Pyrazoline Containing Compounds as Therapeutic Targets for Neurodegenerative Disorders

Abstract

Pyrazolines are a significant class of heterocyclic compounds with essential biological activities. They are quite stable, which has inspired medicinal chemists to experiment with the ring's structure in many different ways to create a variety of pharmacological activities. The structures of numerous commercially available therapeutic agents contain a pyrazoline ring. Pyrazolines are well-known for their ability to treat neurodegenerative diseases. The neurodegenerative diseases that affect huge populations globally include Alzheimer's disease (AD), Parkinson's disease (PD), and psychiatric disorders. The neuroprotective properties of pyrazolines published since 2003 are covered in the current review. Structure-activity relationships (SARs), molecular docking simulation, anticholinesterase (anti-AChE), and monoamine oxidase (MAO A/B) inhibitory actions are all covered in this article. Pyrazolines were discovered to have beneficial effects in the management of AD and were revealed to be inhibitors of acetylcholine esterase (AChE) and beta-amyloid (A_β) plaques. They were discovered to be efficient against PD and also targeted MAO B and COMT. It was discovered that the pyrazolines block MAO A to treat psychiatric diseases. Pyrazolines are significant heteroaromatic scaffolds with a variety of biological functions. They were discovered to be remarkably stable and serve as an indispensable anchor for the development of new drugs. By blocking AChE and MAOs, they may be used to treat neurodegenerative diseases. The discussion outlined here is an essential and helpful resource for medicinal chemists who are investigating and applying pyrazolines in neurodegenerative research initiatives as well as to expedite future research programs on neurodegenerative disorders.

Figure 1

Different isomers of pyrazoline and substitution at positions 1, 3, and 5 on 2-pyrazoline.

Scheme 1. General Method for the Synthesis of 2-Pyrazolines

Scheme 2. Synthesis of 4-(3-(Difluorophenyl)-5-(dimethoxyphenyl)-4,5-dihydropyrazol-1-yl)benzenesulfonamides

Figure 2

AChE inhibitory activity and 2D molecular docking pose compound A01.

Scheme 3. Synthesis of Pyrazoline from Steroids

Figure 3

AChE inhibitory activity and 2D molecular docking pose of compound A02.

Scheme 4. Synthesis of Pyrazoline Benzene Sulfonamides

Figure 4

AChE inhibitory activity and 2D molecular docking pose of compound A03.

Scheme 5. Synthesis of of 16,17-Pyrazolinyl Steroidal Analogues

Figure 5

AChE inhibitory activity and 2D molecular docking pose of compound A04.

Scheme 6. Synthesis of 3-(Anthracene-9-yl)-5-aryl Pyrazolines

Figure 6

AChE inhibitory activity and 2D molecular docking pose of compound A05.

Scheme 7. Synthesis of 1-N-Substituted Thiocarbomoyl-3-phenyl-5-thienyl-2-pyrazolines

Figure 7

AChE inhibitory activity and 2D molecular docking pose of compound A06.

Scheme 8. Synthesis of 2-Pyrazoline Analogues

Figure 8

AChE inhibitory activity and 2D molecular docking pose of compound A07.

Figure 9

AChE inhibitory activity and 2D molecular docking pose of compound A08.

Scheme 9. Synthesis of 2-[(((4-(Diethylamino)butyl)amino)methyl)thio]-1-[5-phenyl-3-(thien-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]ethan-1-ones

Figure 10

AChE inhibitory activity and 2D molecular docking pose of compound A09.

Scheme 10. Synthesis of Thiazolyl-pyrazoline Analogues

Figure 11

AChE inhibitory activity and 2D molecular docking pose of compound A10c.

Scheme 11. Synthesis of Pyrazoline Analogues

Figure 12

AChE inhibitory activity and 2D molecular docking pose of compound A11.

Scheme 12. Synthesis of [2-(3-(4-Methoxyphenyl)-5-aryl-4,5-dihydro-1H-pyrazol-1-yl)benzo[d]thiazoles

Figure 13

AChE inhibitory activity and 2D molecular docking pose of compound A12.

Figure 14

AChE inhibitory activity and 2D molecular docking pose of compound A13.

Scheme 13. Synthesis of Edaravone-N-benzyl Pyridinium Hybrid Pyrazolinone

Figure 15

AChE inhibitory activity and 2D molecular docking pose of compound A14.

Scheme 14. Synthesis of Coumarin-pyrazolinone

Figure 16

AChE inhibitory activity and 2D molecular docking pose of compound A15.

