7-苯基-6H,7H-1,3,4-噻二唑并[3,2-a]-硫色烯并[4,3-d]嘧啶类化合物的合成及抗真菌活性研究

doi:10.6023/cjoc202101056

有机化学 ›› 2021, Vol. 41 ›› Issue (6): 2467-2475.DOI: 10.6023/cjoc202101056 上一篇下一篇

研究论文

7-苯基-6H,7H-1,3,4-噻二唑并[3,2-a]-硫色烯并[4,3-d]嘧啶类化合物的合成及抗真菌活性研究

董金娇^a, 朱昕悦^a, 冯思冉^a, 张超超^a, 刘振明^b, 乔晓强^a^,^c^,^*(), 宋亚丽^a^,^*()

a 河北大学药学院河北省药物质量分析控制重点实验室河北保定 071000
b 北京大学天然药物及仿生药物国家重点实验室北京 100191
c 河北大学药物化学与分子诊断教育部重点实验室河北保定 071000

收稿日期:2021-01-31 修回日期:2021-02-20 发布日期:2021-03-04
通讯作者: 乔晓强, 宋亚丽
基金资助:
河北省自然科学基金(B2018201269); 河北省高等学校科学技术研究(ZD2019060); 河北大学自然科学多学科交叉研究计划(DXK201912); 河北大学研究生创新(hbu2020ss054)

Synthesis and Antifungal Activity of 7-Phenyl-6H,7H-1,3,4-thia- diazolo[3,2-a]-thiochromeno[4,3-d]pyrimidine Compounds

Jinjiao Dong^a, Xinyue Zhu^a, Siran Feng^a, Chaochao Zhang^a, Zhenming Liu^b, Xiaoqiang Qiao^a^,^c(), Yali Song^a()

a Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei 071000
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191
c Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding, Hebei 071000

Received:2021-01-31 Revised:2021-02-20 Published:2021-03-04
Contact: Xiaoqiang Qiao, Yali Song
Supported by:
Natural Science Foundation of Hebei Province(B2018201269); Science and Technology Project of Hebei Education Department(ZD2019060); Young Talent of Hebei Province, the Natural Science Interdisciplinary Research Program of Hebei University(DXK201912); Post-Graduate Innovation Fund Project of Hebei University(hbu2020ss054)

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摘要/Abstract

利用生物电子等排原理和生物活性基团拼接原理, 设计合成了16个7-苯基-6H,7H-1,3,4-噻二唑并[3,2-a]-硫色烯并[4,3-d]嘧啶类化合物. 目标化合物均经核磁共振氢谱(¹H NMR)、核磁共振碳谱(¹³C NMR)和高分辨质谱仪(HRMS)进行了结构确证. 体外抗真菌活性结果表明, 对于动物病原菌, 化合物对总状毛霉、絮状表皮癣菌、红色毛癣菌和须癣毛癣菌等浅部真菌均有较好的抑制活性, 其中化合物5d对红色毛癣菌的最小抑菌浓度为4 μg•mL ^–1, 而对新生隐球菌、白念球菌、烟曲霉等深部真菌的抑制活性较差; 化合物对5种植物病原菌均有一定程度的抑制作用, 化合物5l对花生冠腐病菌和马铃薯晚疫病菌的抑菌活性最好, 最小抑菌浓度为8 μg•mL ^–1.

关键词: 1,3,4-噻二唑并[3,2-a]-硫色烯并[4,3-d]嘧啶, 平板法, 抗真菌活性

According to the principle of active substructure splicing and bioisosterism, sixteen 7-phenyl-6H,7H-1,3,4-thiadia- zolo[3,2-a]-thiochromeno[4,3-d]pyrimidine compounds containing a fused-ring were designed and synthesized. The target compounds were confirmed by¹H NMR, ¹³C NMR and HRMS. The preliminary antifungal activity assay showed that these compounds exhibited a good antifungal activity in vitro on superficial fungi, such as Mucor racemosus,Epidermophyton floccosum,Trichophyton rubrum and Trichophyton mentagrophytes, compound 5d was found to be very sensitive (minimum inhibitory concentration (MIC): 4 μg•mL ^–1) to Trichophyton rubrum. While on invasive fungi, such as Cryptococcus neoformans, Candida albicans and Aspergillus fumigatus, they exhibited lower activity than that of superficial fungi. They exhibited significant inhibition activity against five plant pathogens. MIC value of compound 5l against Aspergillusnigervan tiegh and Phytophthora infestans was 8 μg•mL ^–1.

