Studies on the Synthesis and Biological Activities of Novel Dihydroquinazolinone-Containing Caffeine Derivatives

doi:10.6023/cjoc202206024

Abstract

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

Cite this article

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

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