双子季铵盐氯胺的合成及抗菌应用

doi:10.6023/cjoc202312028

摘要/Abstract

以5,5-二甲基海因为原料, 通过多步合成策略制备了一系列不同长度spacer的双子(Gemini)季铵盐氯胺抗菌剂N,N-双(3-(3-氯-4,4-二甲基-2,5-二氧亚基咪唑烷-1-基)丙基)-N,N,N,N-四甲基丁烷-1,4-二铵氯化物(6)~N,N-双(3-(3-氯-4,4-二甲基-2,5-二氧亚基咪唑烷-1-基)丙基)-N,N,N,N-四甲基癸烷-1,10-二铵氯化物(9), 采用核磁共振波谱(NMR)和高分辨质谱(HRMS)表征了前体和氯胺结构. 以E. coli (ATCC 25922)和S. aureus (ATCC 25923)为模式菌株, 以已报道的Gemini-季铵盐氯胺5为对照, 初步测试了氯胺6~9抗菌活性. 抗菌数据表明, 5~9抗菌活性随结构中spacer增大呈现了先减弱后增强的趋势, 其中spacer为C₁₀H₂₀的氯胺9抗菌活性达到了最佳, 明显优于具有“团队”抗菌效应的5~6, 这可能是9达到了分子触杀所需最佳的亲疏水平衡状态所致. 表明spacer大小决定了“团队”协同抗菌作用的强弱, 且双亲氯胺亲疏水状态对分子触杀贡献极大. 合成了一系列高效阳离子型氯胺抗菌剂, 为今后更高效氯胺抗菌剂研发提供重要参考.

关键词: 双子季铵盐氯胺, 化学多步合成, 抗菌活性, 亲疏水平衡, “团队”抗菌效应

A series of Gemini-quaternary ammonium (QA) N-chloramine biocides N,N-bis(3-(3-chloro-4,4-dimethyl-2,5-di- oxoimidazolidin-1-yl)propyl)-N,N,N,N-tetramethylbutane-1,4-diaminium chloride (6)~N,N-bis(3-(3-chloro-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)propyl)-N,N,N,N-tetramethyldecane-1,10-diaminiumchloride (9) with varied spacers were synthesized via ploy-step strategy started from commercial 5,5-dimethylhydantoin. The structures of precursors and corresponding N-chloramines were characterized by nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectra (HRMS). Antibacterial activity of N-chloramines was preliminarily tested against E. coli (ATCC 25922) and S. aureus (ATCC 25923) using previous Gemini-QA N-chloramine 5 as control. Antibacterial data showed that antibacterial potency of 5~9 declined first and then increased as the spacer length increased. Specifically, 9 (with spacer of C₁₀H₂₀) demonstrated the towering antibacterial capability, superior to 5~6 that exerted noticeable biocidal team effort. The greatly enhanced efficacy of 9 was probably caused by its preferable hydrophilic-lipophilic balance. It means that spacer length determines team effort biocidal and hydrophilic-lipophilic characteristic greatly contributes efficient contact killing. This study provides a series of efficacious cationic N-chloramine disinfectants, and also offers a vital reference for developing new N-chloramine antimicrobials with even higher efficacy.

Key words: Gemini-QA N-chloramine, ploy-step chemical synthesis, antibacterial activity, hydrophilic-lipophilic balance, biocidal team effort

引用此文

李令东, 张维伦, 刘鹏飞, 周子杰, 周豪, 杜中田. 双子季铵盐氯胺的合成及抗菌应用[J]. 有机化学, 2024, 44(6): 2041-2048.

Lingdong Li, Weilun Zhang, Pengfei Liu, Zijie Zhou, Hao Zhou, Zhongtian Du. Synthesis of Gemini-Quaternary Ammonium N-Chloramine Biocides for Antibacterial Applications[J]. Chinese Journal of Organic Chemistry, 2024, 44(6): 2041-2048.

