Synthesis and Antibacterial Activity Evaluation of Guanidine Hydrazone Derivatives Containing Linear Alkanes

doi:10.6023/cjoc202210029

Chinese Journal of Organic Chemistry ›› 2023, Vol. 43 ›› Issue (6): 2163-2170.DOI: 10.6023/cjoc202210029 Previous Articles Next Articles

含直链烷烃的胍基腙衍生物的合成及其抗菌活性评价

宋明霞^a, 朱洋女^a, 王世帅^c, 黄玉萍^d, 邓先清^a^,^*(), 黄玉珊^b^,^*()

a 井冈山大学医学部江西吉安 343009
b 赣南医学院第一附属医院循证医学与临床研究中心江西赣州 341000
c 赣南医学院心脑血管疾病防治教育部重点实验室江西赣州 341000
d 赣南医学院生物化学与分子生物学系江西赣州 341000

收稿日期:2022-10-24 修回日期:2022-12-05 发布日期:2023-01-05
基金资助:
国家自然科学基金(81560561); 江西省自然科学基金(20224ACB206044)

Synthesis and Antibacterial Activity Evaluation of Guanidine Hydrazone Derivatives Containing Linear Alkanes

Mingxia Song^a, Yangnv Zhu^a, Shishuai Wang^c, Yuping Huang^d, Xianqing Deng^a,*(), Yushan Huang^b,*()

a School of Medicine, Jinggangshan University, Ji'an, Jiangxi 343009
b Center for Evidence Based Medical and Clinical Research, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000
c Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases,Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000
d Department of Biochemistry and Molecular Biology, Gannan Medical University, Ganzhou, Jiangxi 341000

Received:2022-10-24 Revised:2022-12-05 Published:2023-01-05
Contact: * E-mail: dengxinqing1121@126.com;3218680@qq.com
Supported by:
National Natural Science Foundation of China(81560561); Natural Science Foundation of Jiangxi Province(20224ACB206044)

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Abstract

The rise of antibiotic resistance and the declining discovery of new antibiotics have created a global health crisis. To obtain effective antibacterial agents and relieve bacterial resistance, a series of novel guanidine hydrazones containing linear alkanes were designed and synthesized. The antimicrobial activities of these compounds were evaluated against five gram-positive strains, four gram-negative strains and four multidrug-resistant strains. All of the targets except (E)-2-hexyli- denehydrazine-1-carboximidamide (1a) exhibited a different degree of antibacterial properties with minimum inhibitory concentration (MIC) in 0.5~64 μg/mL. Among them, (E)-2-dodecylidenehydrazine-1-carboximidamide (1d), (E)-2-tetradecyli- denehydrazine-1-carbox-imidamide (1e), (E)-2-(4-(heptyloxy)benzylidene)hydrazine-1-carboximidamide (2d) and (E)-2-(4- (octyloxy)benzylidene)hydrazine-1-carbox-imidamide (2e) showed equivalent or better antibacterial activity than penicillin and norfloxacin against strains 33693, 29212, 63501, 10104 and 43300. Excellent bactericidal properties of 2d and low frequency of bacteria developing resistance toward 2d were established. The cytotoxicity evaluation showed that the target compounds had certain cytotoxicity, but no cytotoxicity was found under the concentration of antibacterial activity. Molecular docking of 2d with LpxC was performed, which demonstrated that 2d has a forceful binding with LpxC. These findings strongly support the assumption that guanidine hydrazone coupled with linear alkane is a potential skeleton to develop new antimicrobial agents.

Key words: guanidine hydrazone, antimicrobial, linear alkane, resistance

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Mingxia Song, Yangnv Zhu, Shishuai Wang, Yuping Huang, Xianqing Deng, Yushan Huang. Synthesis and Antibacterial Activity Evaluation of Guanidine Hydrazone Derivatives Containing Linear Alkanes[J]. Chinese Journal of Organic Chemistry, 2023, 43(6): 2163-2170.

