different substituted acetophenones (3a–3j) was to individually synthesize by using the Suzuki coupling reaction of the 1-(5-bromo-2-hydroxyphenyl) ethanone (1) and various substituted phenylboronic acids (2a–2j) in the presence of palladium catalyst and Na2CO3. The resulted compounds (3a–3j) were obtained from moderate to good yield, and their analytical data coordinated with all the structures [22] as shown in Scheme 1. The various substituted acetophenones were (3a–3j) separately allowed to react with 4-aminobenzaldehyde in the presence of base by Claisen condensation to produce corresponding substituted chalcones (4a–4j) with moderate to good yield [23]. A variety of the substituted amines were converted into the corresponding azides during the way of the present on-going investigations, a process has been required for the synthesis of aryl azides from respective aryl amines. This focused the current investigation on neutral circumstances for the synthesize of aryl azides.

Scheme 1 Synthesis and structures of compounds 6.
Scheme 1

Synthesis and structures of compounds 6.

It should be noted that several substituted chalcones containing arylamine function group (4a–4j) were converted into corresponding aryl azide containing chalcones (5a–5j) under the mild reaction conditions, in the presence of tert-butyl nitrite, moist sodium azide (NaN3), and tert-butyl alcohol in good yield. Finally, the target chalcone-based 1,2,3-triazole analogs (6a–6j) were prepared by copper(i)-catalyzed cycloaddition reaction of a chalcone containing aryl azides (5a–5j) with 5-ethynyl-1,2,3-trimethoxybenzene producing 5-membered heteroatom 1,2,3-triazole ring at the room temperature for 4 h [24], a good yield of the resulted compounds (6a–6j) were obtained.

In the proton nuclear magnetic resonance (NMR) spectrum of (E)-1-(4-hydroxy-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6a), the two singlet signals at δ 12.64 and 8.09 ppm were assigned to the OH and proton of triazole moiety, respectively. The two doublets at δ 8.18 and 7.33 ppm with coupling constant 12.38 Hz evidenced that they belong to trans geometry olefin protons. The reaming 13 aromatic protons of 6a compound resonated at δ 7.35–7.07 ppm showed as a multiplet. The signals at δ 3.93 ppm can be assigned to 3 methoxy protons. In the 13C NMR spectrum of compound 6a, the chemical signal δ 193.32 ppm showed C═O functional group and δ 163.73 ppm showed hydroxyl group attached carbon. Further, confirmation of compound 6a by mass spectral characterization exhibited a molecular ion peak at 534.20 m/z, which is designated as the M + 1 ion peak.

In the proton NMR spectrum of (E)-1-(4-((1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-ethoxyphenyl)-3-(4-ethoxyphenyl)prop-2-en-1-one (6i), the signal at δ 12.74 ppm value can be assigned to OH proton of the phenolic moiety. Two doublets signal protons at δ 8.22 and 7.30 ppm confirms the chalcone. The multiplet at δ 8.12–6.91 ppm in the proton NMR spectrum of compound 6i accounts for 4 aromatic protons of phenyl and triazole moiety. The singlet at δ 3.98 ppm was assigned to 5 methoxy protons. In the 13C NMR spectrum of compound 6i, the chemical signal δ 193.34 ppm showed C═O functional group and δ 162.71 ppm showed hydroxyl group attached carbon. The chemical signals at δ 60.87, 56.25, and 40.00 ppm were attributed to the carbon of methoxy moiety. Further, confirmation of the compound 6i by mass spectral characterization exhibited a molecular ion peak at 577.24 m/z, which is designated as the M + 1 ion peak. The entire target titled compounds were characterized by their IR, 1H NMR, 13C NMR, and mass spectral studies.

