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. 2024 Oct 23;9(44):44005–44018. doi: 10.1021/acsomega.4c06190

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

Sandeep Bindra a, Ananya Datta b, Haya Khader Ahmad Yasin c,g,*, Riya Rachel Thomas a, Shailesh Verma b, Ankita Patel b, Della Grace Thomas Parambi d, Suraj N Mali e, T M Rangarajan f,*, Bijo Mathew a,*
PMCID: PMC11541507  PMID: 39524663

Abstract

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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.

1. Introduction

Catechol-O-methyltransferase (COMT) is a divalent magnesium (Mg2+) dependent enzyme that catalyzes the transfer of a methyl group to catechol substrates by using S-adenosyl-l-methionine (SAM) as a methyl donor, producing O-methylated catechol and S-adenosyl-l-homocysteine as reaction products.1 Both endogenous and exogenous neurotransmitters, such as epinephrine, noradrenaline, and dopamine, as well as levodopa, the metabolic precursor of dopamine, are examples of COMT substrates.2 The physiological actions of neurotransmitters are terminated by COMT metabolism, which makes this enzyme relevant for therapeutic purposes. Many central and peripheral nervous system disorders, such as Parkinson’s disease (PD), depression, schizophrenia, and other diseases linked to dopamine deficiency, can be treated with drugs that target COMT.3

COMT exists in two isoforms that are expressed from two promoters: the membrane-bound form, MB-COMT, which is more frequently found in the brain, and the soluble S-COMT isoform, which is expressed in most tissues, including the liver, blood, and kidneys.4 MB-COMT is particularly noteworthy to investigate as a target due to its function in controlling extracellular dopamine levels inside the prefrontal cortex.5 The COMT gene is located on chromosome 22q11.2 and is 27.22 kb long.6 The 158th amino acid residue of the membrane-bound isoform (or the 108th amino acid of the soluble form) is changed from valine (Val) to methionine (Met) by a frequent nonsynonymous single-nucleotide polymorphism (rs4680). Because the Met variant is more thermolabile at physiological temperature, its presence causes a 4-fold decrease in COMT enzyme activity levels in the prefrontal cortex.7 There are several crystal structures available for COMTs in rats and humans. Both the human and rat COMTs (Figure 1) are members of the highly structurally conserved SAM-dependent methyltransferase fold family, and they have 81% sequence similarity.8 Specifically, the COMT enzyme is made up of two sets of α-helices (helices α1−α5 on one side and helices α6−α8 on the other) sandwiched around a seven-stranded β-sheet core (ordered in an order of 3, 2, 1, 4, 5, 7, 6). Strand 7 is antiparallel to the others in the β-sheet. Along the first half of the core β-sheet (β1−β4), the cofactor SAM interacts with conserved residues.9 E90 (β2) makes hydrogen bonds with SAM’s ribose hydroxyl groups. SAM’s adenine ring interacts via van der Waals interactions with residues I91 (β2), A118 (β3−α6 loop), and W143 (β4−α7 loop) and forms hydrogen bonds with S119 and Q120 (α6). The coordination of methionine in SAM is achieved through hydrophobic contacts with M40, V42, and Y68, and hydrogen bonds with residues V42 (α2−α3 loop), S72 (α4), and D141 (β4). The methyl group (CH3) of the SAM methionine sulfur atom is orientated toward the substrate binding site, more precisely toward the catechol oxygen atom that has to be methylated. The “gatekeeper” residues W38 and P174, together with M40, L198, and W143, define the shallow pocket that serves as the substrate-binding site. All of these residues being hydrophobic implies that van der Waals interactions are the primary mechanisms underlying ligand binding. Every single crystal structure of COMT complexed with a ligand contains the magnesium ion (Mg2+), a cofactor essential for methylation.10 The side chains of D141, D169, and N170, the two hydroxyl groups of the catechol substrate, and a water molecule all work together to coordinate the Mg2+ ion octahedrally in the active site. This is unambiguous evidence that Mg2+ aids in the enzymatic activity by making the substrate more soluble. This explains why the ion is necessary for catalysis mediated by COMT. It is noteworthy that the pKa of the catechol hydroxyl is lowered by the Mg2+ ion, causing it to be more ionized.11 In general, human COMT has lower Km (Michaelis constant) values for catechol substrate methylation than rat COMT.12 An analysis comparing the human and rat active sites explains why the Km values of these two proteins and other kinetic characteristics differ. Human COMT has shorter Mg2+ ligand distances in its crystal structure than rat COMT, suggesting that substrate binding is more robust (lower Km value) in the human protein.9 The majority of residues in the sites are identical, though three residues are found to differ in the SAM binding sites of these two proteins: M89, M91, and Y95 in the rat protein and I89, I91, and C95 in the human protein. In comparison to the human protein, the rat protein residues are larger and interact with SAM more intimately. Additionally, two changes in charge (R201 and E202 in humans compared to M201 and K202 in rats) are present at the substrate-binding site. It seems unlikely that the two residues will interact directly with the substrate. However, because of their position at the pocket entry, they might have an impact on Vmax in addition to substrate binding and release.