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图/表 6

图1. 已报道的和本文设计的阳离子氯胺结构

Figure 1. Structures of reported cationic N-chloramines and those developed in this paper

图式1. 氯胺6~9的合成路线

Scheme 1. Synthesis route of N-chloramines 6~9 Reaction conditions: (a) NH(CH3)2 aqueous solution, KOH, EtOH, reflux; (b) Br(CH2)nBr, CH3CN, reflux, ion exchange (Amberlite R IRA-900, Cl–); (c) t-BuOCl, t-BuOH/H2O, r.t.

图2. 前体6a和氯胺6的1H NMR谱图

Figure 2. 1H NMR spectra of precursor 6a and N-chloramine 6

细菌	化合物	活性氯/(mmol•L^–1)	接触5 min		接触10 min
细菌	化合物	活性氯/(mmol•L^–1)	减少量/%	log减少值	减少量/%	log减少值
S. aureus^a	5a	0	0	0	0	0
	5	0.56	83.99±2.94	0.80±0.07	100	6.79
	6a	0	0	0	0	0
	6	0.56	75.49±2.36	0.61±0.03	99.35±0.33	2.18±0.30
	7a	0	0	0	0	0
	7	0.56	41.18±1.96	0.23±0.02	98.37±0.33	1.79±0.08
	8a	0	0	0	0	0
	8 9a 9	0.56 0 0.56	52.61±0.65 0 99.35±0.33	0.32±0.01 0 2.18±0.30	100 0 100	6.79 0 6.79
E. coli^b	5a	0	0	0	0	0
	5	0.56	88.07±3.67	0.92±0.12	100	6.34
	6a	0	0	0	0	0
	6	0.56	87.16±1.83	0.89±0.06	100	6.34
	7a	0	0	0	0	0
	7	0.56	62.39±1.83	0.42±0.09	100	6.34
	8a	0	0	0	0	0
	8	0.56	86.14±3.67	0.86±0.10	100	6.34
	9a	0	0	0	0	0
	9	0.56	100	6.34	100	6.34

表1. 氯胺6~9的抗菌活性

Table 1. Antibacterial activity of N-chloramines 6~9

图3. Gemini-QA氯胺抗菌示意图

Figure 3. Schematic illustration of Gemini-QA N-chloramine biocidal action

图4. 模拟log P与Gemini-QA氯胺5~9抗菌活性关系

Figure 4. Relationship between calculated log P and antibacterial activity of N-chloramines 5~9

