Design, Synthesis and Anti-inflammatory Activity of Azulene Derivatives Containing Benzimidazole Unit

doi:10.6023/cjoc202302007

Abstract

Benzimidazole (BI) unit exists in many bioactive compounds and has attracted more and more attention in the field of drug synthesis. Azulene derivatives are natural products obtained from medicinal plants, which have the characteristics of anti-inflammatory, antioxidant, and low toxicity. Using azulene derivatives and BI as raw materials, fourteen azulene derivatives that contain benzimidazole unit were synthesized by using Buchwald-Hartwig coupling strategy. Then their anti-inflammatory activity and structure-activity relationship were studied. The results showed that these compounds can effectively inhibit the production of NO in lipopolysaccharide (LPS) induced macrophages and have higher anti-inflammatory activity than sodium guaiazulene sulfonate (GAS-Na). Among them, three derivatives were screened with low toxicity and high anti-inflammatory activity, and they can inhibit the release of LPS-induced interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in a dose-dependent manner by enzyme-linked immunosorbent assay (ELISA). The results show that 1-guaiaculene benzimidazole (GABI-1) has high anti-inflammatory activity (the inhibitory rate of NO was 33.69% at the doses of 20 μmol/L) and low cytotoxicity, which is expected to become a candidate molecule for new anti-inflammatory drugs.

Key words: azulene, guaiazulene, benzimidazole, sodium guaiazulene sulfonate, anti-inflammatory activity

Cite this article

Mengjia Xiao, Xike Gao. Design, Synthesis and Anti-inflammatory Activity of Azulene Derivatives Containing Benzimidazole Unit[J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3246-3256.

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Fig. & Tab. 7

Figure 1. Chemical structures of benzimidazole, azulene and guaiazulene

Entry	Solvent	Catalyst	Ligand	Base	Temp./℃	Yield^b/%
1	Toluene	Pd₂(dba)₃	Davephos	NaO^tBu	110	49
2	Toluene	Pd₂(dba)₃	Xphos	NaO^tBu	110	80
3	Toluene	Pd₂(dba)₃	Sphos	NaO^tBu	110	80
4	Toluene	Pd₂(dba)₃	Me^tBu-Xphos	NaO^tBu	110	5
5	Toluene	Pd₂(dba)₃	^tBu-Xphos	NaO^tBu	110	85
6	Toluene	Pd(OAc)₂	^tBu-Xphos	NaO^tBu	110	79
7	Toluene	Pd(dppf)Cl₂	^tBu-Xphos	NaO^tBu	110	74
8	Toluene	Pd₂(dba)₃	^tBu-Xphos	K₂CO₃	110	24
9	Toluene	Pd₂(dba)₃	^tBu-Xphos	Cs₂CO₃	110	67
10	Toluene	Pd₂(dba)₃	^tBu-Xphos	K₃PO₄	110	30
11	1,4-Dioxane	Pd₂(dba)₃	^tBu-Xphos	NaO^tBu	110	83
12	DMB	Pd₂(dba)₃	^tBu-Xphos	NaO^tBu	110	82

Table 1. Optimization of Buchwald-Hartwig coupling reaction conditions

Scheme 1. Synthesis routes of GABI-1~GABI-7 and AzBI-1~AzBI-7

Figure 2. X-Ray single crystal structures of products GABI-2 and GABI-7

Figure 3. Inhibitory activities against NO of the different compounds in LPS-induced RAW 264.7 cells Data are given as mean±SEM. *p<0.05 compared to GAS-Na

Figure 4. Effects of compounds on the cell viability of macrophage RAW 264.7 cells

Figure 5. Inhibitory activities against TNF-α and IL-6 of the different compounds in LPS-induced RAW 264.7 cells Data are given as mean±SEM. (a, b) Inhibition of LPS-induced TNF-α and IL-6 of compounds GABI-1, GABI-2, GABI-3, GABI-5, and GABI-6 at 20 μmol/L; (c, d) inhibition of LPS-induced TNF-α and IL-6 of compounds GABI-1, GABI-2, GABI-6. Data are expressed as fold change relative to control values (samples treated with LPS alone). ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05 compared to LPS.

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