Figure 1.

Figure 1

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(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+.

Several COMT inhibitors have been developed to treat neurodegenerative disorders to date. The early developed COMT inhibitors, often referred to as “first-generation” inhibitors, inhibited COMT from extending the physiological action of endogenous neurotransmitters, albeit their effectiveness on noradrenergic, adrenergic, and dopaminergic pathways was limited.13 The derivatives of pyrogallol and catechols, such as gallic acid, caffeic acid, U-0521, 2-hydroxy estrogens, or flavonoids like quercetin or rutin are examples of first-generation COMT inhibitors. Moreover, it was questioned how “first-generation” COMT inhibitors affected the inactivation of neurotransmitters at receptor sites. During the 1970s, there was escalating interest in COMT following the discovery that the enzyme was involved in the metabolic breakdown of the popular antiparkinsonian medication L-DOPA (levodopa). PD is a chronic degenerative neurological disorder caused by the reduction of dopamine levels due to the death of dopaminergic cells in the substantia nigra pars compacta. It is possible to control the levels of this neurotransmitter in the brain by using L-DOPA, a biological precursor of dopamine.14 L-DOPA’s short in vivo half-life is one of its main disadvantages, despite its advantageous capacity to regulate dopamine levels in the brain. COMT inhibitors prolong the pharmacological impact of L-DOPA and reduce the therapeutic dose by inhibiting COMT from converting L-DOPA to 3-O-methyl-L-DOPA (3-OMD) in peripheral tissues. In order to target COMT and provide a more continuous and prolonged distribution of dopamine to the striatum, various research groups from academia and the pharmaceutical industry have been working in the last 30 years to optimize L-DOPA therapy. In the process of finding novel COMT inhibitors, “second-generation” inhibitors were discovered, which had better pharmacokinetic characteristics than their “first-generation” predecessors. Second generation inhibitor examples of clinically relevant COMT inhibitors for the adjunctive therapy of Parkinson’s disease (PD) are nitecapone 1 (OR-462), entacapone 2 (OR-611), tolcapone 3 (Ro40-7592), and nebicapone 4 (BIA 3-202) (Figure 2), while opicapone 5 (BIA 9-1067) (Figure 2) is an example of a third-generation COMT inhibitor having lower toxicity and higher inhibitory activity. Recently, Akhtar et al. summarized the last 50 years of research on COMT inhibitors from 2019 as a review article.15 A timely update is necessary for the further design and development of the novel COMT inhibitors. Therefore, in this review, we cover the COMT inhibitors published from 2019 to 2024.

Figure 2.

Figure 2

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Structures of clinically used COMT inhibitors: nitecapone (1), entacapone (2), tolcapone (3), nebicapone (4), and opicapone (5).

2. COMT Inhibitor Structure Based Design

2.1. Catechol Derivatives

Several FDA-approved drugs, for example, entacapone, as COMT inhibitors for the treatment of Parkinson’s disease showed poor performance due to various pharmacokinetic and pharmacodynamics reasons such as their low bioavailability and low metabolic stability that have resulted in increased and repeated doses throughout the day. Also, some side effects, such as hepatitis, make therapy less efficient. Therefore, continuous efforts have been made to deliver a good therapeutic drug molecule. Recently, Peterson et al. designed and synthesized six substituted dopamine analogues (6–11) and five catechol derivatives (12–16) (Figure 3) for their COMT inhibition studies.16 The authors undertook the work based on an ab initio study of the designed compounds’ binding energies in the enzyme’s active site.17

Figure 3.

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Designed and synthesized (a) dopamine and (b) catechol derivatives.

Dopamine derivatives were synthesized by methods previously reported by the authors,16 and the catechol derivatives were achieved from the corresponding commercially available starting materials by nitration and deprotection of hydroxyl groups by BBr3. The side chain −CN group was introduced from corresponding 2-phenyl ethanol to 2-phenyl ethyl bromide by the Apple reaction and subsequent conversion to nitrile by KCN. Finally, the deprotection of methoxy groups afforded the catechol derivatives (Figure 4).

Figure 4.

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Synthesis of the catechol derivatives.

