Research ArticleExperimental Studies
Open Access

Coumarin-based Oximes Exert Monoamine Oxidase Inhibitory Activity

QUDUS KOLAWOLE, VEERA L.D. BADISA, MUSILIYU A. MUSA and LEKAN LATINWO
Anticancer Research February 2026, 46 (2) 601-610; DOI: https://doi.org/10.21873/anticanres.17972

Abstract

Background/Aim: Coumarins (Benzopyran-2-one) are a broad class of compounds of both natural and synthetic origin with diverse pharmacological properties that have attracted intense interest in recent years. For example, the coumarin nucleus has emerged as a promising scaffold for monoamine oxidase (MAO) inhibitors (MAOIs), an essential target for developing drugs to treat neurodegenerative disorders. In the present study, we report the in vitro cytotoxic and MAO inhibitory activities of 3-acylcoumarin-oximes (7a-l) bearing various substituent groups on the core coumarin ring.

Materials and Methods: The cytotoxic activity was evaluated using crystal violet dye binding, MAO activity was assayed using the MAO-GloTM kit, and the Free radical scavenging activities of the most active compound were tested spectrophotometrically using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and hydrogen peroxide (H2O2) methods.

Results: The in vitro cytotoxic activity indicated that all the synthesized compounds were non-cytotoxic against Neuroblastoma 2A (N2a) cells except compound 7k (cytotoxic concentration, CC50=30.8±0.3 μM), bearing the hydroxy group at the carbon-7 and -8 positions. However, this cytotoxic compound showed the least MAO (hMAO-A and hMAO-B) inhibitory activity. Interestingly, the non-cytotoxic compound 7f, bearing the diethylamino group at the C-7 position, showed the highest MAO inhibitory activity (hMAO-A: IC50=1.27±0.66 μM and hMAO-B: IC50=4.65±0.52 μM), MAO (A/B), non-selectivity (selectivity index, SI=3.66), reversible inhibition against hMAO-A enzyme, neuroprotection in H2O2-treated N2a cells, and capability of neutralizing free radicals in DPPH assay.

Conclusion: The 7-diethylamino–substituted 3-acylcoumarin-oxime derivative (compound 7f, bearing a diethylamino group at the C-7 position of the coumarin ring) can be considered a promising scaffold for developing new and more potent MAOI drugs for treating neurodegenerative disorders.

Keywords:

Introduction

Coumarins or Benzopyran-2-ones are an important class of naturally occurring oxygen heterocyclic compounds consisting of benzene and α-pyrones; first isolated from Tonka beans (Dipteryx odorata Wild; Fabaceae family) in 1820 (1). They belong to the flavonoid class of secondary metabolites found in green plants, fungi, and bacteria, and their extracts are used in traditional medicine (2). Coumarins are classified as natural (NCs) and synthetic (SCs) exhibiting a variety of pharmacological properties, e.g., anti-coagulant, anti-cancer, anti-thrombotic, anti-inflammatory, anti-HIV, anti-bacterial, anti-microbial, anti-influenza, antituberculosis, anti-asthmatic, anti-hyperlipidemic, antiplatelet, anti-alzheimer, anti-oxidant, anti-allergic, CNS stimulant, monoamine oxidase (MAO) inhibitory, vasodilatory, scavenging of reactive oxygen species (ROS), anthelmintic, diuretic, estrogenic, dermal, insecticidal, sedative, hypnotic, hypothermic, and as dyes (3-7). In addition to the above activities, coumarins are used as food and cosmetic additives, as well as optical brightening agents, including dispersed fluorescent and laser dyes (8, 9). Given this, coumarins have attracted intense interest in recent years as novel therapeutic agents in drug discovery. Some of the coumarin derivatives, which are already booming in the market include Auraptene (chemopreventative), Acenocoumarol (anticoagulant), Armillarisin A (antibiotic), Brodifacoum (anticoagulant), Carbochromen (coronary disease), Difenacoum (anticoagulant), Ensaculin (KA-672; NMDA antagonist and a 5HT1A agonist), Hymecromone (choleretic and antispasmodic), Novobiocin (antibiotic), Phenprocoumon (anticoagulant), Scopoletin (antifungal and MAOI), and Warfarin (anticoagulant) (10).

The therapeutic applications and pharmacological properties of coumarins are attributed to the nature and position of substituents on the core coumarin molecule, which facilitates binding to various targets through hydrophobic non-covalent interactions (e.g., π−π stacking, hydrophobic, and electrostatic interactions) (11, 12). Coumarins have been widely reported to exert anticancer and MAO inhibitory activities (13). As anticancer agents, coumarins are known to exert their activity against cancer cells through different mechanisms such as inhibition of kinases, cell cycle progression, cell apoptosis, cellular proliferation, estrogen receptor (ER) signaling, angiogenesis, heat shock protein (HSP90), telomerase, mitosis, carbonic anhydrase (CA), monocarboxylate transporters, aromatase, sulfatase and multiple drug resistance (MDR) (14, 15). However, they inhibit MAO enzymes (MAO-A or MAO-B) through the inhibition of multiple signaling pathways, including neurotransmitter (monoamine alterations), neurotrophic (BDNF activation), inflammatory (cytokine modulation), and neuroinflammatory (restoration of the brain-gut-microbiome colony) pathways (16). It has been reported that coumarin nuclei with an acyl group at the C-3 position (e.g., 3-acyl coumarins) exerts enhanced MAO inhibitory activity (17-20). MAO enzymes are involved in diseases of the nervous system by catalyzing oxidative deamination of various neurotransmitters (e.g., serotonin (5-HT), norepinephrine (NE), and dopamine) that cause an increase in reactive oxygen species (ROS) production (e.g., hydrogen peroxide), which could lead to oxidative stress (21). MAO-A inhibitors (MAOIs-A) are used for the treatment of depression and anxiety. At the same time, MAO-B inhibitors (MAOIs-B) are used for the treatment of Parkinson’s disease (PD) and have also been linked to Alzheimer’s disease (AD) and stroke-related neuronal injury. However, in recent years, there has been increasing interest in the search for selective MAOIs as potential neuroprotective and/or neurorescue agents that reduce oxidative stress.

