Refining the Structural Features of Chromones as Selective MAO‐B Inhibitors: Exploration of Combined Pharmacophore‐Based 3D‐QSAR and Quantum Chemical Studies

Mathew, Bijo; Dev, Sanal; Joy, Monu; Mathew, Githa Elizabeth; Marathakam, Akash; Krishnan, Girish K.

doi:10.1002/slct.201701213

Cited by 13 publications

(3 citation statements)

References 36 publications

(39 reference statements)

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“…MAO‐B inhibition blocks the catabolism of dopamine (DA) and, thus, increases endogenous dopamine levels, [ 8 ] whereas increased MAO‐B activity has been shown to be associated with the generation of reactive astrocytes leading to synaptic dysfunction and impaired cognitive function in the AD brain. [ 9 ] Furthermore, recent studies have shown MAO‐B mediated γ‐aminobutyric acid (GABA) production is linked to pathological pathways in AD and that suppressing GABA synthesis by inhibiting MAO‐B improves synaptic plasticity and reduces reactive astrocyte numbers in the AD brain.…”

Section: Introductionmentioning

confidence: 99%

Design of enamides as new selective monoamine oxidase-B inhibitors

Kavully¹,

Dev³

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives To develop of new class of selective and reversible MAO-B inhibitors from enamides. Methods Syntheses of the titled derivatives (AD1-AD11) were achieved by reacting cinnamoyl chloride and various primary and secondary amines in basic medium. All eleven compounds were investigated for in vitro inhibitory activities against recombinant human MAO-A and MAO-B. The reversibilities of lead compound inhibitions were analysed by dialysis. MTT assays of lead compounds were performed using normal VERO cell lines. Key findings Compounds AD3 and AD9 exhibited the greatest inhibitory activity against MAO-B with IC 50 values of 0.11 and 0.10 µM, respectively, and were followed by AD2 and AD1 (0.51 and 0.71 µM, respectively). Most of the compounds weakly inhibited MAO-A, with the exceptions AD9 and AD7, which had IC 50 values of 4.21 and 5.95 µM, respectively. AD3 had the highest selectivity index (SI) value for MAO-B (>363.6) and was followed by AD9 (SI 42.1). AD3 and AD9 were found to be competitive inhibitors of MAO-B with K i values of 0.044 AE 0.0036 and 0.039 AE 0.0047 µM, respectively. Reversibility experiments showed AD3 and AD9 were reversible inhibitors of MAO-B; dialysis restored the activity of MAO-B to the reference level. MTT assays revealed AD3 and AD9 were non-toxic to normal VERO cell lines with IC 50 values of 153.96 and 194.04 µg/ml, respectively. Computational studies provided hypothetical binding modes for AD3 and AD9 in the binding cavities of MAO-A and MAO-B. Conclusions These results encourage further studies on the enamide scaffold as potential drug candidates for the treatment of Alzheimer's and Parkinson's diseases.

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Section: Introductionmentioning

confidence: 99%

Design of enamides as new selective monoamine oxidase-B inhibitors

Kavully¹,

Dev³

et al. 2020

Journal of Pharmacy and Pharmacology

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“…MAO-B inhibitors have drawn considerable attention, and a variety of MAO-B inhibitors are developed. , Selegiline, rasagiline, and safinamide are often used alone or in combination with levodopa for the treatment of PD in clinics . In addition, recent examples have disclosed a variety of new MAO-B inhibitors, such as chromone, − coumarin, − chalcone, − and N -containing heterocyclic compounds ,,− (Figure ). In Borges’ studies, chromone derivatives were discovered as potential therapeutic compounds for relieving Parkinsonism, and these inhibitors exhibited promising activity against MAO-B. , Gobec et al found that geometric isomers of cis - and trans -1-propargyl-4-styrylpiperidines were potent MAO-B inhibitors and revealed the importance of their chirality for bioactivity .…”

Section: Introductionmentioning

confidence: 99%

Computational Fragment-Based Design Facilitates Discovery of Potent and Selective Monoamine Oxidase-B (MAO-B) Inhibitor

et al. 2020

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Parkinson's disease (PD) is one of the most common agerelated neurodegenerative diseases. Inhibition of monoamine oxidase-B (MAO-B), which is mainly found in the glial cells of the brain, may lead to an elevated level of dopamine (DA) in patients. MAO-B inhibitors have been used extensively for patients with PD. However, the discovery of the selective MAO-B inhibitor is still a challenge. In this study, a computational strategy was designed for the rapid discovery of selective MAO-B inhibitors. A series of (S)-2-(benzylamino)propanamide derivatives were designed. In vitro biological evaluations revealed that (S)-1-(4-((3-fluorobenzyl)oxy)benzyl)azetidine-2-carboxamide (C3) was more potent and selective than safinamide, a promising drug for regulating MAO-B. Further studies revealed that the selectivity mechanism of C3 was due to the steric clash caused by the residue difference of Phe208 (MAO-A) and Ile199 (MAO-B). Animal studies showed that compound C3 could inhibit cerebral MAO-B activity and alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal loss.

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“…7,8 The current scenario of PD therapy focuses on restoring the level of dopamine in the brain and thereby curtailing the motor symptoms. 9 This therapy is accelerated by the administration of dopamine precursors (L-DOPA), dopamine agonists, catechol-O-methyltransferase (COMT) and MAO-B inhibitors such as selegiline and rasagiline (highly selective and irreversible). 10 Molecules which have closer acetylcholinesterase (AChE) and MAO-B affinities are able to limit the neurotoxicity related to sources of ROS in age-related AD diseases.…”

Section: Introductionmentioning

confidence: 99%