The synthesized compounds were checked for their stability under the assay conditions in a phosphate buffer at pH 7.4 for 1 h and then analyzed by HPLC before the inhibition study, revealing that all of the compounds experienced little to no degradation over the time except 5-(2-aminoethyl)benzene-1,2,4-triol (6), 1,2,3,4-tetrahydroisoquinoline-6,7-diol (7), 2-(4,5-dihydroxy-2-nitrophenyl)acetonitrile (14), and 3-(3,4-dihydroxyphenyl)propanenitrile (PCN) (15). The in vitro S-COMT inhibition by the synthesized dopamine derivatives (6–11) was tested at two concentrations, 10 and 100 μM, with reference to 3,5-dinitrocatechol (DNC) as a positive control. The authors did not report the IC50 values for the compounds. Dopamine derivatives (6–11) did not show any inhibition effect at 10 μM. At 100 μM, the catechols 2-(2-aminoethyl)-4,5-dihydroxybenzonitrile (10) and 4-(2-aminoethyl)-5-nitrobenzene-1,2-diol (11) exhibited about 30% to 50% COMT inhibitory activity. At 10 μM, only 2-(4,5-dihydroxy-2-nitrophenyl)acetonitrile (14) showed a significant decrease in the COMT activity. However, at 100 μM, all the nitrile derivatives inhibited COMT activity to some degree with 2-(4,5-dihydroxy-2-nitrophenyl)acetonitrile (14) and 3-(4,5-dihydroxy-2-nitrophenyl)propanenitrile (16) demonstrating complete inhibition of COMT. The pKa values and docking studies supported trends of the COMT inhibition effect of these compounds. The compounds with an electron-withdrawing nitro group help to lower the pKa, but the neutral nitrile tail interacts more favorably with the residues at the back of the active site.

2.1.1. Nitrocatechol Chalcone Derivatives

Hitge et al. (2020) designed and synthesized a series of novel nitrocatechol chalcone and nitrocatechol pyrazoline derivatives as COMT inhibitors.18 The designed compounds were synthesized by nitration of 4-hydroxy-3-methoxyacetophenone (apocynin, 17) with nitric acid in the presence of acetic acid to form the nitro derivative (5-nitro-apocynin; 18). Demethylation of nitro derivative 18 in the presence of AlCl3 in pyridine and ethyl acetate gave 5-acetyl-3-nitrocatechol (19), which on Claisen–Schmidt condensation reaction with an appropriate aldehyde in the presence of KOH in ethanol formed nitrocatechol chalcones (20). The nitrocatechol pyrazoline derivatives (21) were synthesized by reacting compounds 20 with hydrazine hydrate in the presence of acetic acid at 120 °C (Figure 5).19

Figure 5.

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Synthesis of nitrocatechol chalcone derivatives.

Rat liver tissue was used as an enzyme source to determine the COMT inhibitory activity of the synthesized compounds.20 Among the synthesized derivatives, nitrocatechol pyrazoline derivatives were found to be more potent than nitrocatechol chalcone derivatives. In a series of nitrocatechol pyrazoline derivatives, all the designed compounds demonstrated effective COMT inhibitory activity (IC50 = 0.048 to 0.21 μM) compared to the standard molecule entacapone (IC50 = 0.23 μM). In this series, compound 24a was found to be the most active COMT inhibitor with an IC50 value of 0.048 μM. The presence of the −CN group at the fourth position of the spacer phenyl, which attached to the R position, was responsible for the COMT inhibitory activity of compound 24a. Substitution of the −CN group at the third position of spacer phenyl resulted in a slight decrease in COMT inhibitory activity. The replacement of the −CN group with the −OH group at the spacer phenyl also causes a decline in COMT inhibitory activity. In this series, among the heterocyclic derivatives (24d–24g), compound 24d (2-thiazolyl substituted) was found to be the most active compound with an IC50 value of 0.16 μM. Substitution of 2-furyl, 3-furyl, and 2-thienyl at the R position resulted in a slight decrease in COMT inhibitory activity.

In a series of nitrocatechol derivatives, compound 23a showed the highest COMT inhibitory activity with an IC50 value of 0.14 μM. Substitution of the −OH group at the third position of spacer phenyl, which attached to the R position, was responsible for the highest COMT inhibitory activity. Substitution of the −CN group at the fourth position of spacer phenyl retains the COMT inhibitory activity, while substitution of the −CN group at the third position of spacer phenyl results in a decrease in inhibitory activity. The substitution of heterocyclic moieties such as 3-thienyl and 2-furyl at the R position showed similar inhibitory activity compared to that of standard molecule entacapone. Substitution of 2-thiazolyl at the R position resulted in a slight decrease in COMT inhibitory activity; further substitution with 1-methyl-1H-pyrazol-4-yl at the R position resulted in the least potent COMT inhibitor 23i with an IC50 value of 0.29 μM (Figure 6).

Figure 6.

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SAR of nitrocatechol chalcone and pyrazoline derivatives.

2.2. Pyridine Derivatives

de Beer et al. (2021) introduced the design and synthesis of various non-nitrocatechol 3-hydroxypridin-4-ones as COMT inhibitors.21 The designed compounds were synthesized by refluxing maltol with suitable primary amines in an acidified water/ethanol (0.9:0.1) mixture as a solvent to afford the 3-hydroxypyridine-4-ones (Figure 7).

Figure 7.

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Synthesis of 3-hydroxypyridin-4-ones.

