新型γ-咔啉衍生物的合成及其抑菌活性研究

doi:10.6023/cjoc202307018

有机化学 ›› 2024, Vol. 44 ›› Issue (1): 204-215.DOI: 10.6023/cjoc202307018 上一篇下一篇

研究论文

新型γ-咔啉衍生物的合成及其抑菌活性研究

霍海波^a, 李桂霞^b, 王世军^c, 韩春^c, 师宝君^d, 李健^a^,^c^,^*()

a 长治学院生命科学系山西长治 046011
b 长治医学院基础医学部山西长治 046011
c 长治学院化学系山西长治 046011
d 西北农林科技大学植物保护学院陕西杨陵 712100

收稿日期:2023-07-17 修回日期:2023-08-31 发布日期:2023-09-15
作者简介:
^†共同第一作者.
基金资助:
国家自然科学基金(82204247); 山西省基础研究计划(202103021223378); 山西省基础研究计划(202103021223382); 山西省基础研究计划(202203021212168); 山西省高校科技创新(2022L510)

Novel γ-Carboline Derivatives as Antibacterial Agents: Synthesis and Antibacterial Evaluation

Haibo Huo^a, Guixia Li^b, Shijun Wang^c, Chun Han^c, Baojun Shi^d, Jian Li^a^,^c()

a Department of Life Sciences, Changzhi University, Changzhi, Shanxi 046011
b Department of Basic Medicine, Changzhi Medical College, Changzhi, Shanxi 046011
c Department of Chemistry, Changzhi University, Changzhi, Shanxi 046011
d College of Plant Protection, Northwest A&F University, Yangling, Shaanxi 712100

Received:2023-07-17 Revised:2023-08-31 Published:2023-09-15
Contact: *E-mail: lijian3773@163.com
About author:
^†The authors contributed equally to this work.
Supported by:
National Natural Science Foundation of China(82204247); National Natural Science Foundation of Shanxi Province(202103021223378); National Natural Science Foundation of Shanxi Province(202103021223382); the National Natural Science Foundation of Shanxi Province(202203021212168); Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi Province(2022L510)

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摘要/Abstract

以哌啶酮和4-甲氧基苯肼为起始原料, 通过Fischer吲哚合成得到中间体9, 经过氧化、酰化以及烷基化构建出新型衍生物45个. 所有的目标产物都进行了抗金黄色葡萄球菌、大肠埃希菌、铜绿假单胞杆菌、茄科雷尔氏菌的抑菌活性研究. 结果显示: 5-(4'-甲氧基苯甲酰基)-8-甲氧基-γ-咔啉(11g)、5-(2'-呋喃甲酰基)-8-甲氧基-γ-咔啉(11n)、5-(2'-溴苄基)-8-甲氧基-γ-咔啉(12f)、5-(3'-溴苄基)-8-甲氧基-γ-咔啉(12g)、5-(4'-三氟甲氧基苄基)-8-甲氧基-γ-咔啉(12h)、溴化2-(4'-氯苄基)-8-甲氧基-γ-咔啉(13e)具有良好的抑菌活性, 特别是化合物12f和12h展现出了与阳性对照氨苄西林钠相当的活性, 其最小抑菌浓度为8 μg/mL. 探索了化合物12h对铜绿假单胞菌的作用机制, 确定了其抑菌机制是通过破坏细菌的细胞壁发挥抑菌作用. 进一步对该系列衍生物的构效关系进行了讨论, 并总结出若干影响该类化合物生物活性的关键因素, 为开发新的抗生素提供参考.

关键词: 8-甲氧基-N² &, N⁵取代γ-咔啉, 抑菌活性, 构效关系, 抑菌机制

Forty-five novel 8-methoxyl-γ-carboline derivatives were designed and effectively synthesized with commercially available starting materials, 4-methoxyphenylhydrazine hydrochloride 7 and piperidone 8, via Fischer indole synthesis process to prepare key intermediate 9, which underwent oxidation, acylation or alkylation to yield the target derivatives. The antibacterial activities of all compounds were evaluated against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) and Ralstonia solanacearum (R. solanacearum). The results indicated that (8-methoxy-5H- pyrido[4,3-b]indol-5-yl)(4-methoxyphenyl)methanone (11g), furan-2-yl(8-methoxy-5H-pyrido[4,3-b]indol-5-yl)methanone (11n), 5-(2-bromobenzyl)-8-methoxy-5H-pyrido[4,3-b]indole (12f), 5-(3-bromobenzyl)-8-methoxy-5H-pyrido[4,3-b]indole (12g), 8-methoxy-5-(4-(trifluoromethoxy)benzyl)-5H-pyrido[4,3-b]indole (12h) and 2-(4-chlorobenzyl)-8-methoxy-5H-pyri- do[4,3-b]indol-2-ium bromide (13e) showed a broad spectrum of antibacterial activity. Especially compounds 12f and 12h exhibited comparable antibacterial activity with the positive control (ampicillin sodium) with minimum inhibitory concentration (MIC) value of 8 μg/mL. Moreover, membrane-active mechanism was studied further via fluorescent microscopy, which suggested that derivative 12h exerted its antibacterial effect by damaging the membranes of the bacteria. Some structure-activity relationships among the forty-five derivatives are discussed and several important determinants for the activity of these compounds are identified. This work offers useful instructions for the development of new antibiotics.

