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Review
. 2024 Oct 23;9(44):44005-44018.
doi: 10.1021/acsomega.4c06190. eCollection 2024 Nov 5.

Recent Progress in Synthetic and Natural Catechol- O-methyltransferase Inhibitors for Neurological Disorders

Sandeep Bindra  1 , Ananya Datta  2 , Haya Khader Ahmad Yasin  3   4 , Riya Rachel Thomas  1 , Shailesh Verma  2 , Ankita Patel  2 , Della Grace Thomas Parambi  5 , Suraj N Mali  6 , T M Rangarajan  7 , Bijo Mathew  1
Affiliations
Review

Recent Progress in Synthetic and Natural Catechol- O-methyltransferase Inhibitors for Neurological Disorders

Sandeep Bindra et al. ACS Omega. .

Abstract

Catechol-O-methyltransferase (COMT) inhibitors have played a crucial role in the development of potent and selective drugs for the treatment of Parkinson's disease, depression, and anxiety disorders. This review provides a comprehensive analysis of the structure-activity relationship (SAR) of COMT inhibitors, highlighting key structural features and pharmacophoric elements that govern their potency, selectivity, and pharmacokinetic properties. This review also discusses the application of SAR principles in the design and optimization of COMT inhibitors. Our analysis reveals the emergence of novel chemical scaffolds and the potential for COMT inhibitors to address unmet medical needs in neurology and psychiatry. This Perspective serves as a valuable resource for clinicians and researchers, providing insights into the rational design of COMT inhibitors and the development of next-generation therapeutics.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(A) Crystal structure of rat COMT in complex with S-adenosyl-methionine (SAM), dinitrocatechol (DNC), and Mg2+. (B) Crystal structure of human COMT in complex with S-adenosyl-methionine (SAM), 7,8-dihydroxy-4-phenyl-2H-chromen-2-one, and Mg2+.
Figure 2
Figure 2
Structures of clinically used COMT inhibitors: nitecapone (1), entacapone (2), tolcapone (3), nebicapone (4), and opicapone (5).
Figure 3
Figure 3
Designed and synthesized (a) dopamine and (b) catechol derivatives.
Figure 4
Figure 4
Synthesis of the catechol derivatives.
Figure 5
Figure 5
Synthesis of nitrocatechol chalcone derivatives.
Figure 6
Figure 6
SAR of nitrocatechol chalcone and pyrazoline derivatives.
Figure 7
Figure 7
Synthesis of 3-hydroxypyridin-4-ones.
Figure 8
Figure 8
SAR of pyridin-4-one derivatives.
Figure 9
Figure 9
Synthetic route for fused bicyclic hydroxypyridones.
Figure 10
Figure 10
SAR of pyridinone derivatives.
Figure 11
Figure 11
SAR of pyridinone derivatives.
Figure 12
Figure 12
Selected potent inhibitors for in vivo COMT evaluations.
Figure 13
Figure 13
SAR of oleanane derivatives.
Figure 14
Figure 14
SAR of the ursane derivatives.
Figure 15
Figure 15
SAR of the lupane derivatives.
Figure 16
Figure 16
SAR of friedelane derivatives.
Figure 17
Figure 17
SAR of flavonoid derivatives by Zhao et al. (2021).
Figure 18
Figure 18
SAR of flavonoid derivatives.
Figure 19
Figure 19
Synthesis of tetralone and indanone derivatives.
Figure 20
Figure 20
SAR of tetralone and indanone derivatives.
Figure 21
Figure 21
SAR of various COMT inhibitors from Calendula officinalis leaf by Kadowaki et al.
See this image and copyright information in PMC

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