2.2 In-vitro cytotoxicity studies

In the current study, the result of cytotoxicity against the Human Lung adenocarcinoma cell line confirmed the therapeutic value of the titled compounds shown in Table 1. All the targeted compounds were devoid of considerable cytotoxicity at the highest test concentration of 120 μM. After considering several biological and pharmacological importance of a newly synthesized aryl-substituted 1,2,3-triazole, it was assumed useful to evaluate the compounds (6a–6j) for reasonable activities. Thus, these compounds were evaluated for anti-cancer studies using MTT cell viable assays [25,26,27]. The particulars of these studies with the observation are recorded below.

Table 1

Cytotoxicity assay of 6a–j series derivatives

Compound % Cell viability of 6a–j series against A549 cells
10 μM 20 μM 40 μM 60 μM 80 μM 100 μM 120 μM
6a 93.57 87.45 83.24 76.69 71.24 67.52 63.41
6b 91.22 83.57 76.36 70.94 63.19 57.63 48.15
6c 87.36 74.29 57.63 45.82 32.95 23.47 15.97
6d 87.95 75.28 63.47 54.17 41.3 33.41 27.15
6e 91.23 81.27 75.32 71.24 65.23 61.78 55.31
6f 94.26 86.32 82.31 79.84 74.28 70.44 68.21
6g 97.28 93.14 89.97 86.37 81.24 79.36 76.59
6h 97.86 94.58 92.38 89.49 87.12 83.61 79.81
6i 87.69 73.69 61.5 52.48 39.25 24.38 13.59
6j 91.96 86.32 71.84 60.39 51.47 42.36 33.12
Cisplatin 71.58 61.29 55.47 31.56 22.78 15.39 8.17

The newly synthesized chalcone-based 1,2,3-triazole analogs were selected to carry out the in vitro cytotoxicity study against A-549 cell lines. The results indicated that among all the tested compounds (6a–6j), the compounds 6i and 6c showed low cytotoxicity i.e., better activity. The compounds 6d and 6j showed good activity, it may be attributed to that electron-withdrawing nature and hydrogen bonding interactions of fluoro and CF3 groups played a key role and higher polarizability of these molecules led to improve activity. These results revealed that most of the screened compounds exhibited outstanding anti-proliferative activity. The compounds 6c and 6i needed to be further explored for the mechanism of action showing low cytotoxicity against the A549 cell line, which revealed that IC50 values in the array of 65.05 ± 1.12 to 71.56 ± 1.29 µM as shown in Table 2. These values were found to be more effective and worthwhile against A549 cancer cell lines and almost similar to the standard cisplatin (IC50  =  65.22 µM). In this study, the compounds 6d and 6j displayed good cytotoxicity against A549 cells and were almost equipotent as that of 6i and 6c which were recognized as the most potent analogues. Finally, the residual compounds showed moderate to good activities compared to cisplatin. On the other hand, the methyl group containing compound showed none of the activity, it may be credited with very low lipophilicity or none of the binding potential of the molecule with the receptor. Subsequently, the combination of CH3 and OMe group, which have an electron-donating nature, could not play an important role to increase the activity. However, the compound 6h showed six-folds cytotoxicity than cisplatin.

Table 2

IC50 values of 6a–j series molecules against A549 cells

Compound IC50 in μM
6a 177.05 ± 0.51
6b 128.78 ± 0.69
6c 68.55 ± 1.47
6d 81.29 ± 1.22
6e 150.64 ± 0.96
6f 208.60 ± 1.07
6g 265.83 ± 1.31
6h 325.40 ± 1.17
6i 71.56 ± 1.47
6j 92.26 ± 1.82
Cisplatin 65.22 ± 1.19

3 Material and methods

The melting point of newly synthesized compounds was determined on a Casiae-Siamia (VMPAM) melting point apparatus and is uncorrected. Infrared spectra were recorded on a PerkinElmer Fourier transform Infrared spectroscopy 240-C spectrophotometer using KBr optics. 1H NMR spectra were recorded on Bruker AV 400 MHz, in DMSO-d6 using tetramethylsilane as an internal standard. Chemical shifts are given in (δ) ppm and coupling constants (J) are given in Hz. Electron spray ionization (ESI) and high-resolution mass spectra were recorded on a QSTAR XL hybrid MS/MS system (Applied Biosystems, USA) under electrospray ionization. Thin-layer chromatography was carried out on aluminum sheets coated with silica gel 60F254 (Merck, 1.05554) and the spots were visualized with UV light at 254 nm. Flash column chromatography was performed using silica gel (Merck, 60–120 Mesh). Commercially available reagents were used as supplied and some of them were distilled before use. All reactions were performed in oven-dried glassware.

