Synthesis, Antibacterial Activity and Mechanism Research of 1,3,4-Oxadiazole and 1,2,4-Triazole Derivatives Containing Disulfide Bond

doi:10.6023/cjoc202311022

Chinese Journal of Organic Chemistry ›› 2024, Vol. 44 ›› Issue (6): 2014-2026.DOI: 10.6023/cjoc202311022 Previous Articles Next Articles

ARTICLES

含二硫键的1,3,4-噁二唑和1,2,4-三唑衍生物的合成、抗菌活性及机制研究

邱雪梅^a, 胡伟男^a, 王文航^a, 覃丽清^a, 祝丹雪^a, 杨孟芝^a, 邵利辉^a^,^b, 谭画元^a, 王钦^a, 李洙锐^a^,^b, 陈丹萍^a^,^*(), 王贞超^a^,^b^,^c^,^*()

a 贵州大学药学院贵阳 550025
b 贵州大学绿色农药全国重点实验室贵阳 550025
c 贵州大学贵州省合成药物工程实验室贵阳 550025

收稿日期:2023-11-22 修回日期:2023-12-31 发布日期:2024-02-19
基金资助:
国家自然科学基金(22007022); 国家自然科学基金(32360689); 国家自然科学基金(22364008); 国家自然科学基金(32260694); 国家自然科学基金(21867004); 贵州省自然科技基金(ZZK[2021]034); 贵州省教育厅科技拔尖人才计划(2022075)

Synthesis, Antibacterial Activity and Mechanism Research of 1,3,4-Oxadiazole and 1,2,4-Triazole Derivatives Containing Disulfide Bond

Xuemei Qiu^a, Weinan Hu^a, Wenhang Wang^a, Liqing Qin^a, Danxue Zhu^a, Mengzhi Yang^a, Lihui Shao^a^,^b, Huayuan Tan^a, Qin Wang^a, Zhurui Li^a^,^b, Danping Chen^a,*(), Zhenchao Wang^a^,^b^,^c,*()

a School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025
b National Key Laboratory of Green Pesticide, Guizhou University, Guiyang 550025
c Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025

Received:2023-11-22 Revised:2023-12-31 Published:2024-02-19
Contact: * E-mail: wzc.4884@163.com; dpchen@gzu.edu.cn
Supported by:
National Natural Science Foundation of China(22007022); National Natural Science Foundation of China(32360689); National Natural Science Foundation of China(22364008); National Natural Science Foundation of China(32260694); National Natural Science Foundation of China(21867004); Guizhou Provincial Natural Science Foundation(ZZK[2021]034); Top Science and Technology Talent Program of Guizhou Education Department(2022075)

1. .pdf(8918KB)

Abstract

In order to explore novel antibacterial agents, a series of newly designed and synthesized 1,3,4-oxadiazole derivatives (series X) and 1,2,4-triazole derivatives (series M) incorporating disulfide bond were subjected to antibacterial activities evaluation. Interestingly, both series X and series M showed good antibacterial activity against Xanthomonas oryzae pv. Oryzae (Xoo). Among them, 3-(5-(isobutyldisulfaneyl)-4H-1,2,4-triazol-3-yl)-1H-indole (M1) exhibited potent antiba- cterial activity against Xoo, with EC₅₀ value of (1.51±0.24) μg/mL, surpassing those of thiodiazole copper [(87.97±4.79) μg/mL] and bismerthiazol [(66.88±4.06) μg/mL]. In rice plants, compound M1 exhibited superior antibacterial activity to the bismerthiazol. The curative and protective effects of compound M1 on rice were 42.37% and 38.64%, respectively, surpassing the curative and protective effects of bismerthiazol (37.49% and 36.55%). Furthermore, through relevant studies on the mechanism of compound M1, it was demonstrated that compound M1 inhibits the formation of biofilms in Xoo, elevates the level of reactive oxygen species in the bacteria, and induces morphological changes. Proteomic analysis revealed that compound M1 down-regulated the adenosine triphosphate-binding cassette (ABC) transporters, which impacts adenosine triphosphate (ATP) decomposition and phosphorus transport in rice bacterial blight. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) demonstrated that compound M1 was experimentally antibacterial by down-regulating related genes in the phosphate special transport (pst) system of the ABC transporters.