Recently, 3-acylcoumarins (Figure 1) have been reported to show interesting inhibitory activity against human MAO-A/B (hMAO-A/B) enzymes, and the absence of cytotoxicity as a requirement in developing novel MAOIs (17, 18, 22). These studies aroused our interest in the present study, which involves coumarin-oxime, a promising pharmacophore in drug discovery with a broad range of biological and pharmaceutical properties (23, 24). In the present study, we report the evaluation of the in vitro cytotoxicity of 3-acyl coumarin-oximes (7a-l) (bearing different substituents at position C-5, C-6, C-7, and C-8 of the coumarin nucleus) against Neuro 2A (N2a) cells, and their hMAO inhibitory, neuroprotective, and antioxidant activities

Figure 1.
Figure 1.

Chemical structure of the 3-acyl substituted coumarins (1-6) (17, 18, 21, 22).

Materials and Methods

Chemicals. The cell line (Neuro 2A, N2a) and culture medium (DMEM (1X) were obtained from American Type Culture Collection (ATCC) (Rockville, MD, USA). Penicillin-streptomycin anti-biotic solution (100×), fetal bovine serum (FBS), trypsin-EDTA solution (1×), phosphate buffered saline (PBS), 50% glutaraldehyde, crystal violet, clorgyline, paragyline, moclobemide, safinamide mesylate, 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2) and tamoxifen were obtained from Sigma-Aldrich (St. Louis, MO, USA). MAO-Glo TM kit containing hMAO-A and hMAO-B enzymes was obtained from Promega Corporation (Madison, WI, USA).

Cell viability assay. The mouse cell line (N2a) was cultured as we previously reported (22, 25). Cell viability was assessed by maintaining N2a cells in DMEM (1X) complete medium in T-75 cm2 flasks at 37°C in a 5% CO2 incubator. Cells were plated at a density of 5 × 104 cells/well in a 24-well plate and allowed to stabilize overnight in an incubator. The cells were then treated with compounds (7a-l) at different concentrations (0-100 μM) in a final volume of 1 ml per well in triplicate wells and maintained for 48 h, and cytotoxic concentration (CC50) was calculated according to our previous report (24). All experiments were repeated at least two times.

Inhibition of hMAO enzymes. The hMAO inhibitory activities of compounds (7a-l) and reference compounds (clorgyline, paragyline, moclobemide, and safinamide mesylate) were determined using the MAO-GloTM kit as we previously described (22). Briefly, 12.5 μl (4X) of MAO Substrate solution and the tested compounds (7a-l) at various concentrations were added per well to a white 96-well plate, followed by adding 25 μl (2X) of MAO-A (0.3 μg/reaction) or MAO-B (0.9 μg/reaction) enzyme solution. The contents were mixed on a microplate shaker for 30 s and then incubated at room temperature (RT) for 1 h. The constituted luciferin detection reagent (50 μl) was added per well, incubated in the dark at RT for 30 min, and the luminescence was measured using the Promega Glomax Explorer GM3500 Microplate Reader (Promega).

Reversibility assay. The reversibility of hMAO-A enzyme inhibition by the most active compound 7f was compared with that of reference inhibitors (clorgyline and moclobemide) using a preincubation and dilution method, as previously reported (22). Briefly, in HBSS medium (pH 7.4), compound 7f in 10× and 100× IC50 concentrations and inhibitors were preincubated separately with MAO A (3 μg/reaction) enzyme in Eppendorf tubes for 30 min at RT. For the control, compound 7f in 4x IC50 concentration with MAO A (0.3 μg/reaction) enzyme (in 12.5 μl) was also concurrently preincubated without inhibitors. All reactions were diluted to a 20-fold concentration by adding the respective enzyme buffer and enzyme substrate to a final volume of 125 μl for 10× and 100× IC50 concentration reactions, and 50 μl for a 4× concentration reaction in a white 96-well plate (final concentrations of 0.1× IC50 and 1× IC50) and incubated for 1 h at RT. Finally, the reconstituted luciferin detection reagent (50 μl) was added to each well and incubated in the dark at RT to develop the luminescence. The luminescence was measured using a Promega Glomax Explorer GM3500 Microplate Reader (Promega).

Neuroprotection assay. The neuroprotective effect of compound 7f was evaluated using the previously reported method (22). The 5×104 N2a cells/well in DMEM (1X) complete medium were treated with 50 μM H2O2 in a 24-well tissue culture plate and maintained for 24 h at 37°C in a 5% CO2 incubator. Next, neuroprotection was assessed by pretreating cells with compound 7f (1 or 10 μM) for 1 h, followed by the addition of 50 μM H2O2 (or simultaneous co-treatment with compound 7f and 50 μM H2O2), and then incubating for 24 h in a 5% CO2 incubator at 37°C. At the end of the incubation period, the viability of the cells was assessed using a crystal violet dye uptake assay.