3.1 General procedure for the synthesis of substituted 1-(4-hydroxy-[1,1′-biphenyl]-3-yl)ethanone (3a–3j)

1-(5-Bromo-2hydroxyphenyl)ethanone (1), (500 mg, 2.34 mmol), was dissolved in THF/H2O (12.5 mL), and Pd(PPh3)4 (3 mol%), phenylboronic acid (2a–2j) (314 mg, 2.81 mmol), and Na2CO3 (49 mg, 0.472 mmol) were added at room temperature and the mixture was refluxed with stirring for 12 h. When the reaction was complete, the mixture was filtered over a celite bed, the sorbent was washed with EtOAc, and the organic layer was separated, washed with H2O and NaCl solution, and dried over Na2SO4, filtered, and concentrated under the reduced pressure. The purification of crude residue was done using column chromatography with 20% EtOAc in n-hexane to give the compound (3a) yield: 72%; brown solid; M.P.: 152–154°C; IR (KBr): 3,400 (OH), 2,090, 1,745, 1,680, 1,650, 1,350 cm−1; 1H NMR, δ, ppm: 12.10 (s, 1H, OH), 7.78 (s, 1H, Ar–H), 7.59 (d, 1H, J = 9.06 Hz, Ar–H), 7.45–7.28 (m, 4H, Ar–H), 7.38 (s, 1H, Ar–H), 6.95 (d, 1H, Ar–H), 2.62(s, 3H, Me); 13C NMR, δ, ppm: 202.50 (CO), 161.72 (C–OH), 140.70, 138.90, 134.55, 131.01, 129.30 (2C), 127.80 (2C), 122.3, 26.03; MS (ESI+): m/z = 213.08 [M + H]+.

3.2 Synthesis of (E)-3-(4-aminophenyl)-1-(4-hydroxy-[1,1′-biphenyl]-3-yl)prop-2-en-1-one (4a)

A solution of compound (1-(4-hydroxy-[1,1′-biphenyl]-3-yl)ethanone) (3a) (200 mg, 0.94 mmol) and 4-aminobenzaldehyde (178 mg, 1.41 mmol) in 25 mL of ethanol was treated with 10 mL of 60% KOH solution at 5–10°C. The reaction mixture was stirred at room temperature for 4 h. Then it was diluted with water (50 mL) and extracted with diethyl ether (3 mL × 20 mL). The resulted aqueous solution was acidified with dilute hydrochloric acid. The solid produced was filtered, thoroughly washed with water, the crude mass was then dried, and purified by column chromatography with 20% EtOAc in n-hexane to give the compound (4a). Yield: 80%; yellow solid; M.P.: 162–165°C; IR (KBr): 3,550, 3,000, 2,800, 1,650, 1,710, 1,175 cm−1; 1H NMR, δ, ppm: 12.77 (s, 1H, OH), 8.00 (s, 1H, Ar–H), 7.85 (d, 1H, J = 15.25 Hz, chalcone-H), 7.67 (d, 1H, J = 15.28 Hz, chalcone-H), 7.57–7.37 (m, 7H, Ar–H), 7.32 (m, 1H, Ar–H), 7.08 (s, 2H, NH2), 6.83 (s, 3H, Ar–H); 13C NMR, δ, ppm: 193.08 (CO), 163.05 (C–OH), 147.94 (C–NH2), 145.18 (═C), 142.87, 138.52, 132.55, 129.85 (2C), 129.20 (2C), 127.80 (2C), 127.0, 125.30, 123.02, 121.45, 118.74 (C═), 114.20 (2C); MS (ESI+): m/z = 316.14 [M + H]+.