Key words: disulfide bond, rice bacterial blight, proteomics, adenosine triphosphate-binding cassette (ABC) transporters

Cite this article

Xuemei Qiu, Weinan Hu, Wenhang Wang, Liqing Qin, Danxue Zhu, Mengzhi Yang, Lihui Shao, Huayuan Tan, Qin Wang, Zhurui Li, Danping Chen, Zhenchao Wang. Synthesis, Antibacterial Activity and Mechanism Research of 1,3,4-Oxadiazole and 1,2,4-Triazole Derivatives Containing Disulfide Bond[J]. Chinese Journal of Organic Chemistry, 2024, 44(6): 2014-2026.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 9

Figure 1. Design strategy of the target compounds

Scheme 1. Synthetic route of 1,3,4-oxadiazole and 1,2,4-triazole derivatives Reagents and conditions: (A) NH2NH2•H2O, reflux; (B) CS2, KOH, EtOH, reflux; (C) HCl, pH=3~4; (D) SO2Cl2, CH2Cl2, 0~5 ℃; (E) C2H5OC2H5, room temperature; (F) KSCN, HCl, H2O, reflux; (G) (1) 4% NaOH, reflux; (2) HCl, pH=3~4

Compd.	Toxic regression equation	R²	EC₅₀^a/(μg•mL^–1)
X1	y=2.8392x+3.8619	0.9133	2.52±0.33
X2	y=3.5872x+3.0149	0.9512	3.58±0.12
X3	y=2.6741x+4.1261	0.9595	2.12±0.37
X4	y=2.6796x+2.1937	0.9795	11.15±3.78
X5	y=4.1284x+2.4310	0.9106	4.19±0.17
X6	y=1.8622x+3.8906	0.9673	3.94±0.43
X7	y=1.8761x+3.1762	0.9624	9.38±0.56
X8	y=1.2684x+4.0827	0.9499	5.29±0.35
X9	y=2.2436x+3.4254	0.9899	5.03±0.24
X10	y=3.6527x+3.0943	0.9015	2.72±0.35
X11	y=0.9789x+3.8225	0.9324	15.95±1.12
X12	y=1.7160x+3.4499	0.9789	8.00±0.37
X13	y=2.1875x+4.2470	0.9530	2.21±0.86
X14	y=1.5112x+4.3272	0.9826	2.79±0.22
X15	y=4.1328x+1.3607	0.9298	7.60±1.61
X16	y=2.9360x+4.3037	0.9705	1.73±0.40
M1	y=2.9499x+4.4688	0.9781	1.51±0.24
M2	y=3.0540x+4.1412	0.9920	1.91±0.05
M3	y=3.8150x+2.4660	0.9945	4.61±0.11
M4	y=3.5955x+3.8988	0.9878	2.02±0.17
M5	y=2.1930x+3.7662	0.9677	3.65±0.56
M6	y=2.4115x+3.7829	0.9754	3.19±0.11
M7	y=3.5519x+1.5782	0.9669	9.19±1.22
M8	y=2.6874x+3.1483	0.8722	4.89±0.19
M9	y=3.4748x+4.2098	0.9654	1.69±0.62
M10	y=2.3466x+3.7859	0.9328	3.29±0.22
BT^b	y=4.0040x–2.3086	0.9381	66.88±4.06
TC^b	y=4.4997x–3.7491	0.9942	87.97±4.79

Table 1. EC50 results of X1~X16 and M1~M10 against Xoo

Figure 2. Structure-activity relationship of the disulfide bearing 1,3,4-oxadiazole and 1,2,4-triazole derivatives

Compd.	Curative effect			Protective effect
Compd.	Morbidity/%	Disease index/%	Control efficiency^a/%	Morbidity/%	Disease index/%	Control efficiency^a/%
M1	100	54.49	42.37	100	58.02	38.64
BT	100	59.11	37.49	100	60.00	36.55
CK^b	100	94.56	—	100	94.56	—

Table 2. Protective and curative activities of compound M1 against rice bacterial blight at 200 µg/mL

Figure 3. SEM images for the changes in the cell morphologies of Xoo after treatment with compound M1 at different concentrations (A) 0, (B) 12.5, (C) 25 and (D) 50 μg/mL (scale bar: 2.0 μm)

Figure 4. (A) Biofilm formation of compound M1 (from 0 to 100 μg/mL); (B, C) ROS detection of compound M1 (from 0 to 100 μg/mL)

Figure 5. Proteomic analysis (A) Volcano plot of differentially expressed proteins; (B) Gene Ontology (GO) enrichment analysis; (C) and (D) KEGG enrichment analysis: (C) up-regulated and (D) down-regulated; (E) Analysis of differential down-regulated proteins in KEGG pathway.

