C(2)-1,2,4-三氮唑取代的1,5-苯并硫氮杂䓬的合成及抑菌活性

doi:10.6023/cjoc202501011

摘要/Abstract

基于课题组前期研究发现的C(3)-1,2,4-三氮唑取代的1,5-苯并硫氮杂䓬, 以变换药效团在先导化合物分子骨架中的位置为策略, 设计合成了C(2)-1,2,4-三氮唑取代的1,5-苯并硫氮杂䓬Ⅳa~Ⅳf. 在合成C(2)和C(3)两个位置同时含有1,2,4-三氮唑取代的1,5-苯并硫氮杂䓬Ⅳ'a~Ⅳ'f时, 意外得到了喹啉衍生物Ⅴa~Ⅴf, 提出了Ⅴa~Ⅴf生成的可能历程. 测试了目标化合物Ⅳa~Ⅳf和Va~Vf的抑菌活性, Ⅳa~Ⅳf对新生隐球菌、白色念珠菌和金黄色葡萄球菌有中到高度的抑制作用, Va~Vf有轻度到中度的抑制作用, 其中Ⅳa对新生隐球菌和白色念珠菌的抑制作用均高于对照药物氟康唑. 这一结果对于开发抗真菌药物有一定的参考价值.

关键词: 1,2,4-三氮唑, 1,5-苯并硫氮杂䓬, 抑菌活性

Based on the C(3)-1,2,4-triazole substituted 1,5-benzothiazines discovered in the previous report, C(2)-1,2,4-tria- zole substituted 1,5-benzothiazines Ⅳa~Ⅳf were designed and synthesized by the strategy of changing the position of the pharmacophore in the molecular skeleton of the lead compound. Quinoline derivatives Ⅴa~Ⅴf were obtained accidentally during the synthesis of 1,5-benzothiazepines Ⅳ'a~Ⅳ'f containing 1,2,4-triazole at both C(2) and C(3), and the possible mechanism of Ⅴa~Ⅴf formation was studied. The antimicrobial activity of the target compounds Ⅳa~Ⅳf and Ⅴa~Ⅴf was tested, Ⅳa~Ⅳf showed moderate to high inhibitory effects on C. neoformans, C. albicansa and S. aureus, while Ⅴa~Ⅴf had mild to moderate inhibitory effects. The inhibitory effect of Ⅳa on C. neoformans and C. albicans was higher than that of control drug fluconazole. This result had certain reference value for the development of antifungal drugs.

Key words: 1,2,4-triazole, 1,5-benzothiazepine, antimicrobial activity

引用此文

鲁佳琪, 王紫薇, 张磊, 张萍. C(2)-1,2,4-三氮唑取代的1,5-苯并硫氮杂䓬的合成及抑菌活性[J]. 有机化学, 2025, 45(8): 2885-2895.

Jiaqi Lu, Ziwei Wang, Lei Zhang, Ping Zhang. Synthesis and Antimicrobial Activity of C(2)-1,2,4-Triazole Substituted 1,5-Benzothiazepines[J]. Chinese Journal of Organic Chemistry, 2025, 45(8): 2885-2895.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 8

