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
霍海波 1李桂霞 2王世军 3韩春 3师宝君 4李健5
作者信息
- 1. 长治学院生命科学系 山西长治 046011
- 2. 长治医学院基础医学部 山西长治 046011
- 3. 长治学院化学系 山西长治 046011
- 4. 西北农林科技大学植物保护学院 陕西杨陵 712100
- 5. 长治学院生命科学系 山西长治 046011;长治学院化学系 山西长治 046011
- 折叠
摘要
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.
Abstract
Forty-five novel 8-methoxyl-y-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 antibacte-rial activities of all compounds were evaluated against Staphylococcus aureus(S.aureus),Escherichia coli(E.coli),Pseudo-monas 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 concentra-tion(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 struc-ture-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.
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Key words
8-methoxyl-N2 & N5-substituted γ-carbolines/antibacterial activity/structure-activity relationships/mechanism引用本文复制引用
基金项目
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)
山西省高等学校科技创新项目(2022L510)
出版年
2024
NETL
NSTL
万方数据