Design, Synthesis and Anticancer Activity of 2-((Pyridin- 2-ylmethyl)thio)-1H-benzimidazole Derivatives

doi:10.6023/cjoc202201002

Abstract

Benzimidazole is an important class of nitrogen-containing heterocyclic compounds, which has diverse biological activities. A series of novel 2-((pyridin-2-ylmethyl)thio)-1H-benzimidazole derivatives were reported and their antiproliferative activities against human lung cancer A549, human colorectal cancer HCT116 and human prostate cancer PC3 cell lines were evaluated with the MTT assay. Some target compounds demonstrated obvious antiproliferative activities against A549, HCT116 and PC3 cancer cell lines. Among them, 2-(3-((2-(((1H-benzimidazol-2-yl)thio)methyl)-3-methylpyridin-4-yl)oxy)propoxy)-1-(4-benzhydrylpiperazin-1-yl)ethanone (7c) showed the most potent antiproliferative activity with IC₅₀ values of 1.14 μmol/L for A549, 1.67 μmol/L for HCT116 and 2.34 μmol/L for PC3, respectively. Preliminary structure-activity relationships were summaried and preliminary cellular mechanism studies elucidated that compound 7c could arrest the cell cycle at G₀/G₁ phase. The flow cytometry analysis showed that compound 7c could dose-dependently induce A549 cells apoptosis. It is suggested that the 2-((pyridin-2-ylmethyl)thio)-1H-benzimidazole scaffold might be regarded as new scaffold structure for the development of potent cancer chemotherapeutic agents in the drug discovery process.

Key words: benzimidazole derivatives, synthesis, anticancer activity, apoptosis

Cite this article

Jing Zhao, Zhe Jin, Run Wang, Xin'geng Zhang, Yingmei Han, Chun Hu, Xiaoping Liu, Chuanming Zhang, Liping Jin. Design, Synthesis and Anticancer Activity of 2-((Pyridin- 2-ylmethyl)thio)-1H-benzimidazole Derivatives[J]. Chinese Journal of Organic Chemistry, 2022, 42(7): 2172-2183.

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Fig. & Tab. 11

Figure 1. Chemical structures of PPIs

Figure 2. Chemical structures of some anticancer drugs

Figure 3. Spatial distance of the nitrogen atoms in pyridine ring and trifluoromethyl moiety of sorafenib (top) and a target compound (bottom)

Figure 4. Rational design of the target compounds based on molecular hybridization strategy

Scheme 1. Synthetic route of the target compounds 4a~4i Reagents and conditions: (a) CS2, Na2CO3, H2O, 30~90 ℃, 94.2%; (b) 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride, 2 mol/L NaOH (aq.), EtOH, r.t., 79.8%; (c) BBr3, CH2Cl2, –20 ℃, 83.6%; (d) ClCH2CONR1R2, K2CO3, KI, TBAB, acetone, reflux, 55.2%~71.3%

Scheme 2. Synthetic route of the target compounds 7a~7e and 11a~11d Reagents and conditions: (a) 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride, 2 mol/L NaOH (aq.), EtOH, r.t., 60.9%; (b) BBr3, CH2Cl2, –20 ℃, 69.5%; (c) ClCH2CONR3R4, K2CO3, KI, TBAB, acetone, reflux, 44.3%~52.8%; (d) (i) SOCl2, CHCl3, reflux; (ii) phthalimide potassium salt, DMF, 90 ℃, 45.7%; (iii) 80% N2H4•H2O, EtOH, reflux; (e) bis(trichloromethyl)carbonate, Et3N, r.t.; (f) 10a~10d, CH2Cl2, r.t., 47.1%~60.2%

Compd.	NR¹R²	IC₅₀/(μmol•L^–1)
Compd.	NR¹R²	A549	HCT116	PC3
4a		34.18±2.76	76.49±8.21	>100
4b		28.43±4.67	46.52±3.21	>100
4c		37.47±4.11	53.63±3.37	88.50±1.98
4d		44.09±0.17	74.14±1.28	>100
4e		40.69±12.04	37.08±2.82	>100
4f		20.87±1.23	27.90±0.79	72.47±0.46
4g		25.14±0.39	41.04±0.48	89.69±1.32
4h		19.45±0.91	34.63±0.82	79.83±2.58
4i		35.58±2.69	42.54±3.47	>100
Sorafinib		2.12±0.18	2.25±0.71	3.60±1.08

Table 1. Chemical structures and inhibitory activities of target compounds 4a~4i

Compd.	NR³R⁴	IC₅₀/(μmol•L^–1)
Compd.	NR³R⁴	A549	HCT116	PC3
7a		23.04±2.19	33.03±1.88	59.40±3.45
7b		5.04±2.07	9.82±3.81	48.37±4.23
7c		1.14±0.14	1.67±0.56	2.34±0.25
7d		5.59±0.90	12.55±1.04	45.70±3.43
7e		23.07±2.62	30.16±3.10	>100
sorafinib		2.12±0.18	2.25±0.71	3.60±1.08

Table 2. Chemical structures and inhibitory activities of target compounds 7a~7e

Compd.	R⁵	IC₅₀/(μmol•L^–1)
Compd.	R⁵	A549	HCT116	PC3
11a		13.71±2.39	11.90±1.47	>100
11b		9.36±0.76	10.22±1.61	>100
11c		13.29±2.31	15.93±1.11	62.93±1.35
11d		11.98±4.32	17.29±3.55	>100
sorafinib		2.12±0.18	2.25±0.71	3.60±1.08

Table 3. Chemical structures and inhibitory activities of target compounds 11a~11d

Figure 5. Compound 7c induced apoptosis of A549 cells (A) Apoptosis effect on A549 cell line induced by compound 7c for 48 h using Annexin V-FITC/PI double staining and flow-cytometry calculation. The lower left quadrant represents live cells, the lower right is for early apoptotic cells, upper right is for late apoptotic cells, and the upper left represents cells damaged during the procedure. (B) Quantitative analysis of apoptotic cells. The experiments were performed three times, and a representative experiment is shown.

Figure 6. Effects of compound 7c on A549 cell cycle progress for 24 h (A) Treatment of A549 cells with compound (7c) at different concentrations (1, 5, 10 μmol/L) for 24 h; (B) Quantitative analysis of cell cycle. The experiments were performed three times, and a representative experiment is shown

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