图1. C-3上含有1,2,4-三氮唑取代的1,5-苯并硫氮杂䓬化合物

Figure 1. 1,5-Benzothiazepines with 1,2,4-triazole substitution on C-3

图式1. Ⅳa~Ⅳf和Ⅴa~Ⅴf的合成路线

Scheme 1. Synthetic route of compounds Ⅳa~Ⅳf and Ⅴa~Ⅴf

图2. 化合物1~5的结构

Figure 2. Structures of compounds 1~5

图式2. 化合物3的形成历程

Scheme 2. Formation mechanism of compound 3

图3. Ⅴc的晶体结构

Figure 3. Crystal structure of Ⅴc

图式3. 化合物Ⅴa的形成历程

Scheme 3. Formation mechanism of compound Ⅴa

图式4. 化合物6和7的形成历程

Scheme 4. Formation mechanism of compounds 6 and 7

Compd.	R	C. neoformans stand	C. neoformans clinical	C. albicans	E. coli	S. aureus
Ⅳa	H	27.5	27.5	23.07	20.5	20.1
Ⅳb	F	6.0	6.0	6.0	6.1	17.3
Ⅳc	Cl	14.1	12.8	12.7	6.0	16.7
Ⅳd	Br	11.8	11.7	13.9	6.0	16.6
Ⅳe	CH₃	6.0	6.0	6.0	6.0	16.4
Ⅳf	OCH₃	14.0	14.2	12.3	6.0	17.0
Ⅴa Ⅴb Ⅴc Ⅴd Ⅴe Ⅴf Fluconazol	H F Cl Br CH₃ OCH₃ —	6.0 7.5 7.3 6.0 8.1 7.2 22.4	9.3 9.6 11.7 10.3 9.6 10.8 22.4	6.0 6.0 7.9 6.0 6.0 7.0 20.2	6.0 6.0 6.0 6.0 6.0 8.5 —	11.3 8.5 8.5 6.0 7.0 7.8 —
Ciprofloxacin Hydrochloride	—	—	—	—	21.6	21.6

表1. 化合物Ⅳa~Ⅳf和Ⅴa~Ⅴf的抑菌活性(抑菌圈直径/mm) a,b

Table 1. Antimicrobial activity of compounds Ⅳa~Ⅳf and Ⅴa~Ⅴf (diameter of inhibition zone/mm) a,b

