Research Progress on the Synthesis and Structure-Activity Relationship of Five Hypoglycemic Active Heterocycles Based on Dipeptidyl Peptidase 4 (DPP-4) Target Design

doi:10.6023/cjoc202107001

Abstract

Recently, diabetes has gradually become a main life-threatening disease in China. Drug targets for the treatment of diabetes mainly include dipeptidyl peptidase 4 (DPP-4), adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma (PPARγ) receptor and so on, in which targeted drug research targeting DPP-4 is a hot spot in recent years. DPP-4 inhibitor is a drug for the treatment of type 2 diabetes, and its biggest advantage is that it is not easy to induce hypoglycemia and increase weight. It is reported that the currently available DPP-4 targeted drugs can cause adverse reactions, such as pancreatitis and hypersensitivity. Therefore, it is worth further studying to continue to develop new hypoglycemic drugs for DPP-4 inhibitors to avoid adverse reactions. According to the systematic literature review, the potential heterocyclic structures with hypoglycemic activity are summarized and through computer molecular simulation docking, five kinds of heterocyclic structures with high hypoglycemic activity and easy synthesis are finally screened out based on DPP-4 target design. The synthesis routes and structure-activity relationships are summarized and analyzed, which provides a research basis for the development of safe, efficient and novel hypoglycemic drugs for DPP-4 inhibitors in the future.

Key words: diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitor, molecular docking, synthesis methods, structure-activity relationship

Cite this article

Yuanfang Kong, Bin Yang, Yan Zhuang, Jingyu Zhang, Demei Sun, Chunhong Dong. Research Progress on the Synthesis and Structure-Activity Relationship of Five Hypoglycemic Active Heterocycles Based on Dipeptidyl Peptidase 4 (DPP-4) Target Design[J]. Chinese Journal of Organic Chemistry, 2022, 42(3): 770-784.

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Fig. & Tab. 45

Figure 1. Chemical structures of 12 hypoglycemic compounds

Compd.	IC₅₀/(mg•L^–1)
Compd.	α-Glucosidase inhibitory activity	AGEs forming free radical activity
1a	>1000	5.247±0.519
1b	>1000	6.567±0.456
1c	>1000	3.239±0.713
1d	>1000	2.346±0.188
2a	>1000	4.223±0.268
2b	0.469±0.042	2.453±0.069
2c	0.250±0.042	1.132±0.141
2d	1.020±0.062	0.623±0.016
Acarbose	0.042±0.002	—
Aminoguanidine Hydrochloride	—	28.255±0.657

Table 1. In vitro hypoglycemic activity of compounds 1a~1d and 2a~2d

Figure 2. Structure of compound 3

Compd.	R¹	R²	n	Decrease in blood glucose/%
Compd.	R¹	R²	n	18 h	21 h
4a	Me	H	0	-7.0±4.8	3.6±0.7
4b	Me	H	1	24.7±9.1	27.6±5.9
4c	Me	H	2	-5.6±6.2	13.0±9.3
4d	Me	H	3	-3.0±6.1	-9.3±18.3
4e	H	H	1	13.9±12.7	7.4±3.0
4f	Et	H	1	-19.5±8.7	2.4±8.3
4g	Ph	H	1	3.9±5.6	-3.4±22.4
4h	4-ClC₆H₄CH₂	H	1	24.5±8.2	-8.5±19.0
4i	4-PhC₆H₄CH₂	H	1	3.8±13.4	11.4±6.0
4j	Me	Cl	1	37.1±7.7	47.6±6.9

Table 2. Hypoglycemic differentiation activities of thiazole-2,4-dione derivatives

Entry	FPG/(mol•L^–1)		2 h PBG/(mol•L^–1)
Entry	Before treatment	Post treatment	Before treatment	Post treatment
1	7.43±0.70	5.30±0.39	11.33±1.24	6.80±0.53
t	0.569	12.010	0.105	8.000
P	0.285	0.000	0.458	0.000

Table 3. Blood glucose indexes of patients [(x±s), n=82]

Entry	Compound	Binding energy/(kJ•mol^–1)
1	a	–25.62
2	g	–22.68
3	j	–22.68
4	b	–21.84
5	i	–21.42
6	e	–21
7	l	–20.58
8	h	–20.16
9	d	–19.32
10	c	–17.64
11	k	–17.64
12	f	–13.86

Table 4. Computer simulation results

Figure 3. Complexes of five hypoglycemic heterocyclic compounds and DPP-4 (a) Complex of DPP-4 and benzopyran-2-one a; (b) Complex of DPP-4 and hexahydropyrrolo[2,1-b]oxazole c; (c) Complex of DPP-4 and pyrano[3,2- c]pyridine g; (d) Complex of DPP-4 and pyrrolotriazine j; (e) Complex of DPP-4 and triazolopyrazine l.

Figure 4. Skeleton of benzopyran-2-one (chromen-2-one, Coumarin)

Figure 5. Various biological activities of benzopyran- 2-one ring

Scheme 1. Synthetic route of compound 7

Scheme 2. Synthetic route of compound 10

Scheme 3. Synthetic route of compound 13

Scheme 4. Synthetic route of compounds 15a and 15b

Scheme 5. Synthetic route of compounds 16 and 17

Figure 6. Structure-activity relationship of benzopyran-2-one

Figure 7. Skeleton of hexahydropyrrolo[2,1-b]oxazole

Figure 8. Various biological activities of hexahydropyrrolo[2,1- b]oxazole

Scheme 6. Synthetic route of compound 21

Scheme 7. Synthetic route of compounds 23a~23c

Scheme 8. Synthetic route of compound 25

Figure 9. Structure-activity relationship of hexahydropyrrolo[2,1-b]oxazole

Figure 10. Skeleton of pyrano[3,2-c]pyridine

Figure 11. Various biological activities of pyrano[3,2-c]pyridine

Scheme 9. Synthetic route of compound 28

Scheme 10. Synthetic route of compound 31

Scheme 11. Synthetic route of compound 34

Scheme 12. Synthetic route of compound 37

Scheme 13. Synthetic route of compound 41

Figure 12. Structure-activity relationship of pyrano[3,2- c]pyridone

Figure 13. Skeleton of pyrrolotriazine

Scheme 14. Synthetic route of compound 49

Scheme 15. Synthetic route of compound 53

Scheme 16. Synthetic route of compound 57

Scheme 17. Synthetic route of compound 60

Scheme 18. Synthetic route of compound 63

Figure 14. Structure-activity relationship of pyrrolotriazine

Figure 15. Skeleton of triazolopyrazine

Scheme 19. Synthetic route of compound 70

Scheme 20. Synthetic route of compound 74

Scheme 21. Synthetic route of compound 80

Scheme 22. Synthetic route of compound 85

Scheme 23. Synthetic route of compound 88

Figure 16. Structure-activity relationship of triazolopyrazine

Figure 17. Research on five heterocyclic synthesis methods with hypoglycemic activity

Figure 18. In vitro and in vivo activities of five hypoglycemic heterocyclic compounds

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