3.3 Synthesis of (E)-3-(4-azidophenyl)-1-(4-hydroxy-[1,1′-biphenyl]-3-yl)prop-2-en-1-one (5a)

The compound (4a), (500 mg, 2.0 mmol), was dissolved in t BuONO (1.23 mL, 0.206 mmol), and NaN3 (900 mg, 0.13 mmol) was added at room temperature and was to found to be the optimum quantity required for the transformations (amine to azide). Yield: 66%; yellow solid; M.P.: 160–162°C, IR (KBr): 3,440, 2,094, 1,740, 1,680, 1,670, 1,350 cm−1; 1H NMR, δ, ppm: 12.77 (s, 1H, OH), 8.00 (s, 1H, Ar–H), 7.85 (d, 1H, J = 15.25 Hz, chalcone-H), 7.67 (d, 1H, J = 15.28 Hz, chalcone-H), 7.57–7.47 (m, 4H, Ar–H), 7.44–7.38 (m, 3H, Ar–H), 6.83 (s, 3H, Ar–H) ppm; 13C NMR, δ, ppm: 193.10 (CO), 163.08 (C–OH), 143.94 (C–N3), 145.18 (═C), 142.86, 138.52, 132.55, 129.86 (2C), 129.20 (2C), 127.82 (2C), 127.0, 125.40, 123.02, 121.45, 118.64 (C═), 114.22 (2C); MS (ESI+): m/z = 342.12 ([M + H]+).

3.4 General procedure (6a–6j)

To 5-ethynyl-1,2,3 trimethoxybenzene (200 mg, 1.014 mmol) dissolved in 5 mL of acetonitrile was added CuI (5 mol%) followed by azides (5a–5j) (341 mg, 1.014 mmol) individually. The reaction mixture was stirred for 30 min at room temperature. The completion of the reaction was monitored by thin-layer chromatography. After completion of the reaction, the solvent was removed under reduced pressure, and then this reaction mixture was diluted with water (25 mL) and then extracted with ethyl acetate (3 mL × 25 mL). The combined organic layer was washed with brine solution (2 mL × 25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in a vacuum. The resulted crude mass was purified by column chromatography using 100–200 mesh silica gel and EtOAc in pet ether to afford corresponding chalcone-based 1,2,3-triazole derivatives (6a–6j).

3.5 (E)-1-(4-Hydroxy-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6a)

From azide (5a) (341 mg, 1.014 mmol) and 5-ethynyl-1,2,3 trimethoxybenzene (200 mg, 1.014 mmol), the compound (6a) was obtained. Yield: 72%; dark yellow solid; M.P.: 127–129°C; IR (KBr): 3,450, 2,800, 1,710, 1,636, 1,457 cm−1; 1H NMR, δ, ppm: 12.64 (s, 1H, OH), 8.39 (s, 1H, Ar–H), 8.18 (d, 1H, J = 12.38 Hz, chalcone-H), 8.09 (s, 1H, triazol-H), 7.35–7.64 (m, 7H, Ar–H), 7.33 (m, 2H, chalcone-H, Ar–H), 7.28–707 (m, 5H, Ar–H), 3.93 (s, 9H, 3OMe); 13C NMR, δ, ppm: 193.32 (CO), 163.73 (C–OH), 154.94 (2C–OCH3), 145.28 (═C), 149.87, 138.72 (C-OCH3), 136.55 (2C), 135.77, 135.98, 133.82, 136.55, 131.45, 129.33 (2C), 126.77 (2C), 124.45, 123.84 (2C), 122.54, 118.84 (C═), 105.98 (2C), 101.74 (2C), 58.57 (2−OCH3), 58.97 (1−OCH3); MS (ESI+): m/z = 534.20 ([M + H]+).