The COMT from porcine liver was used in the study, and (−)-norepinephrine was used as the enzyme substrate. Among the synthesized derivatives, compounds 27a and 27i were identified as active COMT inhibitors with IC50 values of 4.55 μM and 5.76 μM, respectively, but not as active as the reference inhibitors, entacapone and tolcapone. The spacer between the phenyl group and pyridone moiety by one to four carbon atoms significantly affected the COMT inhibitory activity. The spacers with 1- and 4-carbon atoms showed increased inhibitory effect; however, the spacer with 1-carbon, benzyl, showed the highest COMT inhibitory effect (Figure 8). The methyl substituent at the 4-position of the benzyl group exhibited slightly decreased inhibitory activity. The −Cl substitution at the 4-position of the phenyl group showed a slight increase in inhibition, and the same substitution at the 3-position made no appreciable change in the activity. Docking of compound 27a indicated proper positioning for coordination with Mg2+.

Figure 8.

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SAR of pyridin-4-one derivatives.

2.3. Pyridinone Derivatives

Ernst et al. (2019)22 designed and synthesized a series of fused bicyclic pyridinone derivatives and evaluated their inhibitory activity against COMT. The synthesis of the target molecules was started with −OH protection of the hydroxyl group of kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (28), to form compound 29. The N atom was installed in the kojic acid ring by ethylenediamine at 90 °C in ethanol through replacing the ring O atom of kojic acid (30). The cyclization to a fused heterocyclic system was then achieved by oxidation of the hydroxymethyl group and imine formation in one pot (31). The reduction of the imine with NaBH4 yielded a pyridopyrazine fused bicyclic ring (32). Then functionalization of the N–H group (33) and successive deprotection of the benzyl group lead to the target molecules (34) as shown in Figure 9.

Figure 9.

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Synthetic route for fused bicyclic hydroxypyridones.

Initially, the COMT inhibition was assessed for the parent and seven N-functionalized compounds (Figure 10). Among them, the N-benzylated derivative exhibited COMT inhibition in the submicromolar range with an IC50 value of 220 nM. Others showed many fold loss in COMT inhibition. The group subsequently investigated COMT inhibition with N-benzylated compounds by modifying the electron-withdrawing groups (EWGs) and electron-releasing groups (ERGs) at the ortho- and para-positions. The result clearly showed that the EWGs and ERGs at the ortho-position had higher potency than the groups placed at the para- position. Among them, the −CH3 group and −Cl group at the ortho-position (36d,e) exhibited excellent inhibition effects with IC50 values of 50 and 40 nM, respectively (Figure 11).

Figure 10.

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SAR of pyridinone derivatives.

Figure 11.

Figure 11

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SAR of pyridinone derivatives.

The −CH3 and −Cl substituents were further taken to explore the inhibition effect at different positions of the benzyl group by keeping one at the ortho-position and another at all available positions. (Figure 11). Among the di −CH3 derivatives 37, methyl groups at the 2,4- (37b) and 2,6-positions (37d) exhibited excellent inhibitory effects with IC50 values of 13 and 6.3 nM, respectively.

Similarly, halogen substituents,–F and–Cl (38), were explored for COMT inhibition and 2-F 38a had a slight loss in potency compared to 2-Cl 38b. Among the dihalo derivatives, 2,4-dichloro- (38b2) and 2,6-dichloro- (38b4) exhibited a further increase in potency, with an IC50 value of 10 nM, compared with chloro and fluoro substituted derivatives (Figure 11).

Along with potent compounds, such as 2-chloro 36e, 2,4-dichloro 38b2, and 2,6-dimethyl derivative 37d, the parent and 2-chloro-6-fluoro derivative 38b3 were examined for physicochemical and drug metabolism and pharmacokinetics (DMPK) properties, both in vitro and in vivo. Interestingly, these potent compounds have extraordinarily low levels of protein and tissue binding, which increase the availability of circulating compounds to interact with the target of interest.

The same group subsequently published the in vivo activity of novel COMT inhibitors to identify a COMT inhibitor with good oral bioavailability and significant effects on neurochemical biomarkers and behavior in rats along with tolcapone as a reference drug.23 The selected previously described potent inhibitors (Figure 12) exhibited good in vivo COMT inhibitory activity by significantly decreasing homovanillic acid (HVA) and increasing 3,4-dihydroxyphenylacetic acid (DOPAC) at the tested time points. Then the cognitive function was measured as performance in the ASST. These novel inhibitors produced qualitatively similar effects compared to tolcapone.

Figure 12.

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Selected potent inhibitors for in vivo COMT evaluations.