Key words: 1,3,4-thiadiazolo[3,2-a]-thiochromeno[4,3-d]pyrimidine, plate method, antifungal activities

引用此文

董金娇, 朱昕悦, 冯思冉, 张超超, 刘振明, 乔晓强, 宋亚丽. 7-苯基-6H,7H-1,3,4-噻二唑并[3,2-a]-硫色烯并[4,3-d]嘧啶类化合物的合成及抗真菌活性研究[J]. 有机化学, 2021, 41(6): 2467-2475.

Jinjiao Dong, Xinyue Zhu, Siran Feng, Chaochao Zhang, Zhenming Liu, Xiaoqiang Qiao, Yali Song. Synthesis and Antifungal Activity of 7-Phenyl-6H,7H-1,3,4-thia- diazolo[3,2-a]-thiochromeno[4,3-d]pyrimidine Compounds[J]. Chinese Journal of Organic Chemistry, 2021, 41(6): 2467-2475.

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Compd.	Minimum inhibitory concentration (MIC)/(μg•mL^–1)
Compd.	C. a	C. n	A. f	E. f	M. r	T. r	T. m
FCZ AmB 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5n 5o 5p	32-64 <2 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128	8-16 <2 >128 >128 128 32 64 >128 >128 >128 128 >128 >128 128 128 >128 >128 128	64 <2 64 16 >128 16 128 64 32 128 32 32 16 32 64 128 128 >128	32 4 64 128 32 128 64 32 64 64 32 >128 64 >128 128 32 32 >128	>128 <2 16 16 32 8 8 16 32 16 32 16 32 64 32 32 32 32	8 <2 128 8 8 4 8 16 8 64 16 64 8 32 32 32 16 16	64 <2 128 8 16 32 8 32 16 16 64 64 8 64 8 8 32 8

Compd.	Minimum inhibitory concentration (MIC)/(μg•mL^–1)
Compd.	C. a	C. n	A. f	E. f	M. r	T. r	T. m
FCZ AmB 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5n 5o 5p	32-64 <2 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128	8-16 <2 >128 >128 128 32 64 >128 >128 >128 128 >128 >128 128 128 >128 >128 128	64 <2 64 16 >128 16 128 64 32 128 32 32 16 32 64 128 128 >128	32 4 64 128 32 128 64 32 64 64 32 >128 64 >128 128 32 32 >128	>128 <2 16 16 32 8 8 16 32 16 32 16 32 64 32 32 32 32	8 <2 128 8 8 4 8 16 8 64 16 64 8 32 32 32 16 16	64 <2 128 8 16 32 8 32 16 16 64 64 8 64 8 8 32 8

Compd.	Minimum inhibitory concentration (MIC)/(μg•mL^–1)
Compd.	C. g	R. s. k	A. t	P. i	S. s
Car AmB 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5n 5o 5p	128 8 128 64 32 32 128 32 16 32 16 >128 >128 64 64 128 128 >128	64 >128 64 32 >128 64 >128 >128 64 >128 >128 128 128 >128 32 128 64 64	64 >128 16 64 16 64 128 8 16 64 8 16 16 8 16 64 16 32	16 >128 64 16 32 16 64 64 128 128 64 32 16 8 32 >128 >128 128	32 128 8 128 8 16 16 128 8 >128 >128 8 16 32 128 64 32 16

Compd.	Minimum inhibitory concentration (MIC)/(μg•mL^–1)
Compd.	C. g	R. s. k	A. t	P. i	S. s
Car AmB 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5n 5o 5p	128 8 128 64 32 32 128 32 16 32 16 >128 >128 64 64 128 128 >128	64 >128 64 32 >128 64 >128 >128 64 >128 >128 128 128 >128 32 128 64 64	64 >128 16 64 16 64 128 8 16 64 8 16 16 8 16 64 16 32	16 >128 64 16 32 16 64 64 128 128 64 32 16 8 32 >128 >128 128	32 128 8 128 8 16 16 128 8 >128 >128 8 16 32 128 64 32 16

7-苯基-6H,7H-1,3,4-噻二唑并[3,2-a]-硫色烯并[4,3-d]嘧啶类化合物的合成及抗真菌活性研究

Synthesis and Antifungal Activity of 7-Phenyl-6H,7H-1,3,4-thia- diazolo[3,2-a]-thiochromeno[4,3-d]pyrimidine Compounds

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