3.6 (E)-1-(4′-fluoro-4-hydroxy-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6b)

From azide (5b) (150 mg, 0.417 mmol) and 5-ethynyl-1,2,3-trimethoxybenzene (80 μL, 0.417), the compound (6b) was obtained. Yield: 84%; dark yellow powder; M.P.: 128–130°C; IR(KBr): 3,460, 2,800, 1,700, 1,636, 1,450 cm–1; 1H NMR, δ, ppm: 12.74 (s, 1H, OH), 8.29 (s, 1H, Ar–H), 8.12 (d, 1H, J = 12.58 Hz, chalcone-H), 8.08 (s, 1H, triazol-H), 7.94–7.64 (m, 7H, Ar–H), 7.53 (m, 2H, chalcone-H, Ar–H), 7.23–707 (m, 4H, Ar–H), 3.96 (s, 9H, 3OMe); 13C NMR, δ, ppm: 193.22 (CO), 163.8 (C–OH), 161.98 (C–F), 153.77 (2C−OCH3), 148.94, 146.52 (═C), 139.84, 136.55, 136.24, 135.84, 134.56, 131.98 (2C), 131.54, 126.74 (2C), 123.84, 122.74 (2C), 121.97, 118.60 (C═), 116.54 (2C), 100.98 (2C), 60.74 (O–CH3), 56.62 (2O–CH3); MS (ESI+): m/z = 552.19 ([M + H]+).

3.7 (E)-1-(3′-Chloro-4-hydroxy-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6c)

From azide (5c) (200 mg, 0.533 mmol) and 5-ethynyl-1,2,3-trimethoxybenzene (102 μL, 0.533 mmol), the compound (6c) was obtained. Yield: 84%; dark yellow powder; M.P.: 135–137°C; IR(KBr): 3,400, 2,830, 1,710, 1,636, 1,450 cm–1; 1H NMR, δ, ppm: 12.78 (s, 1H, OH), 8.31 (d, 1H, J = 13.00 Hz, chalcone-H), 8.09–7.76 (s, 4H, triazol-H, Ar–H), 7.81–7.62 (m, 5H, Ar–H), 7.26 (d, 1H, J = 13.85 Hz, chalcone-H), 7.16–7.02 (m, 4H, Ar–H), 6.86 (d, 1H, Ar–H), 3.90 (s, 9H, 3OMe); 13C NMR, δ, ppm: 193.52 (CO), 163.7 (C–OH), 160.97 (C–Cl), 153.78 (2C–OCH3), 149.54, 146.55 (═C), 139.64, 136.65, 136.54, 135.85, 135.56, 132.98 (2C), 132.54, 126.72 (2C), 124.84, 123.74 (2C), 121.87, 119.60 (C═), 116.52 (2C), 101.01 (2C), 61.75 (O–CH3), 56.82 (2O–CH3); MS (ESI+): m/z = 568.16 ([M + H]+).

3.8 (E)-1-(4-Hydroxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimetho xyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6d)

From azide 5d (0.200 mg, 0.488 mmol) and 5-ethynyl-1,2,3-trimethoxybenzene (100 μL, 0.488 mmol), the compound (6d) was obtained. Yield: 80%; yellow solid; M.P.: 127–129°C; IR(KBr): 3,450, 2,800, 1,710, 1,636, 1,457 cm–1; 1H NMR, δ, ppm: 12.68 (s, 1H, OH), 8.25(s, 1H, Ar–H), 8.20 (d, 1H, J = 12.38 Hz, chalcone-H), 8.14 (s, 1H, triazol-H), 7.35–7.68 (m, 6H, Ar–H), 7.38 (m, 2H, chalcone-H, Ar–H), 7.32–7.02 (m, 5H, Ar–H), 3.98 (s, 9H, 3OMe); 13C NMR, δ, ppm: 193.53 (CO), 162.7 (C–OH), 153.75 (2C–OCH3), 149.64, 146.56 (═C), 139.74, 136.75, 136.55, 135.95, 135.66, 132.93 (2C), 132.52, 129.78 (C–CF3), 126.73 (2C), 124.85, 124.26 (CF3), 123.75 (2C), 121.88, 119.66 (C═), 116.57 (2C), 101.41 (2C), 61.35 (O-CH3), 56.72 (2O–CH3); MS (ESI+): m/z = 602.18 ([M + H]+).