Figure 6. Amplification curve and the relative expression level of genes of RT-qPCR The pstB and phoB amplification curve. (A) The relative expression level of pstB and phoB genes. (B) The pstA and pstC amplification curve. (C) The relative expression level of pstA and pstC genes. (D) The pstS and phoU amplification curve. (E) The relative expression level of pstS and phoU genes. (F) ** for P<0.01, *** for P<0.001, **** for P<0.001, ns: not significant; One-way ANOVA followed by Dunnettʼs multiple comparisons test was performed using GraphPad Prism.

References 45

[1]	Mansfield, J.; Genin, S.; Magori, S.; Citovsky, V.; Sriariyanum, M.; Ronald, P.; Dow, M.; Verdier, V.; Beer, S. V.; Machado, M. A. Mol. Plant Pathol. 2012, 13, 614.
[2]	Ray, M.; Ray, A.; Dash, S.; Mishra, A.; Achary, K. G.; Nayak, S.; Singh, S. Biosens. Bioelectron. 2017, 87, 708.
[3]	Strange, R. N.; Scott, P. R. Annu. Rev. Phytopathol. 2005, 43, 83.
[4]	Deng, Y.; Liu, H. B.; Zhou, Y.; Zhang, Q. L.; Li, X. H.; Wang, S. P. Mol. Breed. 2018, 38. 18.
[5]	Scholthof, K. B.; Adkins, S.; Czosnek, H.; Palukaitis, P.; Jacquot, E.; Hohn, T.; Hohn, B.; Saunders, K.; Candresse, T.; Ahlquist, P. Mol. Plant Pathol. 2011, 12, 938.
[6]	Silva, A. R.; Andrade Neto, J. B.; Silva, C. R.; Sousa Campos, R.; Costa Silva, R. A.; Freitas, D. D.; Nascimento, F. B.; Andrade, L. N. D.; Sampaio, L. S.; Grangeiro, T. B. Antimicrob. Agents Chemo- ther. 2016, 60, 3551.
[7]	Wang, L. L.; Li, C.; Zhang, Y. Y.; Qiao, C. H.; Ye, Y. H. J. Agric. Food Chem. 2013, 61, 8632.
[8]	Zhang, J.; Peng, J. F.; Wang, T.; Kang, Y.; Jing, S. S.; Zhang, Z. T. Mol. Diversity 2017, 21, 317.
[9]	Li, L. X.; Jiao, J.; Wang, X. B.; Chen, M.; Fu, X. C.; Si, W. J.; Yang, C. L. Molecules 2018, 23, 746.
[10]	Song, B. A. Pestic. Biochem. Physiol. 2018, 147, 1.
[11]	Xu, W. M.; Han, F. F.; He, M.; Hu, D. Y.; He, J.; Yang, S.; Song, B. A. J. Agric. Food Chem. 2012, 60, 1036.
[12]	Yuan, W. C.; Yu, Z. W.; Song, W. Q.; Li, Y. N.; Fang, Z. Y.; Zhu, B. Z.; Li, X. M.; Wang, H.; Hong, W.; Sun, N. Infect. Drug Resist. 2019, 12, 2283.
[13]	Labriere, C.; Gong, H.; Finlay, B. B.; Reiner, N. E.; Young, R. N. Eur. J. Med. Chem. 2017, 125, 1.
[14]	Jiang, L. L.; Tan, Y.; Zhu, X. L.; Wang, Z. F.; Zuo, Y.; Chen, Q.; Xi, Z.; Yang, G. F. J. Agric. Food Chem. 2010, 58, 2643.
[15]	Kandemir, H.; Ma, C.; Kutty, S. K.; Black, D. S.; Griffith, R.; Lewis, P. J.; Kumar, N. Bioorg. Med. Chem. 2014, 22, 1672.
[16]	Siwach, A.; Verma, P. K. BMC Chem. 2020, 14, 70.
[17]	Zhou, L.; Wang, P. Y.; Zhou, J.; Shao, W. B.; Fang, H. S.; Wu, Z. B. J. Saudi Chem. Soc. 2017, 21, 852.
[18]	Fan, Z. J.; Shi, J.; Bao, X. P. Mol. Diversity 2018, 22, 657.
[19]	Gao, F.; Wang, T.; Xiao, J.; Huang, G. Eur. J. Med. Chem. 2019, 173, 274.
[20]	Shang, J.; Wang, W. M.; Li, Y. H.; Song, H. B.; Li, Z. M.; Wang, J. G. J. Agric. Food Chem. 2012, 60, 8286.
[21]	Wang, J. R.; Hu, Y. M.; Zhou, H.; Li, A. P.; Zhang, S. Y.; Luo, X. F.; Zhang, B. Q.; An, J. X.; Zhang, Z. J.; Liu, Y. Q. J. Agric. Food Chem. 2022, 70, 11782.
