Application of the Mannich reaction in the structural modification of natural products

Figures & data

Figure 1. Mannich reaction under acidic conditions and basic conditions.

Figure 2. Compounds 1–34 for antitumor activity.

Table 1. Applications in modification of natural products for antitumor activity.

Parent compound	Derivative	Target	Pharmacological activity (IC50)	Pharmacological activity(Ki)	SI	PSE	Reference
Chalcone	1	MCF-7	0.03 µg·mL^−1				^6
Chalcone	2	HepG2	1.57 µg·mL^−1				^7
		SK-LU-1	1.16 µg·mL^−1
		MCF-7	1.21 µg·mL^−1
Chalcone	3	MCF-7	2.0 µg·mL^−1				^7
Chalcone	4	MCF-7	2.0 µg·mL^−1				^7
Phenoxodiol	5	MDA-MB-231	0.7 µM				^8
Bergenin	6	HeLa	1.33 µM				^10
Berberine	7	CaSki	5.76 µM				^11
Berberine	8	HeLa	7.53 µM				^11
Berberine	9	HeLa	7.33 µM				^11
Berberine	10	HeLa	8.31 µM				^12
		CaSki	8.59 µM
Berberine	11	HeLa	9.77 µM				^12
		CaSki	8.88 µM
12	13	HSC-2	7.1 µmol·L^−1		7.6	0.2262	^13
12	13	HSC-4	6.8 µmol·L^−1		7.9	0.2262	^13
Curcumin	14	HL-60	1.8 µM		5.94	32.0	^21
		HSC-2	3.9 µM		2.74
		HSC-3	3.0 µM		3.57
		HSC-4	3.0 µM		3.57
Magnolol	15	HCC827	5.01 µM				^26
		H1975	5.61 µM
		H460	5.98 µM
Magnolol	16	HCC827	0.63 µM				^27
		H1975	0.93 µM
		H460	0.86 µM
17	18	B16	16.6 µM				^32
		A549	11.0 µM
17	19	A549	1.9 µM				^32
Bacailein	20	HepG2	19.38 μmol·L^−1				^35
Bacailein	21	HepG2	11.70 μmol·L^−1				^35
Bacailein	22	HepG2	9.56 μmol·L^−1				^35
Bacailein	23	HepG2	13.49 μmol·L^−1				^35
Flavopiridol	24	CDK1	0.28 μM				^36
Flavopiridol	25	CDK1	0.27 μM				^36
26	27	Mcl-1	25.14 μM	9.54 μM			^38
	28	Mcl-1	11.77 μM	1.75 μM			^38
	29	Mcl-1	1.21 μM	0.21 μM			^38
	30	Mcl-1	33.73 μM	9.36 μM			^38
	31	Mcl-1	53.6 μM	11.55 μM			^38
	32	Mcl-1	19.92 μM	4.79 μM			^38
Sionmenine	33	MCF-7	5.73 μM				^40
		Hela	8.20 μM
		SW480	6.08 μM
Sionmenine	34	MCF-7	>25 μM				^40
		Hela	>25 μM
		SW480	>25 μM

Figure 3. Compounds 35–47 for anti-Alzheimer’s disease.

Table 2. Application in modification of natural products for anti-Alzheimer’s disease.

Parent compound	Derivative	Target	Pharmacological activity(IC50)	Reference
Chalcone	35	AChE	0.44 μM	^47
		MAO-B	1.21 μM
		self-induced Aβ1 − 42	55.0%(at 25 μM)
Chalcone	36	AChE	7.15 μM	^49
		MAO-B	0.43 μM
		self-induced Aβ1 − 42	70.65% (at 25 μM)
Flavokawain B	37	AChE	4.15 μM	^50
Flavokawain B	38	AChE	0.85 μM	^51
		SI ^AChE	35.79 μM
Hesperidin	39	AChE	0.54 μmol·L^−1	^52
Homoisoflavonoids	42	AChE	0.00249 μM	^57
		BuChE	19.8%
		MAO-B	1.74 μM
		self-induced Aβ1-42	39.3 μM
		Cu^2+-induced Aβ1-42	47.0 μM
Naringin	43	AChE	0.82 μmol·L^−1	^58
		BuChE	46.30 μmol·L^−1
Resveratrol	44	AChE	2.11 μM	^62
Resveratrol	45	MAO-B	2.68 μM	^62
Resveratrol	46	AChE	1.56 μM	^62
Xanthone	47	AChE	2.60 μM	^67
		BuChE	0.51 μM

Table 3. Application in modification of natural products for antimicrobial activity.

Parent compound	Derivative	Target	Pharmacological activity(EC50)	Reference
Magnolol	48	B. cinerea	2.86 μg·mL^−1	^69
Magnolol	49	F. graminearum	4.39 μg·mL^−1	^69
		R. solani	1.40 μg·mL^−1
Magnolol	50	S. sclerotiorum	5.04 μg·mL^−1	^69
Magnolol	51	S. sclerotiorum	4.64 μg·mL^−1	^69
Ampicillin	52	S. aureus	1.95 μg·mL^−1	^70
		B. subtilis	1.95 μg·mL^−1
Ampicillin	53	S. aureus	3.91 μg·mL^−1	^70
		B. subtilis	3.91 μg·mL^−1
Ampicillin	54	S. aureus	7.81 μg·mL^−1	^70
		B. subtilis	7.81 μg·mL^−1
		E. coli	31.25 μg·mL^−1
		P. aeruginosa	31.25 μg·mL^−1
Luteolin	55	Staphylococcus aureus	2 mg·L^−1	^71
		Listeria monocytogenes	2 mg·L^−1
		Escherichia coli	4 mg·L^−1
		S. gallinarum	0.125 mg·L^−1
Kaempferol	56	Staphylococcus aureus	1 mg·L^−1	^71
		Listeria monocytogenes	0.5 mg·L^−1
		Escherichia coli	2 mg·L^−1
		S. gallinarum	0.05 mg·L^−1
Lawsone	57	C. albicans ATCC 10231	20 μg·mL^−1	^72
		C. glabrata ATCC 2001	170 μg·mL^−1
Lawsone	58	C. albicans ATCC 10231	85 μg·mL^−1	^72
		C. glabrata ATCC 2001	330 μg·mL^−1
Eugenol	59	albicans ATCC10231	600.8 μg·mL^−1	^73
		C. krusei ATCC 6258	600.8 μg·mL^−1
	61	Botrytis cinerea	2.1 nM	^74
		Colletotrichum capsici	19 nM
		Rhizoctonia solani	5.8 nM
Obovatol	63	B. cinerea	28.68 μg·mL^−1	^83
	64	A. solani	63.19 μg·mL^−1	^83
		F. solani	59.13 μg·mL^−1
		B. cinerea	16.9 μg·mL^−1
Berberine	65	B. yeast	16 μg·mL^−1
		A. flavus	32 μg·mL^−1

Figure 4. Compounds 48–66 for antimicrobial activity.

Figure 5. Compounds 67–70 for antidiabetic activity.

Table 4. Application in modification of natural products for antidiabetic activity.

Parent compound	Derivative	Target	Pharmacological activity(EC50)	Reference
Oroxylin A	67	rat intestinal α-glucosidase	35.43 µM	^87
		Yeast α-glucosidase	98.84 µM
Flavonone	68	α-glucosidase	23.4 µM	^88
	69	α-glucosidase	4.1 µM	^88

Figure 6. Compounds 71–76 for anti-inflammatory activity.

Figure 7. Compounds 77–79 for other activities.

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