Antioxidant activity assays. The free radical scavenging activities of compound 7f were tested spectrophotometrically using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and hydrogen peroxide (H2O2) methods, as previously reported (26-28), with slight modifications. DPPH method: In brief, 10 μl of different concentrations (250, 500, 750, and 1,000 μM) of compound 7f was mixed with 10 μl of DPPH (10 mM) to achieve a total volume of 1 ml in methanol. H2O2 Method: In brief, 1 μl of different concentrations (250, 500, 750, and 1,000 μM) of compound 7f was mixed with 0.6 mL of H2O2 solution (40 mM) to achieve a total volume of 1 ml in PBS. For each method, the control experiment was conducted as described above, but without the compound 7f. The reaction mixtures were vortexed and incubated in the dark at RT for 30 min (DPPH assay) and 10 min (H2O2). The Free radical scavenging activities were determined by measuring the absorbance at 517 nm (DPPH) and 230 nm (H2O2) using the UV-VIS spectrophotometer. The % inhibition and IC50 (50% inhibition concentration) were calculated according to previous reports (26, 29, 30).

Statistical analysis. Data are presented as mean±standard deviation (SD, n=3), analyzed for significance using one-way analysis of variance, and then compared using Dunnett’s multiple comparison tests using GraphPad Prism v. 10.00 (GraphPad Software Inc., San Diego, CA, USA). The differences were considered statistically significant when p<0.05.

Results

Cell viability assay. The cytotoxic activity of compounds (7a-l) against N2a cells was evaluated using a simple and reproducible crystal violet dye-staining assay at different concentrations (0, 25, 50, 75, and 100 μM). Interestingly, the IC50 values indicated that only compound 7k (IC50=30.8±0.3 μM), bearing the hydroxyl (HO-) group at the C-7 and C-8 positions of the coumarin nucleus, showed cytotoxic activity against the above cell line compared to untreated control cells (100%). Based on this data, all synthesized compounds (7a-l) were selected for further evaluation as potential hMAO enzyme inhibitors.

Inhibition studies of hMAO enzymes. The ability of compounds (7a-I) to inhibit hMAO A and B enzymes was evaluated using a MAO-GloTM kit. The IC50 and the MAO Selectivity Index (SI) of the synthesized compounds and standard reference inhibitors are shown in Table I. According to the results, the cytotoxic compound 7k showed the least MAO inhibitory activity among the synthesized analogs. In contrast, the non-cytotoxic compound 7f showed the highest MAO non-selective inhibitory activity against both hMAO-A (IC50=1.27±0.66 μM) and B (IC50=4.65±0.52 μM) enzymes compared to other analogs, including moclobemide (IC50=238.3±0.25 μM), and pargyline (IC50=6.22±0.69 μM). Furthermore, the MAO inhibitory activity of compound 7f was higher compared to moclobemide (<100-fold), and pargyline (5-fold), all known MAOIs (Table I). Compound 7f was selected for further study based on the data obtained.

View this table:
Table I.

Inhibitory concentration (IC50) and selectivity index (SI) of 3-acetylcoumarins (7a-l) towards human monoamino oxidase (hMAO)-A and hMAO-B enzymes.

Reversibility assay. The recovery of the hMAO-A enzyme activity after dilution was evaluated to determine whether the inhibition by compound 7f is reversible or irreversible, compared to clorgyline (an irreversible inhibitor) and moclobemide (a reversible inhibitor). The results indicated that (i) compound 7f reduced enzyme activity to 58.73% (41.27%±0.84 inhibition) at 1× IC50 and increased enzyme activity to 121.8 %±1.20 (21.8% increase) at 0.1× IC50, (ii) clorgyline showed reduced enzyme activity to 71.4% (28.6%±2.04 inhibition) at 1× IC50 and 73.0% (27.0%±0.08 inhibition) at 0.1× IC50, and (iii) moclobemide showed reduced enzyme activity to 65.2% (34.8%±3.18 inhibition) at 1× IC50 and 5.3% (94.7%±6.64 inhibition) at 0.1× IC50, all compared to the control reaction without the inhibitor (100%) (Figure 2). This indicates that compound 7f showed a higher recovery of hMAO-A enzyme activity at low 0.1× IC50 value concentrations compared to clorgyline and moclobemide, in the order of reversibility: compound 7f > moclobemide > clorgyline.

Figure 2.
Figure 2.

Reversibility assay of human monoamino oxidase (hMAO)-A enzyme inhibition with active compound 7f, clorgyline and moclobemide. Data are presented as mean±standard deviation (SD), n=3 and #represents statistically significant difference compared to control (p<0.05) using Dunnett’s multiple comparison test.

Neuroprotection assay. The neuroprotective effect of compound 7f on N2a cells was investigated. The results indicated that treatment of the cells with 50 μM H2O2 alone, and incubating for 24 h, decreased the cell viability to 20.8%±0.19. However, pretreatment of cells with compound 7f for 1 h, followed by 50 μM H2O2 treatment and incubating for 24 h, resulted in an increase in the viability to 24.17%±1.55 (1 μM) and 43.19%±1.72 (10 μM). Furthermore, co-treatment of cells with compound 7f, followed by 50 μM H2O2 treatment and incubating for 24 h, resulted in an increase in the viability to 22.0%±0.66 (1 μM) and 25.8%±4.4 (10 μM), compared to untreated control (100%) (Figure 3). The above results indicate that compound 7f showed an increase in viability under both conditions compared to cells treated with H2O2 alone (Figure 3).

Figure 3.
Figure 3.