Scheme 15. Synthesis of Thiazolyl-pyrazoline Derivatives

Figure 17

AChE inhibitory activity and 2D molecular docking pose of compound A16.

Figure 18

Compounds A02 and A04 and their anti-Parkinsonism activity.

Figure 19

hMAO B inhibitory activity and 2D molecular docking pose of compound P01.

Figure 20

hMAO-B inhibitory activity and 2D molecular docking pose of compounds A08 and P02.

Figure 21

hMAO-B inhibitory activity of the compounds P03, P04, P05, and P06 and 2D molecular docking pose of compounds P04.

Scheme 16. Synthesis of Nitro Catechol Derivatives of Pyrazolines

Figure 22

hMAO-B inhibitory activity and 2D molecular docking pose of compounds P07.

Scheme 17. Synthesis of Pyrazolines Containing Quinoline Heterocycle

Figure 23

hMAO-B inhibitory activity and 2D molecular docking pose of compounds P08.

Scheme 18. Synthesis of Pyrazoline Derivatives

Figure 24

hMAO B inhibitory activity and 2D molecular docking pose of compounds P09.

Scheme 19. Synthesis of Pyrazoline Analogues

Figure 25

hMAO-B inhibitory activity and 2D molecular docking pose of compounds P10.

Scheme 20. Synthesis of Pyrazoline Bearing 4-(3H)-Quinazolinone Analogues

Figure 26

hMAO-B inhibitory activity and 2D molecular docking pose of compounds P11.

Scheme 21. Synthesis of Pyrazoline Analogues

Figure 27

HMAOA inhibitory activity and 2D molecular docking pose compound D01.

Figure 28

HMAOA inhibitory activity and 2D molecular docking pose compound D02.

Figure 29

HMAOA inhibitory activity and 2D molecular docking pose compound D03.

Figure 30

HMAOA inhibitory activity and 2D molecular docking pose compound D04.

Figure 31

hMAO A inhibitory activity and 2D molecular docking pose compound D05.

Figure 32

hMAO A inhibitory activity and 2D molecular docking pose compound D06.

Figure 33

HMAOA inhibitory activity and 2D molecular docking pose compound D07.

Scheme 22. Synthesis of 1-[2-(2-Benzoxazolinone-3-yl)acetyl]-3-phenyl-5-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole

Figure 34

HMAOA inhibitory activity and 2D molecular docking pose compound D08.

Scheme 23. Synthesis of Curcumin-Based Pyrazoline Analogues

Figure 35

hMAO A inhibitory activity and 2D molecular docking pose compound D09.

Scheme 24. Synthesis of Curcumin-Based Pyrazoline Analogues

Figure 36

hMAO A inhibitory activity and 2D molecular docking pose compounds D10 and D11.

Scheme 25. Synthesis of 2-Pyrazoline-1-ethanone Derivatives

Figure 37

hMAO A inhibitory activity and 2D molecular docking pose compounds D12 and D13.

Figure 38

HMAOA inhibitory activity and 2D molecular docking pose compound D14.

Scheme 26. Synthesis of Pyrazoline Derivatives

Figure 39

hMAO A inhibitory activity and 2D molecular docking pose compounds D15 and D16.

Scheme 27. Synthesis of Benoxazolin-3-one Pyrazoline Derivatives

Figure 40

hMAO A inhibitory activity and 2D molecular docking pose compounds D17–D19.

Scheme 28. Synthesis of Benoxazolin-3-one Pyrazoline Derivatives

Figure 41

hMAO A inhibitory activity and 2D molecular docking pose compound D20.

Scheme 29. Synthesis of Benoxazolin-3-one Pyrazoline Derivatives

Figure 42

SAR of pyrazoline for MAO A inhibitory activity.

Figure 43

hMAO A inhibitory activity and 2D molecular docking pose compounds D21 and D22.

Scheme 30. Synthesis of 3,5-Diaryl Pyrazolines Analogues

Figure 44

hMAO A inhibitory activity and 2D molecular docking pose compound D23.

Scheme 31. Synthesis of 4,5-Dihydro-(1H)-pyrazolines

Figure 45

hMAO A inhibitory activity and 2D molecular docking pose compound D24.

Scheme 32. Synthesis of Curcumin-Based Pyrazoline Analogues

Figure 46

hMAO A inhibitory activity and 2D molecular docking pose compound D25.

Figure 47

Effect of substituents for selectivity of MAO A and MAO B activities.