新型含二氢喹唑啉酮的咖啡因衍生物的合成及生物活性研究

doi:10.6023/cjoc202206024

摘要/Abstract

基于在咖啡因8-位引入二氢喹唑啉酮活性基团的策略, 以茶碱和靛红酸酐/5-溴靛红酸酐为原料, 通过N-甲基化、钯催化偶联、亲核加成-消除及缩合等多步反应, 合成了13个未见文献报道的新型含二氢喹唑啉酮结构的咖啡因衍生物. 生物活性测试结果表明, 大部分化合物对小菜蛾(Plutella xylostella L.)表现出显著的杀虫活性, 其中1,3,7-三甲基-8-(4-(4-氧亚基-3-丙基-1,2,3,4-四氢喹唑啉-2-基)苯基)-3,7-二氢-1H-嘌呤-2,6-二酮(Ia)和8-(4-(6-溴-3-(4-氟苄基)-4-氧亚基-1,2,3,4-四氢喹唑啉-2-基)苯基)-1,3,7-三甲基-3,7-二氢-1H-嘌呤-2,6-二酮(Im)在50 mg•L^–1时对小菜蛾的致死率分别可达50%和43%, 尤其是Ia在10 mg•L^–1时仍有20%的致死率. 部分化合物也表现出了良好的除草活性, 特别是Ia在100 mg•L^–1浓度下对油菜胚根的生长抑制率达到96.6%, 优于对照药氯磺隆. 此外, 部分化合物在50 mg•L^–1时对油菜菌核病菌(Sclerotinia sclerotiorum)、辣椒疫霉病菌(Phytophthora capsicum)和苹果轮纹病菌(Physalospora piricola)等具有50%以上的抑制活性, 其中Ia对辣椒疫霉病菌的抑制率可达80.6%, 远超对照物咖啡因. Ia在杀虫、除草和抑菌测试中大都表现出良好的活性, 可作为新型农药先导化合物继续开展深入结构优化. 本研究结果对基于天然产物结构的新型农药分子设计具有一定的参考价值.

关键词: 黄嘌呤, 咖啡因, 二氢喹唑啉酮, 合成, 杀虫活性, 抑菌活性, 除草活性

Based on the strategy of introducing the “dihydroquinazolinone” bioactive group into 8-position of caffeine, thirteen novel caffeine derivatives containing dihydroquinazolinone moiety have been synthesized using theophylline and isatoic anhydride/5-bromoisatoic anhydride as materials, via multi-step reactions such as N-methylation, palladium-catalyzed coupling, nucleophilic addition-elimination and condensation, etc. The bioassay results showed that most of the compounds possess favourable insecticidal activity against Plutella xylostella L., among which 1,3,7-trimethyl-8-(4-(4-oxo-3-propyl-1,2,3,4- tetrahydroquinazolin-2-yl)phenyl)-3,7-dihydro-1H-purine-2,6-dione (Ia) and 8-(4-(6-bromo-3-(4-fluorobenzyl)-4-oxo-1,2,3,4- tetrahydroquinazolin-2-yl)phenyl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (Im) held lethality rate of 50% and 43% respectively at a test concentration of 50 mg•L^–1, especially Ia still had 20% lethality rate at 10 mg•L^–1. Partial compounds also showed good herbicidal activities. In particular, Ia held an growth inhibition rate of 96.6% against root of Brassica campestris L. at a test concentration of 100 mg•L^–1, which was better than that of the control chlorsulfuron. In addition, partial compounds possessed >50% fungicidal activities at 50 mg•L^–1 against Sclerotinia sclerotiorum, Phytophthora capsicum, Physalospora piricola, etc. The inhibitory activity of Ia against Phytophthora capsicum reached 80.6%, which greatly exceeded that of the contrast caffeine. Compounds Ia exhibited good biological activities in almost all the insecticidal, herbicidal and fungicidal bioassays, and could be considered as a novel pesticide lead compound to carry out further structural optimizations. The results of this study provide useful reference for the design of new pesticidal agents based on the structure of natural products.

Key words: xanthine, caffeine, dihydroquinazolinone, synthesis, insecticidal activity, fungicidal activity, herbicidal activity

引用此文

汪蕾, 于淑晶, 杨娜, 王宝雷. 新型含二氢喹唑啉酮的咖啡因衍生物的合成及生物活性研究[J]. 有机化学, 2023, 43(1): 299-307.

Lei Wang, Shujing Yu, Na Yang, Baolei Wang. Studies on the Synthesis and Biological Activities of Novel Dihydroquinazolinone-Containing Caffeine Derivatives[J]. Chinese Journal of Organic Chemistry, 2023, 43(1): 299-307.