Neuroprotection against H2O2-induced neurotoxicity in N2a cells by compound 7f. Data are shown as mean±standard deviation (SD), n=3. #represents statistically significant difference compared to control and H2O2-alone treated cells (p<0.05) using Dunnett’s multiple comparison test.

Antioxidant activity assays. The free radical scavenging activity of the compound 7f at different concentrations (250, 500, 750, and 1,000 μg/ml) was investigated spectrophotometrically using DPPH and H2O2 assays. The IC50 values were calculated for compound 7f for the DPPH and the H2O2 assays (Table II). The results indicated a concentration-dependent increase in free radical scavenging activities, with the highest DPPH scavenging activity (51.0%±0.01) observed at 1,000 μg/ml and the highest H2O2 scavenging activity (52.7%±0.04) at 750 μg/ml (all at the highest concentration).

View this table:
Table II.

The IC50 value (μM) for (A) DPPH and (B) H2O2 scavenging activity of compound (7f).

Discussion

Coumarins are used in drug discovery as emerging and promising MAOI drug candidates to target neurological diseases, attracting considerable interest over the years. Recently, we demonstrated that non-cytotoxic 3-acetylcoumarins (against MDA MB-231 and MCF-7 breast cancer cell lines) showed interesting MAO inhibition activities (22), which aroused our interest in 3-acetylcoumarin-oxime (7a-l) as an attractive target for hMAO inhibition. In the present study, 3-acylcoumarin-oximes (7a-l) were designed to evaluate how different substituents [R=H, Br, Cl, OH, N(CH2CH3)2, OCH3, and OCH2CH3] at C-5, C-6, C-7, and C-8 positions of the coumarin nucleus would influence cytotoxicity and hMAO inhibitory activities. The in vitro cytotoxicity study indicated that 3-acylcoumarin-oximes were non-cytotoxic against N2a cells, except for compound 7k (IC50=30.8±0.3 μM), which bears the hydroxyl (HO-) group at the C-7 and C-8 positions, showing an interesting cytotoxic activity compared to the untreated control cells (100%). This finding is supported by previous reports indicating that the hydroxyl (HO-) group at the C-7 and C-8 positions on the coumarin ring enhances cytotoxic activity in various cancer cell lines (26, 29, 30). Based on the present in vitro cytotoxicity data, compounds (7a-l) were selected for further evaluation as potential hMAO enzyme inhibitors. The results of hMAO enzyme inhibition studies showed that compounds 7b (6-Br), 7f (7-N(CH2CH3)2), and 7h (6,8-diCl) caused an increase in hMAO-A enzyme inhibition (exhibiting IC50 values between 1.27–9.62 μM) in comparison to 7a (unsubstituted analog). Furthermore, compounds 7b (6-Br), 7e (6-Cl), and 7f (7-N(CH2CH3)2) showed an increase in hMAO-B enzyme inhibition (exhibiting IC50 values between 4.65-9.12 μM) in comparison to 7a (unsubstituted analog). Interestingly, the non-cytotoxic compound 7f bearing the 7-N(CH2CH3)2 group showed the highest non-selective inhibitory activity against MAO-A/B enzymes (MAO inhibitory activity A>B). In contrast, the cytotoxic compound 7k bearing the 7,8-dihydroxy group showed the least inhibitory activity. Furthermore, compound 7f showed higher potency than moclobemide (MAO-A inhibitor) and pargyline (MAO-B inhibitor) and lower potency than clorgyline (MAO-A inhibitor) and safinamide mesylate (MAO-B inhibitor) (Table I). This result is supported by previous reports indicating that coumarins are emerging and promising MAOI drug candidates for targeting neurodegenerative diseases (21, 22, 31, 32).

The reversibility of MAO-A enzyme inhibition is a strategy that assesses how a potential drug candidate binds to the enzyme temporarily, allowing displacement by competing substrates. Our result showed that the reversibility of compound 7f is comparable to that of moclobemide (reversible MAO-A inhibitors) (Figure 2); thus, it could have an efficient therapeutic application for the treatment of neurological diseases, including anxiety and depression, by eliminating the classical side effects associated with MAOI irreversibilities (33-36). MAOIs are therapeutic drugs used to treat neurological diseases and possess neuroprotective activity by inhibiting the production of oxidative stress mediators (hydrogen peroxide, aldehyde, and substituted amine), producing specific antioxidant actions (22, 37-40). Oxidative stress has been considered a pathogenic mechanism underlying neuronal cell death in neurodegenerative disorders (41, 42). Therefore, the H2O2-induced cytotoxicity model is considered suitable for studying neurodegeneration induced by oxidative stress (43-45). Figure 3 shows that compound 7f protects N2a cells from H2O2-induced cell death by reducing free radicals, thereby exhibiting antioxidant properties and potentially preventing neuronal loss in patients with Alzheimer’s or Parkinson’s disease (40, 46, 47). We further evaluated the compound’s antioxidant activity using free radical (DPPH and H2O2) scavenging assays. The results showed a dose-dependent scavenging activity of compound 7f, exhibiting 51.0%±0.011 (DPPH) and 52.7±0.055% (H2O2) radical scavenging activity at the highest concentration, respectively (Table II). As the compound concentration increased, the absorbance of the reaction mixture decreased, while the scavenging activity increased, indicating enhanced antioxidant activity. The results support previous reports indicating that coumarins have a unique ability to reduce the formation of ROS and stimulate their scavenging, thus exhibiting antioxidant properties (28, 48, 49).