3.9 (E)-1-(4-Hydroxy-3′,4′-dimethoxy-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimethoxy phenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6e)

From azide 5e (165 mg, 0.376 mmol) and 5-ethynyl-1,2,3-trimethoxybenzene (72 μL, 0.376 mmol), the compound (6e) was obtained. Yield: 82%; pale yellow solid; M.P.: 130–132°C; IR(KBr): 3,420, 2,780, 1,710, 1,680, 1,636, 1,457, 1,087 cm−1; 1H NMR, δ, ppm: 12.68 (s, 1H, OH), 8.21 (d, J = 13.00 Hz, chalcone-H), 8.08–7.86 (s, 5H, triazol-H, Ar–H), 7.83–7.63 (m, 5H, Ar–H), 7.25 (d, 1H, J = 13.00 Hz, chalcone-H), 7.16–7.02 (m, 4H, Ar–H), 6.96 (d, 2H, Ar–H), 3.94 (s, 15H, 5OMe); 13C NMR, δ, ppm: 193.34 (CO), 162.71 (C–OH), 153.72 (2C), 149.27 (C–OMe), 148.57 (C–OMe), 143.68 (C–N═N), 140.86 (CH═), 138.21 (2C), 136.32 (C–OMe), 135.91, 135.52 (═CH), 134.84, 132.45, 131.35 (2C), 130.09 (2C), 129.59, 128.64, 127.65, 125.47, 120.29, 111.59, 110.43, 113.04, 103.31 (2C), 60.97 (OMe), 56.25 (4OMe); MS (ESI+): m/z = 594.22 ([M + H]+).

3.10 (E)-1-(4-Hydroxy-4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6f)

From azide (5f) (250 mg, 0.700 mmol) and 5-ethynyl-1,2,3-trimethoxybenzene (134 μL, 0.700 mmol), the compound (6f) was obtained. Yield: 82%; pale yellow solid; M.P.: 127–129°C; IR(KBr): 3,470, 2,850, 1,710, 1,636, 1,457, 1,315 cm−1; 1H NMR, δ, ppm: 12.78 (s, 1H, OH), 8.34 (s, 1H, Ar–H), 8.03 (d, J = 13.00 Hz, chalcone-H), 8.08–7.82 (s, 4H, triazol-H, Ar–H), 7.80–7.65 (m, 2H, Ar–H), 7.59 (d, 1H, J = 13.00 Hz, chalcone-H), 7.33(d, 1H, J = 7.54 Hz, Ar–H), 7.19–7.11 (m, 2H, Ar–H), 3.95 (s, 9H, 3OMe); 13C NMR, δ, ppm: 193.35 (CO), 163.85 (C–OH), 153.98 (2C–OCH3), 150.85 (C–OCF3), 148.02, 145.57 (═C), 139.24 (OCH3), 136.02, 136.30, 135.52, 134.82, 133.52, 132.32, 131.51, 130.15 (2C), 129.80 (CF3), 127.53, 126.84 (2C), 123.25, 122.85 (2C), 121.30, 118.82 (C═), 115.82 (2C), 100.75 (2C), 60.50 (OCH3), 55.98 (2OCH3); MS (ESI+): m/z = 617.18 ([M + H]+).

3.11 (E)-1-(4,4′-Dihydroxy-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6g)