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Compd.	R	R'	致死率/%				抑制率/%
			小菜蛾				油菜		稗草
			200 mg•L^–1	100 mg•L^–1	50 mg•L^–1	10 mg•L^–1	100 mg•L^–1	10 mg•L^–1	100 mg•L^–1	10 mg•L^–1
Ia	ⁿPr	H	90	73	50	20	96.6	0	0	0
Ib	ⁱPr	H	47	n.t.^a	n.t.	n.t.	0	0	0	0
Ic	ⁿBu	H	43	n.t.	n.t.	n.t.	67.5	5.2	0	0
Id	Bn	H	60	30	n.t.	n.t.	46.0	0	0	0
Ie	4-MeBn	H	100	60	37	n.t.	20.8	2.2	0	0
If	4-FBn	H	75	55	40	n.t.	51.7	7.7	47.6	0
Ig	4-ClBn	H	30	n.t.	n.t.	n.t.	0	0	33.3	0
Ih	4-BrBn	H	50	30	n.t.	n.t.	0	0	0	0
Ii	2-ClBn	H	60	37	n.t.	n.t.	0	0	0	0
Ij	ⁿPr	Br	68	45	n.t.	n.t.	0	0	0	0
Ik	ⁿBu	Br	60	37	n.t.	n.t.	0	0	0	0
Il	Bn	Br	60	40	n.t.	n.t.	0	0	0	0
Im	4-FBn	Br	90	77	43	n.t.	0	0	0	0
C-1^b	—	—	90	70	n.t.	n.t.	12.8	0	0	0
C-2^c	—	—	100	100	82	47	n.t.	n.t.	n.t.	n.t.
C-3^d	—	—	n.t.	n.t.	n.t.	n.t.	64.1	54.6	71.4	66.7

Compd.	R	R'	致死率/%				抑制率/%
			小菜蛾				油菜		稗草
			200 mg•L^–1	100 mg•L^–1	50 mg•L^–1	10 mg•L^–1	100 mg•L^–1	10 mg•L^–1	100 mg•L^–1	10 mg•L^–1
Ia	ⁿPr	H	90	73	50	20	96.6	0	0	0
Ib	ⁱPr	H	47	n.t.^a	n.t.	n.t.	0	0	0	0
Ic	ⁿBu	H	43	n.t.	n.t.	n.t.	67.5	5.2	0	0
Id	Bn	H	60	30	n.t.	n.t.	46.0	0	0	0
Ie	4-MeBn	H	100	60	37	n.t.	20.8	2.2	0	0
If	4-FBn	H	75	55	40	n.t.	51.7	7.7	47.6	0
Ig	4-ClBn	H	30	n.t.	n.t.	n.t.	0	0	33.3	0
Ih	4-BrBn	H	50	30	n.t.	n.t.	0	0	0	0
Ii	2-ClBn	H	60	37	n.t.	n.t.	0	0	0	0
Ij	ⁿPr	Br	68	45	n.t.	n.t.	0	0	0	0
Ik	ⁿBu	Br	60	37	n.t.	n.t.	0	0	0	0
Il	Bn	Br	60	40	n.t.	n.t.	0	0	0	0
Im	4-FBn	Br	90	77	43	n.t.	0	0	0	0
C-1^b	—	—	90	70	n.t.	n.t.	12.8	0	0	0
C-2^c	—	—	100	100	82	47	n.t.	n.t.	n.t.	n.t.
C-3^d	—	—	n.t.	n.t.	n.t.	n.t.	64.1	54.6	71.4	66.7

Compd.			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	ⁿPr	H	42.9	80.6	50.0	10.5	23.3	8.2
Ib	ⁱPr	H	14.3	77.4	46.9	10.5	46.4	18.8
Ic	ⁿBu	H	21.4	54.8	59.4	10.5	59.4	12.9
Id	Bn	H	7.1	25.8	50.0	15.8	26.1	25.9
Ie	4-MeBn	H	35.7	9.7	65.6	5.3	53.6	10.6
If	4-FBn	H	28.6	16.1	75.0	5.3	55.1	20
Ig	4-ClBn	H	21.4	6.5	50.0	15.8	33.3	12.9
Ih	4-BrBn	H	7.1	6.5	43.8	5.3	44.9	9.4
Ii	2-ClBn	H	7.1	6.5	62.5	21.1	66.7	25.9
Ij	ⁿPr	Br	35.7	45.2	71.9	15.8	30.4	10.6
Ik	ⁿBu	Br	7.1	6.5	62.5	21.1	66.7	25.9
Il	Bn	Br	21.4	16.1	50.0	5.3	40.6	8.2
Im	4-FBn	Br	21.4	6.5	34.4	5.3	59.4	10.6
C-1^a	—	—	22.2	44.8	50.0	13.6	7.2	9.4
C-2^b	—	—	92.9	96.8	100.0	15.8	88.4	65.9
C-3^c	—	—	42.9	87.1	100.0	57.9	89.9	77.6

Compd.			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	ⁿPr	H	42.9	80.6	50.0	10.5	23.3	8.2
Ib	ⁱPr	H	14.3	77.4	46.9	10.5	46.4	18.8
Ic	ⁿBu	H	21.4	54.8	59.4	10.5	59.4	12.9
Id	Bn	H	7.1	25.8	50.0	15.8	26.1	25.9
Ie	4-MeBn	H	35.7	9.7	65.6	5.3	53.6	10.6
If	4-FBn	H	28.6	16.1	75.0	5.3	55.1	20
Ig	4-ClBn	H	21.4	6.5	50.0	15.8	33.3	12.9
Ih	4-BrBn	H	7.1	6.5	43.8	5.3	44.9	9.4
Ii	2-ClBn	H	7.1	6.5	62.5	21.1	66.7	25.9
Ij	ⁿPr	Br	35.7	45.2	71.9	15.8	30.4	10.6
Ik	ⁿBu	Br	7.1	6.5	62.5	21.1	66.7	25.9
Il	Bn	Br	21.4	16.1	50.0	5.3	40.6	8.2
Im	4-FBn	Br	21.4	6.5	34.4	5.3	59.4	10.6
C-1^a	—	—	22.2	44.8	50.0	13.6	7.2	9.4
C-2^b	—	—	92.9	96.8	100.0	15.8	88.4	65.9
C-3^c	—	—	42.9	87.1	100.0	57.9	89.9	77.6