[22]	Tian, K.; Li, X. Q.; Zhang, L.; Gan, Y. Y.; Meng, J.; Wu, S. Q.; Wan, J. L.; Xu, Y.; Cai, C. T.; Ouyang, G. P. Chem. Pap. 2018, 73, 17.
[23]	Wei, Z. Y.; Cui, B. R.; Cui, X.; Wu, Y. L.; Fu, Y.; Liu, L. P.; Piao, H. R. Chem. Biol. Drug Des. 2017, 89, 47.
[24]	Fong, J.; Yuan, M. J.; Jakobsen, T. H.; Mortensen, K. T.; Delos Santos, M. M.; Chua, S. L.; Yang, L.; Tan, C. H.; Nielsen, T. E.; Givskov, M. J. Med. Chem. 2017, 60, 215.
[25]	Huang, Y. Y.; Xu, Y. X.; Song, R. R.; Ni, S. S.; Liu, J. Q.; Xu, Y. H.; Ren, Y. L.; Rao, L.; Wang, Y. J.; Wei, L.; Feng, L. L.; Su, C.; Peng, C.; Li, J.; Wan, J. J. Med. Chem. 2020, 63, 6238.
[26]	Li, P.; Hu, D. Y.; Xie, D. D.; Chen, J. X.; Jin, L. H.; Song, B. A. J. Agric. Food Chem. 2018, 66, 3093.
[27]	Wang, S.; Zhao, Y.; Breslawec, A. P.; Liang, T.; Deng, Z.; Kuperman, L. L.; Yu, Q. npj Biofilms Microbiomes 2023, 9, 63.
[28]	Wuichet, K.; Cantwell, B. J.; Zhulin, I. B. Curr. Opin. Microbiol. 2010, 13, 219.
[29]	Lewis, V. G.; Ween, M. P.; McDevitt, C. A. Protoplasma 2012, 249, 919.
[30]	Yuan, Z. C.; Zaheer, R.; Finan, T. M. J. Bacteriol. 2006, 188, 1089.
[31]	Spira, B.; Aguena, M.; de Castro Oliveira, J. V.; Yagil, E. Mol. Genet. Genomics 2010, 284, 489.
[32]	Hudek, L.; Premachandra, D.; Webster, W. A.; Brau, L. Appl. Environ. Microbiol. 2016, 82, 6344.
[33]	Neznansky, A.; Blus-Kadosh, I.; Yerushalmi, G.; Banin, E.; Opatowsky, Y. FASEB J. 2014, 28, 5223.
[34]	Vuppada, R. K.; Hansen, C. R.; Strickland, K. A. P.; Kelly, K. M.; McCleary, W. R. BMC Microbiol. 2018, 18. 8.
[35]	Tan, Y.; Ma, S.; Leonhard, M.; Moser, D.; Haselmann, G. M.; Wang, J.; Eder, D.; Schneider-Stickler, B. Carbohydr. Polym. 2018, 200, 35.
[36]	Ajiboye, T. O.; Aliyu, M.; Isiaka, I.; Haliru, F. Z.; Ibitoye, O. B.; Uwazie, J. N.; Muritala, H. F.; Bello, S. A. Chem.-Biol. Interact. 2016, 258, 276.
[37]	Peng, J.; Zhang, Y.; Liu, X.; Zou, Y.; Song, H. Y.; Wang, S.; Cai, Q. F.; Chen, J. X.; Hu, D. Y. Pestic. Biochem. Physiol. 2023, 193, 105457.
[38]	Wu, Q.; Cai, H.; Yuan, T.; Li, S. Y.; Gan, X. H.; Song, B. A. Bioorg. Med. Chem. Lett. 2020, 30, 127113.
[39]	Xiang, J.; Liu, D. Y.; Chen, J. X.; Hu, D. Y.; Song, B. A. Pestic. Biochem. Physiol. 2020, 170, 104695.
[40]	Shi, J.; Ding, M. H.; Luo, N.; Wan, S. R.; Li, P. J.; Li, J. H.; Bao, X. P. J. Agric. Food Chem. 2020, 68, 9613.
[41]	Tao, Q. Q.; Liu, L.W.; Wang, P. Y.; Long, Q. S.; Zhao, Y. L.; Jin, L. H.; Xu, W. M.; Chen, Y.; Li, Z.; Yang, S. J. Agric. Food Chem. 2019, 67, 7626.
[42]	Habartova, K.; Havelek, R.; Seifrtova, M.; Kralovec, K.; Cahli- kova, L.; Chlebek, J.; Cermakova, E.; Mazankova, N.; Marikova, J.; Kunes, J. Sci. Rep. 2018, 8, 4829.
[43]	Shafiei, S. N. S.; Ahmad, K.; Ikhsan, N. F. M.; Ismail, S. I.; Sijam, K. Braz. J. Biol. 2021, 81, 11.
[44]	Long, X. S.; Zhang, G. L.; Long, H. T.; Wang, Q.; Wang, C. Y.; Zhu, M.; Wang, W. H.; Li, C. P.; Wang, Z. C.; Ouyang, G. P. Int. J. Mol. Sci. 2023, 24, 10900.
[45]	Chakravortty, D.; Yu, X.; Liang, X.; Liu, K.; Dong, W.; Wang, J.; Zhou, M. G. Plos One 2015, 10, e0134237.