From azide (5g) (150 mg, 0.390 mmol) and 5-ethynyl-1,2,3-trimethoxybenzene (75 μL, 0.390 mmol), the compound (6g) was obtained. Yield: 74%; white solid; M.P.: 127–129°C; IR(KBr): 3,450, 3,100, 2,800, 1,710, 1,680, 1,600, 1,457, 1,360 cm−1; 1H NMR, δ, ppm: 12.67 (s, 2H, OH), 8.37 (s, 1H, Ar–H), 8.02 (d, J = 12.45 Hz, chalcone-H), 8.00–7.59 (s, 9H, triazol-H, Ar–H), 7.43 (d, 1H, J = 12.45 Hz, chalcone-H), 7.17 (s, 1H, Ar–H), 7.08 (d, 1H, J = 8.00 Hz), 6.98 (d, 1H, J = 7.84 Hz, Ar–H), 3.97 (s, 9H, 3OMe); 13C NMR, δ, ppm: 193.34 (CO), 163.34 (C–OH), 158.2 (C–OH), 153.85 (2C–OCH3), 148.03, 145.57 (═C), 139.26 (OCH3), 136.00, 136.32, 135.55, 134.85, 133.53, 132.33, 131.52, 130.16 (2C), 127.54, 126.82 (2C), 123.35, 122.55 (2C), 121.37, 118.72 (C═), 115.88 (2C), 101.75 (2C), 60.52 (OCH3), 55.94 (2OCH3); MS (ESI+): m/z = 550.19 ([M + H]+).

3.12 (E)-1-(4-Hydroxy-4′-methoxy-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6h)

From azide 5h (200 mg, 0.630 mmol) and 5-ethynyl-1,2,3-trimethoxybenzene (70 μL, 0.630 mmol), the compound (6h) was obtained. Yield: 74%; off white solid; M.P.: 125–127°C; IR(KBr): 3,450, 3,000, 2,800, 1,715, 1,636, 1,600, 1,457, 1,350, 1,720, 1,680 cm−1; 1H NMR, δ, ppm: 12.58 (s, 1H, OH), 8.25 (d, 1H, J = 13.54 Hz, chalcone-H), 8.12–7.86 (s, 5H, triazol-H, Ar–H), 7.80–7.63 (m, 4H, Ar–H), 7.35 (d, 1H, J = 13.54 Hz, chalcone-H), 7.15–7.10 (m, 4H, Ar–H), 6.90 (d, 2H, Ar–H), 3.97 (s, 12H, 4OMe); 13C NMR, δ, ppm: 193.24 (CO), 163.71 (C–OH), 153.62 (2C), 149.26 (C-OMe), 148.54 (C–OMe), 143.58 (C–N═N), 146.86 (CH═), 138.61 (2C), 134.32 (C–OMe), 135.51, 135.53 (═CH), 134.64, 132.35, 131.34 (2C), 130.19 (2C), 128.59, 128.24, 127.60, 125.45, 120.39, 111.52, 110.48, 103.32 (2C), 60.87 (OMe), 56.25 (4OMe) ppm; MS (ESI+): m/z = 550.19 ([M + H]+).

3.13 (E)-1-(4′-(Dimethylamino)-4-hydroxy-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimethoxy phenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6i)

From azide (5i) (250 mg, 0.623 mmol) and 5-ethynyl-1,2,3-trimethoxybenzene (120 μL, 0.623 mmol), the compound (6i) was obtained. Yield: 74%; off white solid; M.P.: 127–129°C; IR(KBr): 3,460, 3,000, 2,860, 1,710, 1,686, 1,636, 1,455, 1,365 cm−1; 1H NMR, δ, ppm: 12.74 (s, 1H, OH), 8.22 (d, 1H, J = 13.44 Hz, chalcone-H), 8.12–7.80 (s, 5H, triazol-H, Ar–H), 7.85–7.66 (m, 4H, Ar–H), 7.30 (d, 1H, J = 13.44 Hz, chalcone-H), 7.16–7.10 (m, 4H, Ar–H), 6.91 (d, 2H, Ar–H), 3.98 (s, 9H, 3OMe), 309 (s, 6H, 2CH2); 13C NMR, δ, ppm: 193.26 (CO), 163.76 (C–OH), 154.28 (C–NCH3), 153.63 (2C), 149.36 (C–OMe), 148.54 (C–OMe), 143.55 (C–N═N), 146.87 (CH═), 138.66 (2C), 134.42 (C–OMe), 135.55, 135.51 (═CH), 134.54, 132.35, 131.36 (2C), 130.18 (2C), 128.59, 128.14, 127.62, 125.44, 120.35, 111.52, 110.48, 102.32 (2C), 60.87 (OMe), 56.25 (2OMe), 40.00 (2OCH3) ppm; MS (ESI+): m/z = 577.24 ([M + H]+).