Conclusion

The present study demonstrated that among the synthesized 3-acetylcoumarin-oximes (7a-l), only compound 7k showed cytotoxic activity against N2a cells. However, the non-cytotoxic compound 7f showed the highest non-selective inhibitory activity against MAO-A/B enzymes compared to other analogs and reference inhibitors (moclobemide and pargyline), and demonstrated reversibility of MAO-A enzyme inhibition. In contrast, the cytotoxic compound 7k showed the least inhibitory activity. Furthermore, compound 7f exhibited neuroprotective and antioxidant properties by reducing oxidative stress and damage caused by monoamine oxidation, thereby contributing to the prevention of neuronal cell death and increasing the interest in MAO-AIs for treating neurodegenerative diseases. Finally, this structure-activity relationship study provides new insights into how certain functionalizing groups on the core coumarin ring can serve as a variable template for developing new, attractive, and more promising MAOI drugs for treating neurodegenerative disorders.

Acknowledgements

This work was supported by Florida A & M University TITLE III funding received from the U. S. Department of Education.

Footnotes

  • Authors’ Contributions

    Musiliyu A. Musa: supervision, formal analysis, conception and design, interpretation of the data, writing – original draft of the paper. Veera LD Badisa: supervision, formal analysis, interpretation of the data, writing – review, and editing, revising it critically for intellectual content. Qudus Kolawole: conceptualization, investigation, methodology. Lekan Latinwo: revising it critically for intellectual content, writing – review and editing. All Authors approved the submitted version of the manuscript.

  • Conflicts of Interest

    The Authors declare that they have no financial or non-financial competing interests.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received November 14, 2025.
  • Revision received December 4, 2025.
  • Accepted December 5, 2025.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