2.4. Natural Pentacyclic Triterpene Derivatives

Wang et al. (2021) isolated and determined the structure–activity relationship of various series of natural pentacyclic triterpenes such as oleananes, lupanes, friedelanes, and ursanes as COMT inhibitors.24 A two-photon fluorescent probe was used to determine the COMT inhibitory activity. The reaction was carried out in an incubation mixture containing recombinant human S-COMT (2.0 μg/mL), MgCl2 (5 mM), DTT (1 mM), SAM (200 μM), 3-BTD (2 μM), and varying concentrations (from 0.125 to 20 μM) of tested compounds in a final volume of 200 μL in PBS buffer (50 mM, pH 7.4) in order to determine the IC50 values of COMT inhibition. In a series of oleanane derivatives, compound 43a was found as the most active COMT inhibitor with an IC50 value of 4.7 μM. The substituent −COOH group at R1 and −CH3 group at R3 and R4 positions was responsible for the COMT inhibitory activity of compound 43a. On replacement of the −CH3 group at the R4 position of compound 43a with the CH2OH group, the derivative retains the COMT inhibitory activity. The substituent −COOH group at R1, −CH3 group at R3 and R4 positions, and −OH group at R5 position effect a decrease in COMT inhibitory activity with respect to standard drug epicatechin having an IC50 value of 9.5 μM. The substituents −CH3 at R1 and R3 positions and −COOH at R4 position effect a further decrease in COMT inhibitory activity. The substituent −CH3 at R1, R3, and R4 positions led to the least potent molecule of this series, 43e, with an IC50 value of 114.9 μM. The substituents −COOH at R1, −OH at R2, −CH2OH at R3, −CH3 at R4, and −OH at R5 position (43f) led to loss of COMT inhibitory activity (Figure 13).

Figure 13.

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SAR of oleanane derivatives.

In the series of ursane derivatives, all compounds show less activity as compared to the standard drug epicatechin having an IC50 value of 9.5 μM. Among all these derivatives, compound 44a was found as the most effective COMT inhibitor. The substituents −COOH at R2, −OH at R4, and −CH3 at R3, R7, and R8 positions were responsible for the highest COMT inhibition of compound 44a. The substituents −COOH at R1, −OH at R4, and CH3 at R3, R7, and R8 positions led to a decrease in COMT inhibitory activity. The substituents −COOH at R1, −CH2OH at R3, −OH at R4 and R5 positions, and −CH3 at R2, and R8 position led to the least potent molecule of this series with IC50 value 43.1 μM. With substituents −COOH at R2, −OH at R4, =O at R6, and −CH3 at R3 and R8 positions, 44d exhibited loss of COMT inhibitory activity (Figure 14).

Figure 14.

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SAR of the ursane derivatives.

In the series of lupane derivatives, the substituent −COOH at R1, −CH3 at R2 and R3 positions, and −OH at R4 position conferred the highest efficacy for COMT inhibition within this series, with an IC50 value of 5.07 μM. The substituents −CH2OH at R1, −CH3 at R2 and R3 positions, and −OH at R4 position produced a slight increase in COMT inhibitory activity with respect to standard drug epicatechin. The substituents −CH3 at R1, R2, and R3 positions and −OH at R4 position further increased COMT inhibitory activity. The substituents −C=O at R1, −CH3 at R2 and R3 positions, and −OH at the R4 position slightly decreased COMT inhibitory activity. Substituents −COOH at R1, −CH3 at R2 and R3 positions, and =O at R4 position further decreased COMT inhibitory activity. Substituents −CH3 and COOH at R1, −CH2OH at R2, −CH3 at R3, and −OH at R4 produced the least potent molecule (45f) of this series with an IC50 value of 31.42 μM (Figure 15).

Figure 15.

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SAR of the lupane derivatives.

In the series of friedelane derivatives, they found three derivatives, namely, known as celastrol, hydrocelastrol, and friedelin. Among these compounds, celastrol demonstrates the most significant inhibitory efficacy against COMT, evidenced by an IC50 value of 3.89 μM; conversely, hydrocelastrol exhibits a comparatively diminished COMT inhibitory efficacy relative to the reference compound epicatechin, which has an IC50 value of 9.5 μM, whereas friedelin manifests no observable COMT inhibitory activity (Figure 16).

Figure 16.

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SAR of friedelane derivatives.

2.5. Flavonoid Derivatives

Zhao et al. (2021) isolated and characterized naturally occurring potent COMT inhibitors from the medicinally active plant Scutellariae radix.25 A Triple TOF 5600 mass spectrometer (AB SCIEX) running in negative ion mode was coupled to a UPLC system (Shimazu) for the analysis of the samples, and mixed standards were used to determine the composition. To determine the COMT inhibitory activity, 3-(benzo[d]thiazol-2-yl)-7,8-dihydroxy-2H-chromen-2-one (3-BTD), an extremely selective optical probe substrate specifically designed for measuring the residual activities of human catechol-O-methyltransferase (hCOMT) in the presence or absence of inhibitors, was used. Among the isolated derivatives, compound 49a was found to be the most active molecule against COMT having an IC50 value of 0.018 μM. The substituent −OCH3 at R2 position was responsible for the highest significant COMT inhibitory activity of compound 49a. Substituents (1S,2R,3S,4S,5R)-2,3,4-trihydroxy-5-(λ-oxidaneyl)cyclohexane-1-carboxylic acid at Ar2 and −OCH3 at R5 position (51a) increased COMT inhibitory activity with respect to entacapone, having IC50 value 0.23 μM. The substituent −OH group at the R1 and R2 positions conferred a further increase in COMT inhibitory activity. Substituent −OH at the R2 position slightly decreased the COMT inhibitory activity. Furthermore, the substitution −OCH3 at the R3 position resulted in a decrease in the COMT inhibitory activity. The substituent (1S,2R,3S,4S,5R)-2,3,4-trihydroxy-5-(λ-oxidaneyl)cyclohexane-1-carboxylic acid at Ar2 position produced the least active compound (51b) against COMT with IC50 value greater than 100 μM (Figure 17).