含二硫键的1,3,4-噁二唑和1,2,4-三唑衍生物的合成、抗菌活性及机制研究

Synthesis, Antibacterial Activity and Mechanism Research of 1,3,4-Oxadiazole and 1,2,4-Triazole Derivatives Containing Disulfide Bond

RichHTML

PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

Fig. & Tab. 9

References 45

Related Articles 6

Recommended Articles

Metrics

Comments

[1]	Yannan Ma, Ya'ni Liu, Jinyan Wang, Xitong Chen, Hao Yin, Qiaona Chi, Shixi Jia, Shanshan Du, Yunkun Qi, Kewei Wang. DIC/Oxyma Based Efficient Synthesis and Activity Evaluation of Spider Peptide Toxin GsMTx4 [J]. Chinese Journal of Organic Chemistry, 2022, 42(2): 498-506.
[2]	Jinyan Wang, Liying Dong, Ya'ni Liu, Xitong Chen, Yannan Ma, Hao Yin, Shanshan Du, Yunkun Qi, Kewei Wang. Efficient Synthesis and Oxidative Folding Studies of Centipede Toxin RhTx [J]. Chinese Journal of Organic Chemistry, 2021, 41(7): 2800-2809.
[3]	LI Ling-Dong,b,TANG Wei,b,LIU Wu-Jun,b,ZHAO Zong-Bao*^,a. Synthesis and Activity of the Photoaffinity-Labeled Functional Probe Based on Prenyl Side-Chain [J]. Chin. J. Org. Chem., 2008, 28(03): 489-493.
[4]	HUANG Xiao-Yi, WANG Tao, XIA Chuan-Qin, YU Xiao-Qi, XIE Ru-Gang. Synthesis of Novel Disulfide Bond-Bearing Cyclopeptides [J]. Chinese Journal of Organic Chemistry, 2004, 24(12): 1629-1632.
[5]	Jiang Hui;Zhong Mingnai;Chen Jisheng;Miao Zhenwei. The advances in the synthesis of multiple disulfide bond-containing peptides [J]. Chin. J. Org. Chem., 1999, 19(3): 214-223.
[6]	Wang Liangyou;Pan Heping;Chen Zhengying. Methods of disulfide formation in peptide synthesis [J]. Chin. J. Org. Chem., 1998, 18(6): 576-580.