References

  1. ↵
    1. Borges F,
    2. Roleira F,
    3. Milhazes N,
    4. Santana L,
    5. Uriarte E
    : Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Curr Med Chem 12(8): 887-916, 2005. DOI: 10.2174/0929867053507315
    OpenUrlCrossRefPubMed
  2. ↵
    1. Annunziata F,
    2. Pinna C,
    3. Dallavalle S,
    4. Tamborini L,
    5. Pinto A
    : An overview of coumarin as a versatile and readily accessible scaffold with broad-ranging biological activities. Int J Mol Sci 21(13): 4618, 2020. DOI: 10.3390/ijms21134618
    OpenUrlCrossRefPubMed
  3. ↵
    1. Stefanachi A,
    2. Leonetti F,
    3. Pisani L,
    4. Catto M,
    5. Carotti A
    : Coumarin: a natural, privileged and versatile scaffold for bioactive compounds. Molecules 23(2): 250, 2018. DOI: 10.3390/molecules23020250
    OpenUrlCrossRefPubMed
    1. Dandriyal J,
    2. Singla R,
    3. Kumar M,
    4. Jaitak V
    : Recent developments of C-4 substituted coumarin derivatives as anticancer agents. Eur J Med Chem 119: 141-168, 2016. DOI: 10.1016/j.ejmech.2016.03.087
    OpenUrlCrossRefPubMed
    1. Sandhu S,
    2. Bansal Y,
    3. Silakari O,
    4. Bansal G
    : Coumarin hybrids as novel therapeutic agents. Bioorg Med Chem 22(15): 3806-3814, 2014. DOI: 10.1016/j.bmc.2014.05.032
    OpenUrlCrossRefPubMed
    1. Sharifi-Rad J,
    2. Cruz-Martins N,
    3. López-Jornet P,
    4. Lopez EP,
    5. Harun N,
    6. Yeskaliyeva B,
    7. Beyatli A,
    8. Sytar O,
    9. Shaheen S,
    10. Sharopov F,
    11. Taheri Y,
    12. Docea AO,
    13. Calina D,
    14. Cho WC
    : Natural coumarins: exploring the pharmacological complexity and underlying molecular mechanisms. Oxid Med Cell Longev 2021: 6492346, 2021. DOI: 10.1155/2021/6492346
    OpenUrlCrossRefPubMed
  7. ↵
    1. Citarella A,
    2. Vittorio S,
    3. Dank C,
    4. Ielo L
    : Syntheses, reactivity, and biological applications of coumarins. Front Chem 12: 1362992, 2024. DOI: 10.3389/fchem.2024.1362992
    OpenUrlCrossRefPubMed
  8. ↵
    1. Lončar M,
    2. Jakovljević M,
    3. Šubarić D,
    4. Pavlić M,
    5. Buzjak Služek V,
    6. Cindrić I,
    7. Molnar M
    : Coumarins in food and methods of their determination. Foods 9(5): 645, 2020. DOI: 10.3390/foods9050645
    OpenUrlCrossRefPubMed
  9. ↵
    1. Chimenti F,
    2. Secci D,
    3. Bolasco A,
    4. Chimenti P,
    5. Granese A,
    6. Gagliardi L,
    7. Orsi DD
    : LC determination of coumarin-3-acyl derivatives for evaluation of the stability and monoamine oxidase inhibition mechanism. Chroma 61(9-10): 519-522, 2005. DOI: 10.1365/s10337-005-0534-7
    OpenUrlCrossRef
  10. ↵
    1. Keri RS,
    2. Sasidhar BS,
    3. Nagaraja BM,
    4. Santos MA
    : Recent progress in the drug development of coumarin derivatives as potent antituberculosis agents. Eur J Med Chem 100: 257-269, 2015. DOI: 10.1016/j.ejmech.2015.06.017
    OpenUrlCrossRefPubMed
  11. ↵
    1. Bruna-Haupt EF,
    2. Perretti MD,
    3. Garro HA,
    4. Carrillo R,
    5. Machín F,
    6. Lorenzo-Castrillejo I,
    7. Gutiérrez L,
    8. Vega-Hissi EG,
    9. Mamberto M,
    10. Menacho-Marquez M,
    11. Fernández CO,
    12. García C,
    13. Pungitore CR
    : Synthesis of structurally related coumarin derivatives as antiproliferative agents. ACS Omega 8(29): 26479-26496, 2023. DOI: 10.1021/acsomega.3c03181
    OpenUrlCrossRefPubMed
  12. ↵
    1. Flores-Morales V,
    2. Villasana-Ruíz AP,
    3. Garza-Veloz I,
    4. González-Delgado S,
    5. Martinez-Fierro ML
    : Therapeutic effects of coumarins with different substitution patterns. Molecules 28(5): 2413, 2023. DOI: 10.3390/molecules28052413
    OpenUrlCrossRefPubMed
  13. ↵
    1. Dettori T,
    2. Sanna G,
    3. Cocco A,
    4. Serreli G,
    5. Deiana M,
    6. Palmas V,
    7. Onnis V,
    8. Pilia L,
    9. Melis N,
    10. Moi D,
    11. Caria P,
    12. Secci F
    : Synthesis and antiproliferative effect of halogenated coumarin derivatives. Molecules 27(24): 8897, 2022. DOI: 10.3390/molecules27248897
    OpenUrlCrossRefPubMed
  14. ↵
    1. Thakur A,
    2. Singla R,
    3. Jaitak V
    : Coumarins as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Eur J Med Chem 101: 476-495, 2015. DOI: 10.1016/j.ejmech.2015.07.010
    OpenUrlCrossRefPubMed
  15. ↵
    1. Wu Y,
    2. Xu J,
    3. Liu Y,
    4. Zeng Y,
    5. Wu G
    : A review on anti-tumor mechanisms of coumarins. Front Oncol 10: 592853, 2020. DOI: 10.3389/fonc.2020.592853
    OpenUrlCrossRefPubMed
  16. ↵
    1. Akwu NA,
    2. Lekhooa M,
    3. Deqiang D,
    4. Aremu AO
    : Antidepressant effects of coumarins and their derivatives: A critical analysis of research advances. Eur J Pharmacol 956: 175958, 2023. DOI: 10.1016/j.ejphar.2023.175958
    OpenUrlCrossRefPubMed
  17. ↵
    1. Chimenti F,
    2. Secci D,
    3. Bolasco A,
    4. Chimenti P,
    5. Granese A,
    6. Befani O,
    7. Turini P,
    8. Alcaro S,
    9. Ortuso F
    : Inhibition of monoamine oxidases by coumarin-3-acyl derivatives: biological activity and computational study. Bioorg Med Chem Lett 14(14): 3697-3703, 2004. DOI: 10.1016/j.bmcl.2004.05.010
    OpenUrlCrossRefPubMed
  18. ↵
    1. Secci D,