Figure 17.

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SAR of flavonoid derivatives by Zhao et al. (2021).25

Zhao et al. further isolated and characterized flavonoid derivatives from vine tea as COMT inhibitors in 2021.26 A Triple TOF 5600 Mass Spectrometer system (AB SCIEX, Foster City, USA) in conjunction with a UPLC system (Agilent, California, USA) was used to carefully analyze the main ingredients of the bioactive fractions of vine tea. A highly selective optical probe substrate called 3-BTD was utilized to measure the COMT inhibitory activity in the presence or absence of inhibitors. For comparison of the COMT activity, quercetin was used as a standard. Among the isolated flavonoid derivatives, compound 53a exhibited the highest level of potency with an IC50 value of 0.96 μM. Substituents benzene-1,2,3-triol at the Ar2 position and −OH group at R1 position were responsible for the highest COMT inhibitory activity of compound 53a. Substituents benzene-1,2,3-triol at the Ar2 position and (2S,3R,4S,5S,6R)-2-methyl-6-(oxidaneyl) tetrahydro-2H-pyran-3,4,5-triol at R1 position slightly decreased COMT inhibitory activity with respect to standard molecule quercetin. Removal of the double bond from a core molecule of flavonoid at the second position of ring A results in a decrease in COMT inhibitory activity. Substitution of benzene-1,2,3-triol at the Ar1 position of saturated ring A of the flavonoid molecule results in a further decrease in COMT inhibitory activity. Substitution of 4-methylbenzene-1,2-diol at the Ar1 position of saturated ring A of the flavonoid molecule resulted in the least active molecule against COMT with an IC50 value of 42 μM (Figure 18).

Figure 18.

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SAR of flavonoid derivatives.

2.6. Tetralone and Indanone Derivatives

de Beer et al. (2021) designed and synthesized a series of novel tetralone and indanone derivatives as COMT inhibitors.27 The designed compounds were synthesized from 5-nitrovanillin (54), treated with aluminum trichloride (AlCl3) in the presence of pyridine to give intermediate 3,4-dihydroxy-5-nitrobenzaldehyde (55), which was reacted in acidic medium with appropriate 1-indanone (56) and 1-tetralone (57) derivatives to give the corresponding indanone derivatives (58) and tetralone derivatives (59) (Figure 19).

Figure 19.

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Synthesis of tetralone and indanone derivatives.

The soluble fractions from homogenates of rat liver tissue were used as an enzyme source for the COMT inhibition investigations.28 Among the synthesized compounds, indanone derivatives were found to be more potent inhibitors as compared to tetralone derivatives. In a series of indanone derivatives, the one with a substituent −CH2O– group at the R1 position (61a) showed the highest COMT inhibitory activity with IC50 value of 0.16 μM. The substituent −OCH3 at the R1 position slightly increased COMT inhibitory activity as compared to the standard molecule entacapone (IC50 = 0.23 μM). Substitution of hydrogen and −OCH3 at R1 and R2 positions simultaneously results in a decrease in COMT inhibitory activity. Substitution of the hydroxy (−OH) group at the R1 position, 61e, results in the least potent COMT inhibitor of this series with an IC50 value of 0.38 μM.

In the series of tetralone derivatives, all molecules were found to be less potent COMT inhibitors compared to entacapone. In this series, the substitution of electron donating groups (−NH2, −OCH3) and hydrogen resulted in a decrease in COMT inhibitory activity as compared to entacapone. Substitution of the −NH2 group at the R2 position (60a) resulted in the highest COMT inhibition in this series with an IC50 value of 0.24 μM. The substituents −OCH3 at R2 and R3 positions slightly decreased COMT inhibitory activity. The substituent hydrogen at the R1, R2, and R3 positions decreased the COMT inhibitory activity. The substituent −OCH3 at the R1 or R3 position further decreased COMT inhibitory activity. The substitution of −OCH3 at the R2 position (60f) resulted in the least potent COMT inhibitor of this series with an IC50 value of 0.79 μM. Overall indanone derivatives showed better COMT inhibitory activity than tetralone derivatives (Figure 20).

Figure 20.

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SAR of tetralone and indanone derivatives.