Key words: 8-methoxyl-N² &, N⁵-substituted γ-carbolines, antibacterial activity, structure-activity relationships, mechanism

引用此文

霍海波, 李桂霞, 王世军, 韩春, 师宝君, 李健. 新型γ-咔啉衍生物的合成及其抑菌活性研究[J]. 有机化学, 2024, 44(1): 204-215.

Haibo Huo, Guixia Li, Shijun Wang, Chun Han, Baojun Shi, Jian Li. Novel γ-Carboline Derivatives as Antibacterial Agents: Synthesis and Antibacterial Evaluation[J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 204-215.

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Compd.	R¹	Compd.	R¹	Compd.	R¹	Compd.	R¹	Compd.	R¹
11a		11b		11c		11d		11e
11f		11g		11h		11i		11j
11k		11l		11m		11n
Compd.	R²	Compd.	R²	Compd.	R²	Compd.	R²	Compd.	R²
12a		12b		12c		12d		12e
12f		12g		12h		12i		12j
12k
Compd.	R³	Compd.	R³	Compd.	R³	Compd.	R³	Compd.		R³
13a		13b		13c		13d		13e
13f		13g		13h		13i		13j
13k^b		13l		13m		13n^b		13o
13p		13q		13r		13s		13t

Compd.	R¹	Compd.	R¹	Compd.	R¹	Compd.	R¹	Compd.	R¹
11a		11b		11c		11d		11e
11f		11g		11h		11i		11j
11k		11l		11m		11n
Compd.	R²	Compd.	R²	Compd.	R²	Compd.	R²	Compd.	R²
12a		12b		12c		12d		12e
12f		12g		12h		12i		12j
12k
Compd.	R³	Compd.	R³	Compd.	R³	Compd.	R³	Compd.		R³
13a		13b		13c		13d		13e
13f		13g		13h		13i		13j
13k^b		13l		13m		13n^b		13o
13p		13q		13r		13s		13t

Compound	S.a	E.c	P.a	R.s	Compound	S.a	E.c	P.a	R.s
11a	—	—	16	32	12g	64	—	—	32
11b	—	32	64	32	12h	16	—	8	64
11c	—	—	64	64	12i	16	—	16	16
11d	—	—	64	64	12k	16	64	64	16
11e	—	—	—	64	13a		—		64
11f	—	—	—	64	13b		—		64
11g	16	—	16	16	13c		64		16
11h	—	—	64	—	13e	16	—		8
11i	—	16	—	—	13f	16	—		32
11j	16	—	—	16	13j		64
11k	—	—	—	16	13k	32	64		32
11m	—	—	—	16	13o	-	—		64
11n	—	64	32	—	13p	64	—		64
12a	—	—	64	32	13q	64	—
12b	64	—	64	16	13s	—	64
12c	—	—	32	—	13t	—	64
12d	—	—	—	64	13u	—	64
12f	8	—	64	8	A.S.^b	8	4	8	2

Compound	S.a	E.c	P.a	R.s	Compound	S.a	E.c	P.a	R.s
11a	—	—	16	32	12g	64	—	—	32
11b	—	32	64	32	12h	16	—	8	64
11c	—	—	64	64	12i	16	—	16	16
11d	—	—	64	64	12k	16	64	64	16
11e	—	—	—	64	13a		—		64
11f	—	—	—	64	13b		—		64
11g	16	—	16	16	13c		64		16
11h	—	—	64	—	13e	16	—		8
11i	—	16	—	—	13f	16	—		32
11j	16	—	—	16	13j		64
11k	—	—	—	16	13k	32	64		32
11m	—	—	—	16	13o	-	—		64
11n	—	64	32	—	13p	64	—		64
12a	—	—	64	32	13q	64	—
12b	64	—	64	16	13s	—	64
12c	—	—	32	—	13t	—	64
12d	—	—	—	64	13u	—	64
12f	8	—	64	8	A.S.^b	8	4	8	2

新型γ-咔啉衍生物的合成及其抑菌活性研究

Novel γ-Carboline Derivatives as Antibacterial Agents: Synthesis and Antibacterial Evaluation

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