参考文献 23

[1]	Garland, M.; Loscher, S.; Bogyo, M. Chem. Rev. 2017, 117, 4422.
[2]	(a) Lee, D. H.; Bertran, K.; Kwon, J. H. J. Vet. Med. Sci. 2017, 18, 269.
	(b) Fung, T. S.; Liu, D. X. Annu. Rev. Microbiol. 2019, 73, 529.
[3]	Stephens, C. R. A.; Mcammond, B. M.; Hamme, J. D. V.; Otter, K. A.; Reudink, M. W.; Bottos, E. M. Can. J. Microbiol. 2021, 67, 572.
[4]	(a) Fisher, M. C.; Hawkins, N. J.; Sanglard, D.; Gurr, S. J. Science 2018, 360, 739.
	(b) Huang, L. Biochem. Eng. J. 2019, 5, 135. (in Chinese)
	(黄亮, 生物化工, 2019, 5, 135.)
[5]	(a) Liu, C.; Shi, R.-J.; Han, L.-Y.; Huang, Y.-X.; Feng, J.-H; Zhou, C.-E. Dyeing Finish. 2023, 49, 74. (in Chinese)
	(刘畅, 石荣金, 韩璐怡, 黄雅驯, 冯嘉禾, 周嫦娥, 印染, 2023, 49, 74.)
	(b) Ma, W.; Tuo, T.-T.; Zhang, S.-F. Fine Chem. 2012, 29, 521. (in Chinese)
	(马威, 拓婷婷, 张淑芬, 精细化工, 2012, 29, 521.)
[6]	(a) Dong, A.; Wang, Y.-J.; Gao, Y.; Gao, T.; Gao, G. Chem. Rev. 2017, 117, 4806.
	(b) Chen, Y.; Wang, Z.; Zhang, C.; Xin, Y.; Li, L.; Han, Q.; Zhang, Q.; Teng, H. Cellulose 2023, 30, 3473.
	(c) Liu, Y.; Zhang, J.; Zhong, T.; Ren, X. Fibers Polym. 2023, 24, 845.
[7]	(a) Han, Y.-C.; Wang, Y.-L. Acta Chim. Sinica 2023, 81, 1196. (in Chinese)
	(韩玉淳, 王毅琳, 化学学报, 2023, 81, 1196.)
	(b) Wan, J.-S.; Li, H.; Zhang, S.-H.; Yan, J. Fine Chem. 2022, 39, 1320. (in Chinese)
	(万建升, 李红, 张世豪, 闫俊, 精细化工, 2022, 39, 1320.)
[8]	Li, L.-D.; Chi, X.-F.; Yan, J.-W.; Zhao, Z.-H. Chin. J. Org. Chem. 2018, 38, 955. (in Chinese)
	(李令东, 迟晓芳, 闫佳威, 赵梓含, 有机化学, 2018, 38, 955.)
[9]	Li, L.; Pu, T.; Zhanel, G.; Zhao, N.; Ens, W.; Liu, S. Adv. Healthc. Mater. 2012, 1, 609.
[10]	Ning, C.; Li, L.; Logsetty, S.; Ghanbar, S.; Guo, M.; Ens, W.; Liu, S. RSC Adv. 2015, 5, 93877.
[11]	Li, L.; Zhao, Y.; Zhou, H.; Ning, A.; Zhang, F.; Zhao, Z. Tetrahedron Lett. 2017, 58, 321.
[12]	Li, L.; Zhou, H.; Gai, F.; Chi, X.; Zhang, F.; Zhao, Z. RSC Adv. 2017, 7, 13244.
[13]	Li, L.; Jia, D.; Wang, H.; Chang, C.; Yan, J.; Zhao, Z. K. New J. Chem. 2020, 44, 303.
[14]	Li, L.; Wang, H.; Jia, D.; Wang, P. ChemistrySelect 2019, 4, 13198.
[15]	Hoque, J.; Konai, M. M.; Sequeira, S. S.; Samaddar, S.; Haldar, J. J. Med. Chem. 2016, 59, 10750.
[16]	Gilbert, P.; Moore, L. E. J. Appl. Microbiol. 2005, 99, 703.
[17]	Black, J. W.; Jenings, M. C.; Azarewicz, J.; Paniak, T. J.; Grenier, M. C.; Wuest, W. M.; Minbiole, K. P. C. Bioorg. Med. Chem. Lett. 2014, 24, 99.
[18]	Kaczerewska, O.; Brycki, B.; Ribosa, I.; Comelles, F.; Garci, M. T. J. Ind. Eng. Chem. 2018, 59, 141.
[19]	Seferyan, M. A.; Saverina, E. A.; Frolov, N. A.; Detusheva, E. V.; Kamanina, O. A.; Arlyapov, V. A.; Ostashevskaya, I. I.; Ananikov, V. P.; Vereshchagin, A. N. ACS Infect. Dis. 2023, 9, 1206.
[20]	Pisárčik, M.; Devínsky, F. Open Chem. 2014, 12, 577.
[21]	Danino, D.; Talmon, Y.; Zana, R. Langmuir 1995, 11, 1448.
[22]	Zhao, J.-X. Prog. Chem. 2014, 26, 1339. (in Chinese)
	(赵剑曦, 化学进展, 2014, 26, 1339.)
[23]	Jennings, J.; Ašćerić, D.; Semeraro, E, F.; Malanovic, N.; Pabst, G. ACS Appl. Mater. Interfaces 2023, 15, 40178.