2.7. Miscellaneous

Kadowaki et al. (2023) isolated various COMT inhibitors from Calendula officinalis leaf.29 The primary constituents of Calendula leaves were determined by isolating ten specific compounds through a variety of chromatographic methods. The isolated compounds were identified by mass spectroscopy (MS) and nuclear magnetic resonance (NMR) spectroscopy to be quercetin 3-O-β-glucoside (62a), isorhamnetin 3-O-β-glucoside (62b), quercetin 3-O-β-neohesperidoside (62c), quercetin 3-O-6″-O-methylmalonyl)-β-glucoside (63a), quercetin 3-O-(6″-O-malonyl)-β-glucoside (63b), quercetin 3-O-(2″-O-α-rhamnosyl-6′′-O-malonyl)-β-glucoside (63c), isorhamnetin 3-O-(6″-O-malonyl)-β-glucoside (63d), chlorogenic acid (64a), 3,4-dicaffeoylquinic acid (64b), and syringic acid (65). For determining the COMT inhibitory 3-(benzo[d]thiazol-2-yl)-7,8-dihydroxy-2H-chromen-2-one (3-BTD) was used.30 For comparison of the COMT inhibitory activity, tolcapone was used as a standard drug. All of the isolated compounds showed less COMT inhibitory activity than the standard drug tolcapone, having an IC50 value of 0.55 μM. Among all isolated derivatives, compound 64a was found to be the most active COMT inhibitor with an IC50 value of 21 μM. The substituent caffeoyl at R6 and R7 positions was responsible for the COMT inhibitory activity of compound 64a. The substituent caffeoyl at the R7 position resulted in a decrease in COMT inhibitory activity. The substituent hydrogen at R1 and R2 positions maintained the COMT inhibitory activity with IC50 value 50 μM. Substituents −CH3 at the R1 position and rhamnose at the R2 position simultaneously decreased the COMT inhibitory. The substituents hydrogen at the R3 and R4 positions and −CH3 at the R5 position produced promising COMT inhibitory activity with an IC50 value of 42 μM. Substituent hydrogen at R3, R4 and R5 positions decreased COMT inhibitory activity. The substituents hydrogen at the R3 and R5 positions and rhamnose at the R4 position further decreased in the COMT inhibitory activity. Compound 63d with substituents −CH3 at R3 position and hydrogen at R4 and R5 positions and compound 65 showed the least potent COMT inhibition with an IC50 value greater than 100 μM (Figure 21).

Figure 21.

Figure 21

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SAR of various COMT inhibitors from Calendula officinalis leaf by Kadowaki et al.29

3. Conclusion

The SAR of COMT inhibitors has emerged as a vital tool in the pursuit of novel therapeutics for Parkinson’s disease, depression, and anxiety disorders. In this review, we discussed the synthesis and SAR of various catechol, nitrocatechol, pyridine, pyridinone, flavonoid, tetralone, indanone, and natural pentacyclic triterpene derivatives which have been recently discovered (2019–2024). By elucidating the intricate relationships between chemical structure and biological activity, this review will provide a roadmap for researchers for the design and optimization of next-generation COMT inhibitors. As the field continues to evolve, the insights gleaned from SAR will be crucial in unlocking the full potential of COMT inhibitors and enabling the development of safer, more effective, and personalized treatments for patients in need. Through leveraging the potential of SAR, researchers and clinicians can collaborate to influence the future trajectory of neurology and psychiatry, enhancing lives and improving outcomes.

Acknowledgments

H.K.A.Y. would like to thank the Deanship of Graduate Studies and Research, Ajman University, UAE, for their support in providing assistance in article processing charges for this manuscript.

Biographies

Riya Rachel Thomas is a dedicated researcher with a strong academic background in pharmaceutical sciences. She completed her Bachelor of Pharmacy (B.Pharm) at Amrita School of Pharmacy in Kochi and is currently advancing her studies with a Master of Pharmacy (M.Pharm) in Pharmaceutical Chemistry from the same institution under the guidance of Prof. Dr. Bijo Mathew. Her research interests lie in the synthesis of small molecules and their potential applications in treating neurodegenerative disorders. Driven by a passion for innovative therapeutic development, she aims to contribute to the field of pharmaceutical chemistry by discovering new compounds that could offer hope for patients with neurological diseases.

Rangarajan T. M. is an Assistant Professor of Chemistry at Sri Venkateswara College, University of Delhi, India. He obtained his Ph.D. in Organic Chemistry in 2015 from the University of Delhi. His research interests include organic synthesis, fluoroorganic chemistry, electrochemical perfluorination reactions, and drug development for neurodegenerative diseases and antimalarial treatment.

Ananya Datta is a third-year B.Sc. (H) Biochemistry student at Sri Venkateswara College, University of Delhi, India. She is a recipient of the prestigious INSPIRE Scholarship by the Department of Science and Technology, Government of India. She is one of the Editorial board members of the “Biochemical Society-CATALYSIS” of Sri Venkateswara College. Her research interests include psychoneuroimmunology, oncology, and neurodegenerative disorders and related drug development.

Shailesh Verma is currently in the third year of B.Sc. (H) Biochemistry at Sri Venkateswara College, University of Delhi, India. His major area of research interest is Genomics and Neuroscience.

Ankita Patel is a third year Undergraduate Biochemistry student at Sri Venkateshwara College, University of Delhi, India. She is one of the members of the “Biochemical Society- CATALYSIS” of Sri Venkateshwara College. Her research interests include molecular biology and bioinformatics.

