Synthesis and biological evaluation of novel 7-hydroxy-4-phenylchromen-2-one–linked to triazole moieties as potent cytotoxic agents

Figures & data

Figure 1. Representative examples of coumarin molecules with 1,2,4-triazoles moieties that exhibit anticancer activity.

Table 1. In vitro anticancer activity of 1a, its derivatives, and 5-fluorouracil against six cancer cell lines^a (IC₅₀ μM^b).

		IC50 (μM)
Comp.	R	AGS	MGC	A-549	HepG2	HCT	HeLa
4a	–C6H5	10.60 ± 0.36	13.49 ± 0.58	26.42 ± 0.62	34.15 ± 0.24	ND	ND
4b	–C6H4 (o-Cl)	15.02 ± 0.21	18.31 ± 0.22	59.18 ± 0.66	18.75 ± 0.85	ND	ND
4c	–C6H4 (m-Cl)	17.99 ± 0.38	17.54 ± 0.43	42.56 ± 0.53	ND	3.66 ± 0.24	40.46 ± 0.71
4d	–C6H4 (p-Cl)	2.63 ± 0.17	3.05 ± 0.29	50.24 ± 0.51	67.83 ± 0.83	11.57 ± 0.53	13.62 ± 0.86
4e	–C6H4 (p-F)	55.96 ± 0.71	ND	ND	ND	79.16 ± 0.45	ND
4f	–C6H4 (m-Br)	22.4 ± 0.83	ND	ND	ND	12.41 ± 0.52	ND
4g	–C6H4 (p-Br)	41.36 ± 0.62	36.22 ± 0.61	33.35 ± 0.42	50.21 ± 0.36	15.58 ± 0.28	ND
4h	–C6H4 (o-CH3)	33.11 ± 0.36	18.93 ± 0.54	41.15 ± 0.61	8.33 ± 0.27	7.47 ± 0.69	30.93 ± 0.39
4i	–C6H4 (m-CH3)	61.97 ± 0.53	40.56 ± 0.29	56.77 ± 0.43	48.97 ± 0.19	7.97 ± 0.56	46.35 ± 0.43
4j	–C6H4 (p-CH3)	11.66 ± 0.22	8.72 ± 0.35	17.32 ± 0.63	17.71 ± 0.24	17.91 ± 0.42	7.20 ± 0.54
4k	–C6H3 (2,4-(CH3)2)	23.95 ± 0.36	32.26 ± 0.36	28.50 ± 0.87	8.45 ± 0.15	9.54 ± 0.52	20.4 ± 0.62
4l	–C6H3 (2,6-(CH3)2)	62.71 ± 0.79	43.37 ± 0.27	ND	23.41 ± 0.26	15.72 ± 0.31	57.91 ± 0.69
4m	–C6H4 (p-OCH3)	9.00 ± 0.64	ND	ND	ND	ND	ND
5a	–C6H5	16.80 ± 0.83	54.53 ± 0.42	63.72 ± 0.60	ND	98.14 ± 0.61	73.70 ± 0.76
5b	–C6H4 (o-Cl)	96.21 ± 0.26	74.50 ± 0.30	ND	ND	45.47 ± 0.49	29.39 ± 0.63
5c	–C6H4 (p-Cl)	ND	72.99 ± 0.51	ND	ND	ND	ND
5d	–C6H4 (p-F)	ND	ND	ND	ND	99.46 ± 0.28	26.23 ± 0.72
5e	–C6H4 (p-CH3)	ND	ND	ND	ND	ND	ND
7a	–C6H5	ND	ND	ND	ND	ND	ND
7b	–CH2C6H5	ND	ND	ND	ND	ND	ND
7c	–CH2C6H4 (p-Cl)	ND	48.16 ± 0.46	ND	ND	ND	ND
7d	–CH2C6H4 (p-F)	ND	ND	ND	ND	94.36 ± 1.32	ND
7e	–CH2C6H4 (p-CH3)	ND	ND	ND	ND	ND	ND
1a		>100	>100	>100	>100	>100	>100
5-FU		29.61 ± 0.21	30.52 ± 0.36	23.65 ± 0.19	23.45 ± 0.37	24.80 ± 0.29	34.61 ± 0.42

Bold values signify that the bioactivity of the compound is outstanding.

^a Cytotoxicity as IC₅₀ for each cell line, refers to the concentration of compound which reduced by 50% the optical density of treated cells with respect to untreated cells using the MTT assay.

^b Data represent the mean values of three independent determinations. ND: not determined (these compounds did not pass the preliminary screening).

Scheme 1. Reagents and conditions: (a) perchloric acid, rt; (b) K₂CO₃, ethyl bromoacetate, acetone, 56 °C; (c) hydrazine hydrate, ethyl alcohol, 78 °C; (d) (i) dimethylacetal, acetonitrile, 60 °C, 1 h; (ii) amines, glacial acetic acid, 120 °C; (e) K₂CO₃, propargyl bromide, acetone, 56 °C; (f) aromatic azides, CuSO₄^.5H₂O, sodium ascorbate, t-BuOH/H₂O (1:1), rt.

Figure 2. (A) Flow cytometry analyses of cell cycle distribution of gastric cancer cell AGS after treatment of compound 4d (10 and 5 μM) and no treatment (Ctrl) as reference control for 12 h. (B) Apoptosis induction in lung carcinoma cell AGS after 12 h treatment with 4d (10 and 50 μM) and no treatment.