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Fig. & Tab. 10

References 24

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Compd.	R	Gram-positive strain					Gram-negative strain
Compd.	R	26003^a	25923^b	33693^c	29212^d	63501^e	25922^f	44568^g	27853^h	10104ⁱ
1a	C₅H₁₁	>64	>64	>64	>64	>64	>64	>64	>64	>64
1b	C₇H₁₅	64	64	64	64	64	64	64	64	64
1c	C₉H₁₉	0.5	8	16	8	2	8	8	16	8
1d	C₁₁H₂₃	0.5	2	2	2	1	2	2	8	2
1e	C₁₃H₂₇	0.5	8	1	1	0.5	2	4	16	2
1f	C₁₅H₃₁	4	64	8	16	8	>64	>64	>64	>64
2a	C₄H₉	4	2	16	16	4	32	16	16	16
2b	C₅H₁₁	4	2	8	4	2	8	8	8	8
2c	C₆H₁₃	2	2	2	2	2	8	4	8	4
2d	C₇H₁₅	0.5	0.5	1	1	1	4	4	8	2
2e	C₈H₁₇	0.5	0.5	1	1	1	8	8	32	4
Penicillin	—	0.125	0.125	0.125	128	128	128	>128	>128	32
Norfloxacin	—	0.125	0.125	16	1	2	0.125	0.125	2	4

Compd.	R	Gram-positive strain					Gram-negative strain
Compd.	R	26003^a	25923^b	33693^c	29212^d	63501^e	25922^f	44568^g	27853^h	10104ⁱ
1a	C₅H₁₁	>64	>64	>64	>64	>64	>64	>64	>64	>64
1b	C₇H₁₅	64	64	64	64	64	64	64	64	64
1c	C₉H₁₉	0.5	8	16	8	2	8	8	16	8
1d	C₁₁H₂₃	0.5	2	2	2	1	2	2	8	2
1e	C₁₃H₂₇	0.5	8	1	1	0.5	2	4	16	2
1f	C₁₅H₃₁	4	64	8	16	8	>64	>64	>64	>64
2a	C₄H₉	4	2	16	16	4	32	16	16	16
2b	C₅H₁₁	4	2	8	4	2	8	8	8	8
2c	C₆H₁₃	2	2	2	2	2	8	4	8	4
2d	C₇H₁₅	0.5	0.5	1	1	1	4	4	8	2
2e	C₈H₁₇	0.5	0.5	1	1	1	8	8	32	4
Penicillin	—	0.125	0.125	0.125	128	128	128	>128	>128	32
Norfloxacin	—	0.125	0.125	16	1	2	0.125	0.125	2	4

Compd.	R	Multidrug-resistant Gram-positive strain		Multidrug-resistant Gram-negative strain
Compd.	R	43300^a	33591^b	BAA-196^c	BAA-2111^d
1b	C₇H₁₅	64	64	64	64
1c	C₉H₁₉	4	4	8	16
1d	C₁₁H₂₃	0.5	1	2	4
1e	C₁₃H₂₇	0.5	1	1	16
1f	C₁₅H₃₁	>64	4	64	>64
2a	C₄H₉	4	16	16	32
2b	C₅H₁₁	2	8	8	16
2c	C₆H₁₃	1	4	4	16
2d	C₇H₁₅	0.5	4	2	32
2e	C₈H₁₇	0.5	8	2	64
Penicillin	—	32	>32	>32	>32
Norfloxacin	—	0.5	0.25	0.5	1

Compd.	R	Multidrug-resistant Gram-positive strain		Multidrug-resistant Gram-negative strain
Compd.	R	43300^a	33591^b	BAA-196^c	BAA-2111^d
1b	C₇H₁₅	64	64	64	64
1c	C₉H₁₉	4	4	8	16
1d	C₁₁H₂₃	0.5	1	2	4
1e	C₁₃H₂₇	0.5	1	1	16
1f	C₁₅H₃₁	>64	4	64	>64
2a	C₄H₉	4	16	16	32
2b	C₅H₁₁	2	8	8	16
2c	C₆H₁₃	1	4	4	16
2d	C₇H₁₅	0.5	4	2	32
2e	C₈H₁₇	0.5	8	2	64
Penicillin	—	32	>32	>32	>32
Norfloxacin	—	0.5	0.25	0.5	1

Compd.	IC₅₀/(µmol•L^–1)
1a	100.3
1b	95.8
1c	86.6
1d	57.4
1e	79.2
1f	117.5
2a	56.2
2b	61.8
2c	74.4
2d	45.3
2e	62.5

含直链烷烃的胍基腙衍生物的合成及其抗菌活性评价

Synthesis and Antibacterial Activity Evaluation of Guanidine Hydrazone Derivatives Containing Linear Alkanes

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