Synthesis and Anti-inflammatory Evaluation of Novel 1,2,3-Triazole Derivatives

doi:10.6023/cjoc202209033

Chinese Journal of Organic Chemistry ›› 2023, Vol. 43 ›› Issue (6): 2143-2155.DOI: 10.6023/cjoc202209033 Previous Articles Next Articles

新型1,2,3-三氮唑类衍生物的合成及抗炎活性研究

孙泽人^a, 翟冰新^a, 何光超^b, 沈慧^b, 陈琳雅^b, 张杉^b, 邹毅^a^,^b, 朱启华^a^,^b^,^*(), 徐云根^a^,^b^,^*()

a 中国药科大学药学院江苏省药物分子设计与成药性优化重点实验室南京 211198
b 中国药科大学药学院药物化学教研室南京 211198

收稿日期:2022-09-27 修回日期:2022-11-10 发布日期:2023-01-05
作者简介:
^† 共同第一作者
基金资助:
国家自然科学基金(81872750)

Synthesis and Anti-inflammatory Evaluation of Novel 1,2,3-Triazole Derivatives

Zeren Sun^a, Bingxin Zhai^a, Guangchao He^b, Hui Shen^b, Linya Chen^b, Shan Zhang^b, Yi Zou^a^,^b, Qihua Zhu^a^,^b,*(), Yungen Xu^a^,^b,*()

a Jiangsu Key Laboratory of Drug Design and Optimization, School of Pharmacy, China Pharmaceutical University, Nanjing 211198
b Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198

Received:2022-09-27 Revised:2022-11-10 Published:2023-01-05
Contact: * E-mail: xyg64@126.com; zhuqihua@vip.126.com
About author:
^† These authors contributed equally to this work
Supported by:
National Natural Science Foundation of China(81872750)

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Abstract

As the role of indoleamine 2,3-dioxygenase 2 (IDO2) in inflammation, especially in rheumatoid arthritis (RA), is gradually being explained, IDO2 has become a potential target for the treatment of RA. No small molecule inhibitor of IDO2 with strong activity and high selectivity has been reported yet. With the help of computer-aided drug design, twenty-four 1,2,3-triazole derivatives were designed and synthesized by using epacadostat as a lead compound. The results of biological activity show that all target compounds display the inhibitory effects on IDO1 and IDO2 enzymes. Among them, the inhibition rates of (Z)-N-((1-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxyformamidine)-1,2,5-oxadiazo-3-yl)amino)ethyl)-1H-1,2,3- triazol-4-yl)methyl) (I-11) on indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 enzymes were 76% and 49% at 100 nmol/L concentration, respectively, which are better than those of epacadostat (62% and 25%). The anti-inflammatory activity study showed that compound I-11 could significantly inhibit the secretion of inflammatory factor TNF-α at the cellular level. Compound I-11 also showed good in vivo anti-inflammatory activity in mouse ear swelling model, and the inhibition rate was 56.81% at the dose of 100 mg/kg (Ig) which was better than that of naproxen (45.29%, 150 mg/kg, Ig).

Key words: indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), 1,2,3-triazole, anti-inflammatory activity

Cite this article

Zeren Sun, Bingxin Zhai, Guangchao He, Hui Shen, Linya Chen, Shan Zhang, Yi Zou, Qihua Zhu, Yungen Xu. Synthesis and Anti-inflammatory Evaluation of Novel 1,2,3-Triazole Derivatives[J]. Chinese Journal of Organic Chemistry, 2023, 43(6): 2143-2155.

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Fig. & Tab. 9

References 18

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Compd.	Cell viability/%				IC₅₀/(μmol•L^–1)
Compd.	50 μmol/L	16.67 μmol/L	5.55 μmol/L	1.85 μmol/L	IC₅₀/(μmol•L^–1)
I-11	32.8	74.4	78.3	76.9	57
I-7	9.1	55.6	59.2	65.3	>16
Naproxen	35.5	>100	>100	>100	—^a
Epacadostat	40.5	>100	>100	>100	—
I-11+LPS (1 μg/mL)	53.8	74.5	80.6	91.2	69
I-7+LPS (1 μg/mL)	47.5	91.5	>100	>100	48
Naproxen+LPS (1 μg/mL)	44.4	>100	>100	>100	—
Epacadostat+LPS (1 μg/mL)	44.4	>100	>100	>100	—

Compd.	Cell viability/%				IC₅₀/(μmol•L^–1)
Compd.	50 μmol/L	16.67 μmol/L	5.55 μmol/L	1.85 μmol/L	IC₅₀/(μmol•L^–1)
I-11	32.8	74.4	78.3	76.9	57
I-7	9.1	55.6	59.2	65.3	>16
Naproxen	35.5	>100	>100	>100	—^a
Epacadostat	40.5	>100	>100	>100	—
I-11+LPS (1 μg/mL)	53.8	74.5	80.6	91.2	69
I-7+LPS (1 μg/mL)	47.5	91.5	>100	>100	48
Naproxen+LPS (1 μg/mL)	44.4	>100	>100	>100	—
Epacadostat+LPS (1 μg/mL)	44.4	>100	>100	>100	—

Group	Swelling rate/%	Swelling inhibition ratio/%
Model	58.21±12.79	—
Naproxen (150 mg/kg)	31.85±17.29	45.29
I-11 (100 mg/kg)	25.14±15.80	56.81

Group	Swelling rate/%	Swelling inhibition ratio/%
Model	58.21±12.79	—
Naproxen (150 mg/kg)	31.85±17.29	45.29
I-11 (100 mg/kg)	25.14±15.80	56.81

新型1,2,3-三氮唑类衍生物的合成及抗炎活性研究

Synthesis and Anti-inflammatory Evaluation of Novel 1,2,3-Triazole Derivatives

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Compd.	Inhibition rate/%
Compd.	IDO1 (100 nmol/L)	IDO2 (100 nmol/L)	IDO2 (1 μmol/L)
I-1	40	27	72
I-2	52	12	48
I-3	68	14	47
I-4	67	18	63
I-5	59	26	60
I-6	70	34	65
I-7	75	30	49
I-8	37	14	32
I-9	65	18	51
I-10	65	10	54
I-11	76	49	96
I-12	77	12	76
I-13	66	18	87
I-14	61	20	50
I-15	62	10	40
I-16	64	10	45
I-17	57	16	42
I-18	42	9	37
I-19	49	15	61
I-20	67	5	41
I-21	36	12	59
I-22	15	4	36
I-23	43	4	44
I-24	44	3	32
Epacadostat	62	25	—^a

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