    2. Carradori S,
    3. Bolasco A,
    4. Chimenti P,
    5. Yáñez M,
    6. Ortuso F,
    7. Alcaro S
    : Synthesis and selective human monoamine oxidase inhibition of 3-carbonyl, 3-acyl, and 3-carboxyhydrazido coumarin derivatives. Eur J Med Chem 46(10): 4846-4852, 2011. DOI: 10.1016/j.ejmech.2011.07.017
    OpenUrlCrossRefPubMed
    1. Patil PO,
    2. Bari SB,
    3. Firke SD,
    4. Deshmukh PK,
    5. Donda ST,
    6. Patil DA
    : A comprehensive review on synthesis and designing aspects of coumarin derivatives as monoamine oxidase inhibitors for depression and Alzheimer’s disease. Bioorg Med Chem 21(9): 2434-2450, 2013. DOI: 10.1016/j.bmc.2013.02.017
    OpenUrlCrossRef
  20. ↵
    1. Meletli F,
    2. Gündüz C,
    3. Alparslan MM,
    4. Attar A,
    5. Demir S,
    6. İskit E,
    7. Danış Ö
    : Design, synthesis and biological evaluation of novel benzocoumarin derivatives as potent inhibitors of MAO-B activity. Bioorg Med Chem Lett 113: 129984, 2024. DOI: 10.1016/j.bmcl.2024.129984
    OpenUrlCrossRefPubMed
  21. ↵
    1. Iacovino LG,
    2. Pinzi L,
    3. Facchetti G,
    4. Bortolini B,
    5. Christodoulou MS,
    6. Binda C,
    7. Rastelli G,
    8. Rimoldi I,
    9. Passarella D,
    10. Di Paolo ML,
    11. Dalla Via L
    : Promising non-cytotoxic monosubstituted chalcones to target monoamine oxidase-B. ACS Med Chem Lett 12(7): 1151-1158, 2021. DOI: 10.1021/acsmedchemlett.1c00238
    OpenUrlCrossRefPubMed
  22. ↵
    1. Aghimien MO,
    2. Kolawole Q,
    3. Igbinoba PO,
    4. Musa MA,
    5. Latinwo L
    : Non-cytotoxic 3-acetylcoumarin as an attractive target for human monoamine oxidase (HMAO) enzymes. Anticancer Res 44(6): 2335-2341, 2024. DOI: 10.21873/anticanres.17040
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Schepetkin IA,
    2. Plotnikov MB,
    3. Khlebnikov AI,
    4. Plotnikova TM,
    5. Quinn MT
    : Oximes: novel therapeutics with anticancer and anti-inflammatory potential. Biomolecules 11(6): 777, 2021. DOI: 10.3390/biom11060777
    OpenUrlCrossRef
  24. ↵
    1. Thomas Parambi DG,
    2. Oh JM,
    3. Kumar S,
    4. Sudevan ST,
    5. Hendawy OM,
    6. Abdelgawad MA,
    7. Musa A,
    8. Al-sanea MM,
    9. Ahmad I,
    10. Patel H,
    11. Kim H,
    12. Mathew B
    : Halogenated class of oximes as a new class of monoamine oxidase-B inhibitors for the treatment of Parkinson’s disease: Synthesis, biochemistry, and molecular dynamics study. Comput Biol Chem 105: 107899, 2023. DOI: 10.1016/j.compbiolchem.2023.107899
    OpenUrlCrossRefPubMed
  25. ↵
    1. Musa MA,
    2. Kolawole Q
    : 7,8-Diacetoxy-3-(4-methylsulfonylphenyl)-4-phenylcoumarin Induces ROS-dependent Cell Death in the A549 Human Lung Cancer Cell Line. Anticancer Res 43(3): 1001-1007, 2023. DOI: 10.21873/anticanres.16244
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Musa MA,
    2. Gbadebo AJ,
    3. Latinwo LM,
    4. Badisa VL
    : 7,8-Dihydroxy-3-(4-nitrophenyl)coumarin induces cell death via reactive oxygen species–independent S-phase cell arrest. J Biochem Mol Toxicol 32(12): e22203, 2018. DOI: 10.1002/jbt.22203
    OpenUrlCrossRefPubMed
    1. Pleh A,
    2. Mahmutović L,
    3. Hromić-Jahjefendić A
    : Evaluation of phytochemical antioxidant levels by hydrogen peroxide scavenging assay. Bioengineering Studies 2(1): 1-10, 2021. DOI: 10.37868/bes.v2i1.id178
    OpenUrlCrossRef
  28. ↵
    1. Al-Amiery A,
    2. Al-Majedy Y,
    3. Al-Duhaidahawi D,
    4. Amir Kadhum A,
    5. Bakar Mohamad A
    : Green antioxidants: synthesis and scavenging activity of coumarin-thiadiazoles as potential antioxidants complemented by molecular modeling studies. Free Rad Antiox 6(2): 173-177, 2016. DOI: 10.5530/fra.2016.2.7
    OpenUrlCrossRef
  29. ↵
    1. Wang Y,
    2. Li CF,
    3. Pan LM,
    4. Gao ZL
    : 7,8-Dihydroxycoumarin inhibits A549 human lung adenocarcinoma cell proliferation by inducing apoptosis via suppression of Akt/NF-κB signaling. Exp Ther Med 5(6): 1770-1774, 2013. DOI: 10.3892/etm.2013.1054
    OpenUrlCrossRefPubMed
  30. ↵
    1. Wu J,
    2. Peng T,
    3. Chen F,
    4. Leng Y,
    5. Tong L,
    6. Li M,
    7. Qu R,
    8. Xie H,
    9. Ding J,
    10. Duan W
    : Synthesis and anticancer activity of 7,8-dihydroxy-4-arylcoumarins. Lett Drug Des Discov 12(5): 366-373, 2015. DOI: 10.2174/1570180812666141111235026
    OpenUrlCrossRef
  31. ↵
    1. Mzezewa SC,
    2. Omoruyi SI,
    3. Zondagh LS,
    4. Malan SF,
    5. Ekpo OE,
    6. Joubert J
    : Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents. J Enzyme Inhib Med Chem 36(1): 1607-1621, 2021. DOI: 10.1080/14756366.2021.1913137
    OpenUrlCrossRefPubMed
  32. ↵
    1. Bester E,
    2. Petzer A,
    3. Petzer JP
    : Coumarin derivatives as inhibitors of d-amino acid oxidase and monoamine oxidase. Bioorg Chem 123: 105791, 2022. DOI: 10.1016/j.bioorg.2022.105791
    OpenUrlCrossRefPubMed
  33. ↵
    1. Reyes-Chaparro A,
    2. Flores-Lopez NS,
    3. Quintanilla-Guerrero F,
    4. Nicolás-Álvarez DE,
    5. Hernandez-Martinez AR
    : Design of new reversible and selective inhibitors of monoamine oxidase A and a comparison with drugs already approved. Bull Natl Res Cent 47: 46, 2023. DOI: 10.1186/s42269-023-01018-9
