Studies on the Synthesis, Structural Characterization and Biological Activities of Novel Caffeine Derivatives Containing Substituted-Piperazine Moiety

doi:10.6023/cjoc202105020

Abstract

Based on a strategy of introducing the “piperazine” bioactive group into 8-position of caffeine, sixteen novel caffeine derivatives containing substituted-piperazine moiety (Ia~Ip) have been synthesized using 8-chlorotheophylline and substituted-piperazine as materials, via multi step reactions of N-methylation, nucleophilic substitution, (protection)deprotection, etc. The structures of the title compounds were confirmed and characterized by melting point, ¹H NMR, ¹³C NMR, and HRMS. The single-crystal structure of 8-(4-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl)piperazin- 1-yl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (Ip) was obtained. The bioassay results showed that most of the title compounds possess good insecticidal activities against Plutella xylostella L. and Mythimna separata Walker. In particular, some of the compounds exhibited better larvicidal effect towards Plutella xylostella L. than that of control caffeine, among which 8-(4-(4-fluorophenyl)piperazin-1-yl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (Ie) and 1,3,7-trimethyl-8-(4-(4- nitrobenzoyl)piperazin-1-yl)-3,7-dihydro-1H-purine-2,6-dione (In) at a test concentration of 100 mg•L^–1 held lethality rate of 60% and 53%, respectively. In addition, partial compounds at 50 mg•L^–1 concentration possessed >50% fungicidal activities against Physalospora piricola, Rhizoctonia cerealis, Sclerotinia sclerotiorum, etc. The research results in this paper provide useful reference for further design of novel agrochemicals based on the natural product structure of xanthine.

Key words: xanthine, caffeine, piperazine, synthesis, insecticidal activity, fungicidal activity

Cite this article

Shuyun Zhang, Hang Liu, Lei Wang, Zhengming Li, Baolei Wang. Studies on the Synthesis, Structural Characterization and Biological Activities of Novel Caffeine Derivatives Containing Substituted-Piperazine Moiety[J]. Chinese Journal of Organic Chemistry, 2021, 41(10): 4075-4082.

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Compd.	杀虫活性, 致死率%				离体抑菌活性(50 mg•L^–1), 抑制率%
	东方粘虫	小菜蛾			番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌
	500 mg•L^–1	500 mg•L^–1	250 mg•L^–1	100 mg•L^–1	番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌
Ia	5	100	70	28	29.4	13.9	30.4	18.2	71.1	55.4
Ib	50	100	80	47	5.9	5.6	17.9	4.5	47.4	27.7
Ic	45	79	43	NT	17.6	5.6	7.1	13.6	63.2	29.2
Id	60	70	32	NT	29.4	13.9	50.0	27.3	71.1	40.0
Ie	0	100	92	60	5.9	13.9	3.6	27.3	52.6	56.9
If	20	90	63	NT	17.6	11.1	17.9	4.5	5.3	32.3
Ig	0	88	55	NT	11.8	13.9	8.9	13.6	44.7	30.8
Ih	30	43	NT	NT	23.5	8.3	7.1	27.3	31.6	24.6
Ii	20	65	NT	NT	17.6	13.9	26.8	13.6	57.9	41.5
Ij	15	53	NT	NT	35.3	22.2	26.8	18.2	31.6	29.2
Ik	60	18	NT	NT	5.9	8.3	25.0	27.3	52.6	27.7
Il	5	58	NT	NT	5.9	19.4	7.1	27.3	13.2	53.8
Im	20	30	NT	NT	11.8	13.9	32.1	18.2	0	52.3
In	0	100	87	53	17.6	11.1	8.9	4.5	0	29.2
Io	10	100	71	37	23.5	5.6	7.1	13.6	23.7	21.5
Ip	50	100	77	42	17.6	8.3	14.3	22.7	57.9	27.7
C-1^a	65	88	30	NT	5.3	8.8	8.3	9.4	37.3	13.2
C-2^b	NT^d	NT	NT	NT	100.0	82.4	100.0	50.0	98.5	75.0
C-3^c	NT	NT	NT	NT	26.3	73.5	91.7	81.3	91.0	81.6

Compd.	杀虫活性, 致死率%				离体抑菌活性(50 mg•L^–1), 抑制率%
	东方粘虫	小菜蛾			番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌
	500 mg•L^–1	500 mg•L^–1	250 mg•L^–1	100 mg•L^–1	番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌
Ia	5	100	70	28	29.4	13.9	30.4	18.2	71.1	55.4
Ib	50	100	80	47	5.9	5.6	17.9	4.5	47.4	27.7
Ic	45	79	43	NT	17.6	5.6	7.1	13.6	63.2	29.2
Id	60	70	32	NT	29.4	13.9	50.0	27.3	71.1	40.0
Ie	0	100	92	60	5.9	13.9	3.6	27.3	52.6	56.9
If	20	90	63	NT	17.6	11.1	17.9	4.5	5.3	32.3
Ig	0	88	55	NT	11.8	13.9	8.9	13.6	44.7	30.8
Ih	30	43	NT	NT	23.5	8.3	7.1	27.3	31.6	24.6
Ii	20	65	NT	NT	17.6	13.9	26.8	13.6	57.9	41.5
Ij	15	53	NT	NT	35.3	22.2	26.8	18.2	31.6	29.2
Ik	60	18	NT	NT	5.9	8.3	25.0	27.3	52.6	27.7
Il	5	58	NT	NT	5.9	19.4	7.1	27.3	13.2	53.8
Im	20	30	NT	NT	11.8	13.9	32.1	18.2	0	52.3
In	0	100	87	53	17.6	11.1	8.9	4.5	0	29.2
Io	10	100	71	37	23.5	5.6	7.1	13.6	23.7	21.5
Ip	50	100	77	42	17.6	8.3	14.3	22.7	57.9	27.7
C-1^a	65	88	30	NT	5.3	8.8	8.3	9.4	37.3	13.2
C-2^b	NT^d	NT	NT	NT	100.0	82.4	100.0	50.0	98.5	75.0
C-3^c	NT	NT	NT	NT	26.3	73.5	91.7	81.3	91.0	81.6

新型含取代哌嗪的咖啡因衍生物的合成、结构表征及生物活性研究