参考文献 32

[1]	Baburajeev, C. P.; Mohan, C. D.; Pandey, V.; Rangappa, S.; Shivalingegowda, N.; Kalash, L.; Devaraja, S.; Bender, A.; Lobie, P. E.; Rangappa, K. S.; Basappa Bioorg. Chem. 2019, 87, 142. doi: S0045-2068(18)30646-1 pmid: 30884308
[2]	Zhang, P.; Hu, H.-R.; Bian, S.-H.; Huang, Z.-H.; Chu, Y.; Ye, D.-Y. Eur. J. Med. Chem. 2013, 61, 95. doi: 10.1016/j.ejmech.2012.09.021 pmid: 23047001
[3]	Li, T.; Zhang, J.; Pan, J.; Wu, Z.; Hu, D.; Song, B. Eur. J. Med. Chem. 2017, 125, 657.
[4]	Dreyfuss, J.; Cohen, A. I.; Hess, S. M. J. Pharm. Sci. 1968, 57, 1505.
[5]	Feng, Z.-Y.; Wang, Z.-G. J. Psychiatry 2010, 23, 475 (in Chinese).
	(冯志颖, 王中刚, 精神医学杂志, 2010, 23, 475.)
[6]	Saha, D.; Jain, G.; Sharma, A. RSC Adv. 2015, 5, 70619.
[7]	Chaffmann, M.; Brogden, R. N. Drugs 1985, 29, 387. pmid: 3891302
[8]	Kawakita, S.; Kinoshita, M.; Ishikawa, H.; Kagoshima, T.; Katori, R.; Ishikawa, K.; Hirota, Y. Clin. Cardiol. 1991, 14, 53. pmid: 2019030
[9]	Morlion, F.; Magdalenic, K.; Camp, J. V.; D'hooghe, M. Monatsh. Chem. 2024, 155, 535.
[10]	Wang, B.; Wang, L.-R.; Liu, L.-L.; Wang, W.; Man, R.-J.; Zheng, D.-J.; Deng, Y.-S.; Yang, Y.-S.; Xu, C.; Zhu, H.-L. Bioorg. Chem. 2021, 108, 104585.
[11]	Balaji, P. N.; Kamsali, M.; Kamsali, A. Asian J. Pharm. Pharmacol. 2020, 6, 261.
[12]	Xu, T.-X.; Wang, Y.; Tian, K.-Q.; Wang, R.-R.; Yan, J.-Y.; Zhang, P. Chin. J. Org. Chem. 2018, 38, 2731 (in Chinese).
	(许同绣, 王岩, 田克情, 王冉冉, 闫静怡, 张萍, 有机化学, 2018, 38, 2731.) doi: 10.6023/cjoc201804029
[13]	Shaik, A. B.; Prasad, Y. R. J. Int. Acad. Phys. Sci. 2021, 25, 165.
[14]	Frimayanti, N.; Yaeghoobi, M.; Namavar, H.; Ikhtiarudin, I.; Afzali, M. J. Appl. Pharm. Sci. 2020, 10, 86.
[15]	Ayral, E.; Gloanec, P.; Bergé, G.; de Nanteuil, G.; Mennecier, P.; Rupin, A.; Verbeuren, T. J.; Fulcrand, P.; Martinez, J.; Hernandez, J. F. Bioorg.Med. Chem. Lett. 2009, 19, 1386.
[16]	Slade, J.; Stanton, J. L.; Ben-David, D.; Mazzenga, G. C. J. Med. Chem. 1985, 28, 1517. pmid: 2995670
[17]	Lo, W.-H.; Deng, F.-H.; Chang, C.-J.; Lin, C.-H. Molecules 2020, 25, 5114.
[18]	Cai, D. Da Yisheng 2024, 9, 10 (in Chinese).
	(蔡丹, 大医生, 2024, 9, 10.)
[19]	Göbel, C. H.; Heinze, A.; Cirkel, A.; Göbel, H. Pain Ther. 2024, 13, 813. doi: 10.1007/s40122-024-00625-2 pmid: 38886287
[20]	Fagiolini, A.; González-Pinto, A.; Miskowiak, K. W.; Morgado, P.; Young, A. H.; Vieta, E. Ann. Gen. Psychiatr. 2023, 22, 1.
[21]	Cairns, J.; Ingle, J. N.; Kalari, K. R.; Goetz, M. P.; Weinshilboum, R. M.; Gao, H.-Y.; Li, H.; Bari, M. G.; Wang, L.-W. Mol. Cancer Ther. 2022, 21, 206.
[22]	Mayor, J.; Engler, O.; Rothenberger, S. Microorganisms 2021, 9, 1306.
[23]	Li, Y.-P.; Shi, L.; Min, H.; Wang, Y.-L.; Cao, X. Modern Agrochem. 2020, 19, 53 (in Chinese).
	(李永平, 石磊, 闵红, 王雅丽, 曹溪, 现代农药, 2020, 19, 53.)
[24]	Jones, P. Plant Pathol. 1997, 46, 946.
[25]	Shahzadi, I.; Zahoor, A. F.; Rasul, A.; Shahzadi, I.; Mansha, A.; Ahmad, S.; Raza, Z. ACS Omega 2021, 6, 11943. doi: 10.1021/acsomega.1c00424 pmid: 34056349
[26]	Blokhina, S. V.; Sharapova, A. V.; Olkhovich, M. V.; Doroshenko, I. A.; Levshin, I. B.; Perlovich, G. L. Bioorg. Med. Chem. Lett. 2021, 40, 127944.
[27]	Ishmetova, R. I.; Ganebnykh, I. N.; Ignatenko, N. K.; Tolshchina, S. G.; Korotina, A. V.; Eltsov, O. S.; Kravchenko, M. A.; Rusinov, G. L. Russ. Chem. Bull. 2021, 70, 1093.
[28]	Wang, Y.; Kong, L.-M.; Wang, R.-R.; Tian, K.-Q.; Zhang, P. Chin. J. Org. Chem. 2019, 39, 2663 (in Chinese).
	(王岩, 孔令满, 王冉冉, 田克情, 张萍, 有机化学, 2019, 39, 2663.) doi: 10.6023/cjoc201901041
[29]	Sun, Y.-J.; Wang, Z.-W.; Wang, Y.; Xu, T.-X.; Tian, K.-Q.; Zhang, P. Chin. J. Org. Chem. 2021, 41, 2361 (in Chinese).
	(孙雨佳, 王紫薇, 王岩, 许同绣, 田克情, 张萍, 有机化学, 2021, 41, 2361.) doi: 10.6023/cjoc202012044
[30]	Joule, J. A.; Mills, K. Heterocyclic Chemistry, A John Wiley & Sons Ltd, New York, 2010, p. 558.
[31]	Wu, Y.-Y.; Tian, K.-Q.; Yang, T.; Du, X.-Q.; Zhang, P. Chin. J. Org. Chem. 2013, 33, 1465 (in Chinese).
	(武云云, 田克情, 杨田, 杜星琼, 张萍, 有机化学, 2013, 33, 1465.) doi: 10.6023/cjoc201212027
[32]	Xing, Q.-Y.; Xu, R.-Q.; Zhou, Z.; Pei, W.-W. Basic Organic Chemistry, Higher Education Press, Beijing, 1994, p. 940 (in Chinese).
	(邢其毅, 徐瑞秋, 周政, 裴伟伟, 基础有机化学, 高等教育出版社, 北京, 1994, p. 940.)