    OpenUrlCrossRef
    1. El-Damasy AK,
    2. Oh JM,
    3. Kim HJ,
    4. Mun SK,
    5. Al-Karmalawy AA,
    6. Alnajjar R,
    7. Choi YJ,
    8. Kim JJ,
    9. Nam G,
    10. Kim H,
    11. Keum G
    : Novel coumarin benzamides as potent and reversible monoamine oxidase-B inhibitors: Design, synthesis, and neuroprotective effects. Bioorg Chem 142: 106939, 2024. DOI: 10.1016/j.bioorg.2023.106939
    OpenUrlCrossRef
    1. Ekström F,
    2. Gottinger A,
    3. Forsgren N,
    4. Catto M,
    5. Iacovino LG,
    6. Pisani L,
    7. Binda C
    : Dual reversible coumarin inhibitors mutually bound to monoamine oxidase b and acetylcholinesterase crystal structures. ACS Med Chem Lett 13(3): 499-506, 2022. DOI: 10.1021/acsmedchemlett.2c00001
    OpenUrlCrossRefPubMed
  36. ↵
    1. Musa MA,
    2. Badisa VLD,
    3. Aghimien MO,
    4. Eyunni SVK,
    5. Latinwo LM
    : Identification of 7,8-dihydroxy-3-phenylcoumarin as a reversible monoamine oxidase enzyme inhibitor. J Biochem Mol Toxicol 35(2): e22651, 2021. DOI: 10.1002/jbt.22651
    OpenUrlCrossRefPubMed
  37. ↵
    1. Pisani L,
    2. Farina R,
    3. Nicolotti O,
    4. Gadaleta D,
    5. Soto-Otero R,
    6. Catto M,
    7. Di Braccio M,
    8. Mendez-Alvarez E,
    9. Carotti A
    : In silico design of novel 2H-chromen-2-one derivatives as potent and selective MAO-B inhibitors. Eur J Med Chem 89: 98-105, 2015. DOI: 10.1016/j.ejmech.2014.10.029
    OpenUrlCrossRefPubMed
    1. Matos MJ,
    2. Herrera Ibatá DM,
    3. Uriarte E,
    4. Viña D
    : Coumarin-rasagiline hybrids as potent and selective hMAO-B inhibitors, antioxidants, and neuroprotective agents. ChemMedChem 15(6): 532-538, 2020. DOI: 10.1002/cmdc.202000018
    OpenUrlCrossRefPubMed
    1. Mishra PS,
    2. Kumar A,
    3. Kaur K,
    4. Jaitak V
    : Recent developments in coumarin derivatives as neuroprotective agents. Curr Med Chem 31(35): 5702-5738, 2024. DOI: 10.2174/0929867331666230714160047
    OpenUrlCrossRef
  40. ↵
    1. Chaurasiya ND,
    2. Leon F,
    3. Muhammad I,
    4. Tekwani BL
    : Natural products inhibitors of monoamine oxidases-potential new drug leads for neuroprotection, neurological disorders, and neuroblastoma. Molecules 27(13): 4297, 2022. DOI: 10.3390/molecules27134297
    OpenUrlCrossRefPubMed
  41. ↵
    1. Lin MT,
    2. Beal MF
    : Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113): 787-795, 2006. DOI: 10.1038/nature05292
    OpenUrlCrossRefPubMed
  42. ↵
    1. Tumilaar SG,
    2. Hardianto A,
    3. Dohi H,
    4. Kurnia D
    : A comprehensive review of free radicals, oxidative stress, and antioxidants: overview, clinical applications, global perspectives, future directions, and mechanisms of antioxidant activity of flavonoid compounds. J Chem 2024: 1-21, 2024. DOI: 10.1155/2024/5594386
    OpenUrlCrossRef
  43. ↵
    1. Lingappa S,
    2. Shivakumar MS,
    3. Manivasagam T,
    4. Somasundaram ST,
    5. Seedevi P
    : Neuroprotective effect of Epalrestat on hydrogen peroxide-induced neurodegeneration in SH-SY5Y cellular model. J Microbiol Biotechnol 31(6): 867-874, 2021. DOI: 10.4014/jmb.2101.01002
    OpenUrlCrossRefPubMed
    1. Jeong JH,
    2. Noh MY,
    3. Choi JH,
    4. Lee H,
    5. Kim SH
    : Neuroprotective and antioxidant activities of bamboo salt soy sauce against H(2)O(2)-induced oxidative stress in rat cortical neurons. Exp Ther Med 11(4): 1201-1210, 2016. DOI: 10.3892/etm.2016.3056
    OpenUrlCrossRefPubMed
  45. ↵
    1. Ghaffari H,
    2. Ghassam BJ,
    3. Chandra Nayaka S,
    4. Ramachandra Kini K,
    5. Prakash HS
    : Antioxidant and neuroprotective activities of Hyptis suaveolens (L.) Poit. against oxidative stress-induced neurotoxicity. Cell Mol Neurobiol 34(3): 323-331, 2014. DOI: 10.1007/s10571-013-0016-7
    OpenUrlCrossRef
  46. ↵
    1. Chen X,
    2. Drew J,
    3. Berney W,
    4. Lei W
    : Neuroprotective natural products for Alzheimer’s disease. Cells 10(6): 1309, 2021. DOI: 10.3390/cells10061309
    OpenUrlCrossRef
  47. ↵
    1. Osman LY,
    2. Awad TA,
    3. Abdalla S,
    4. El-Faki MO,
    5. Ali A,
    6. Fadul Alla EF
    : In silico and in vitro profiling of coumarins and flavonoids for anti-Alzheimer and antioxidant activity. Pure Appl Chem 96(3): 327-339, 2024. DOI: 10.1515/pac-2023-1110
    OpenUrlCrossRef
  48. ↵
    1. Todorov L,
    2. Saso L,
    3. Kostova I
    : Antioxidant activity of coumarins and their metal complexes. Pharmaceuticals (Basel) 16(5): 651, 2023. DOI: 10.3390/ph16050651
    OpenUrlCrossRefPubMed
  49. ↵
    1. Kostova I,
    2. Bhatia S,
    3. Grigorov P,
    4. Balkansky S,
    5. Parmar VS,
    6. Prasad AK,
    7. Saso L
    : Coumarins as antioxidants. Curr Med Chem 18(25): 3929-3951, 2011. DOI: 10.2174/092986711803414395
    OpenUrlCrossRefPubMed
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Coumarin-based Oximes Exert Monoamine Oxidase Inhibitory Activity
QUDUS KOLAWOLE, VEERA L.D. BADISA, MUSILIYU A. MUSA, LEKAN LATINWO
Anticancer Research Feb 2026, 46 (2) 601-610; DOI: 10.21873/anticanres.17972
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