3.14 (E)-1-(4-Hydroxy-3′,4′,5′-trimethoxy-[1,1′-biphenyl]-3-yl)-3-(4-(4-(3,4,5-trimethoxy phenyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (6j)

From chalcone (5j) (300 mg, 0.67 mmol) and 5-ethynyl-1,2,3-trimethoxybenzene (140 μL, 3.21 mmol)), the compound (6j) was obtained. Yield: 74%; off white solid; M.P.: 127–129°C; IR(KBr): 3,450, 3,150, 2,800, 1,700, 1,680, 1,636, 1,459, 1,360 cm−1; 1H NMR, δ, ppm: 12.63 (s, 1H, OH), 8.15 (d, 1H, J = 13.00 Hz, chalcone-H), 8.01 (s, 1H, triazol-H), 7.96–780 (m, 5H, Ar–H), 7.77 (d, 1H, J = 13.00 Hz, chalcone-H), 7.64 (d, 1H, J = 8.00 Hz, Ar–H), 7.08 (s, 3H, Ar–H), 6.66 (s, 2H, Ar–H), 3.94 (s, 18H, 6OMe); 13C NMR, δ, ppm: 193.42 (CO), 163.83 (C–OH), 154.84 (4C–OCH3), 145.2 (═C), 138.92 (C-OCH3), 137.98 (C–OCH3), 136.55 (2C), 135.87, 134.98, 133.82, 136.55, 130.45, 128.33, 126.87 (2C), 123.45, 122.84 (2C), 121.54, 118.34 (C═), 105.95 (2C), 100.74 (2C), 62.87 (2-OCH3), 55.97 (4-OCH3) ppm; MS (ESI+): m/z = 624.23 ([M + H]+).

4 Conclusion

In conclusion, we have successfully synthesized a new series of 1,2,3-triazole (6a–6j) via the Huisgen azide–alkyne method in good yields and the structure of the compounds were characterized by various spectroscopic techniques. The compounds (6c) and (6i) have proven to be potential molecules against cancer cell lines. It is also recognized that as the concentration of the test compound is increased, the cytotoxicity nature also increased.

  1. Funding information: The author, Raghavender M, thanks the DST-PURS OU and Central Facilities for Research & Development, Osmania University, Hyderabad, India, for providing financial and analytical support. Bhookya Shankar thanks the UGC-New Delhi, India, No. F.4-2/2006 (BSR) CH/18-19/0194, for financial support in the form of UGC-Dr D.S. Kothari postdoctoral fellowship.

  2. Author contributions: BS, MR, and NU were responsible in each stage in the preparation of this manuscript like organic synthesis and purification of compounds, characterization experiments, and cytotoxicity with the direct supervision of PJ. All authors read and approved the final manuscript.

  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: 2021-11-14
Revised: 2022-06-04
Accepted: 2022-06-10
Published Online: 2022-10-06

© 2022 Matta Raghavender et al., 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-2022-0147
Keywords for this article
chalcone; 1,2,3-triazole analogs; cytotoxicity
Creative Commons
BY 4.0

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  2. Sono and nano: A perfect synergy for eco-compatible Biginelli reaction
  3. Study of the reactivity of aminocyanopyrazoles and evaluation of the mitochondrial reductive function of some products
  4. “Click” assembly of novel dual inhibitors of AChE and MAO-B from pyridoxine derivatives for the treatment of Alzheimer’s disease
  5. Synthesis of 2,2-difluoro-2-arylethylamines as fluorinated analogs of octopamine and noradrenaline
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  7. Two independent and consecutive Michael addition of 1,3-dimethylbarbituric acid to (2,6-diarylidene)cyclohexanone: Flying-bird-shaped 2D-polymeric structure
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