Sandeep Bindra is a dedicated postgraduate student pursuing an M. Pharm. in Pharmaceutical Chemistry at Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Coimbatore, India. With a strong passion for medicinal chemistry, particularly synthetic chemistry, he is committed to deepening his knowledge and making significant contributions to the academic community. He earned his Bachelor’s degree from Dr. Bhim Rao Ambedkar University in Agra, India. Currently, as a postgraduate student, he is actively engaged in the design and synthesis of thio/semicarbazide-acetophenone based carbonic anhydrase inhibitors. His research focuses on developing novel inhibitors to treat neurodegenerative diseases.

Haya Yasin is currently a faculty member at the Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, United Arab Emirates. She earned her Master of Science in Pharmaceutical Technology from Jordan University of Science and Technology, Irbid/Amman, in August 2011, following her Bachelor of Pharmacy degree from the same institution in June 2009. Her research focuses on areas such as drug delivery and targeting, 3D printing of pharmaceutical formulations, and pharmacy practice, contributing to advancements in pharmaceutical education and innovation. Haya Yasin has received several prestigious awards and honors in her field. At the 26th Dubai International Pharmaceutical and Technology Conference and Exhibition (DUPHAT 2021), she earned the First Best Pharmacy Poster under the “Thematic” category and the Fourth Best Pharmacy Poster under the “Quality” category. Additionally, she achieved second and third place in the poster competition at the International Conference of Pharmacy and Medicine (ICPM), demonstrating her excellence in research and contribution to pharmaceutical science. Currently, she has 25 publications of repute as per Scopus Database.

Suraj Mali holds a Ph.D. in Pharmacy and currently serves as an Assistant Professor of Pharmaceutical Chemistry at the School of Pharmacy, DY Patil University, Navi Mumbai, India. A former analytical scientist at Dr. Reddy’s Laboratories in Hyderabad, India, Dr. Mali has an M. Pharm. in Pharmaceutical Science and Technology from the Institute of Chemical Technology, Mumbai. He is a distinguished reviewer for 267 scientific journals and was named a Bentham Science Brand Ambassador for 2019–2020. With over 140 international journal publications and an H-index of 27 (Scopus Citations: 1635), Dr. Mali’s research focuses on molecular modeling, synthetic chemistry, phytochemistry, pharmacology, and analytics, with a keen interest in drug design and synthesis. His notable achievements include the Institute of Chemical Technology’s Masters Best Thesis Aditya Birla Award in 2019. His work has garnered international recognition, including a publication in Nature Scientific Reports on identifying antimycobacterial agents through computational methods. Furthermore, Dr. Mali was ranked among the world’s top 2% of scientists by Stanford University in both 2023 and 2024, a testament to his outstanding contributions to pharmaceutical science.

Della Grace Thomas Parambi is presently working as Associate Professor in the Faculty of Pharmacy, Jouf University, Saudi Arabia. She has accomplished her pharmacy Ph.D. in Pharmaceutical analysis and has more than 20 years of teaching experience in Analytical Chemistry, Medicinal Chemistry, Molecular Modeling, and Drug Design. The primary research activities in her research group focus on the design of MAO/ChE inhibitors for neurodegenerative disorders. She has also published more than 70 research articles in peer-reviewed international journals and authored one book, 9 book chapters and one patent to her credit. Dr. Della, despite being one of the best chemists and academicians, has also been able to translate difficult chemistry into general understanding for students.

Bijo Mathew is a Professor in the Pharmaceutical Chemistry department at Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi, India. In 2024, Dr. Mathew worked as Visiting Professor in the department of medicinal chemistry at University of Bari, Italy. Bijo Mathew obtained his M.Pharm. in Pharmaceutical Chemistry from The Tamilnadu Dr. M.G.R. Medical University, Tamilnadu, India, in 2008 and Ph.D. in Pharmaceutical Sciences from Jawaharlal Nehru Technological University, Hyderabad, India, in 2016. Mathew’s primary focus areas are drug discovery of neurodegenerative disorders and cancer and molecular modeling. His main research interest is in the design of enzyme inhibitors, especially MAOs, ChEs, and BACE1. He received the Top 2% Scientists category from the world Stanford’s list in 2020 to 2024. He has published 245 papers [h-index = 44; the number of citations: 6423 in Google Scholar, h-index = 41; the number of citations: 370 in Scopus; Cumulative Impact factor: 790.0: August 2024]. With 16 years of teaching and research experience, Mathew authored one book, edited two books, authored seven book chapters, and gave 37 invited talks at national and international levels. Dr. B. Mathew serves as a chief executive guest editor of the journals Molecules, Current Topics in Medicinal Chemistry, and Current Drug Targets. He serves on the editorial board of journals Brain Sciences and Combinatorial Chemistry and High Throughput Screening. For the development of MAO inhibitor drugs, Dr. Mathew obtained funds from many government funding organizations in India, including DRDO and ICSSR. He received Amrita Vishwa Vidyapeetham Chancellor’s Publication and Merit awards in 2021 and 2024. He received three patents from the Korean and two from the German Intellectual Property office.

The authors declare no competing financial interest.

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