Potent and highly selective dual‐targeting monoamine oxidase‐B inhibitors: Fluorinated chalcones of morpholine versus imidazole

Mathew, Bijo; Baek, Seung Cheol; Parambi, Della Grace Thomas; Lee, Jae P; Mathew, Githa Elizabeth; Jayanthi, Sivaraman; Devaraji, Vinod; Rapheal, Clariya; Devikrishna, Vinod; Kondarath, Shahin Shad; Uddin, Sahab; Kim, Hoon

doi:10.1002/ardp.201800309

Cited by 49 publications

(28 citation statements)

References 48 publications

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“…Most recently, Mathew et al developed two series of fluorinated chalcones containing either morpholine or imidazole and found that the morpholine‐based compounds were potent and highly selective hMAO‐B inhibitors, whereas the imidazole analogs demonstrated weak hMAO‐A and ‐B inhibitory activity. The morpholine series also demonstrated moderate inhibitory activity on AChE (IC 50 ~ 24‐54 μM) and good BBB permeation.…”

Section: Pharmacological Activity Of Morpholine Derivatives On Varioumentioning

confidence: 99%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

187

114

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Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active‐site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug‐like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

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Section: Pharmacological Activity Of Morpholine Derivatives On Varioumentioning

confidence: 99%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

187

114

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“…Of those synthesized, compound 15 inhibited AChE and MAO‐B with IC 50 values of 4.91 and 0.29 µM, respectively, and at 25 µM reduced self‐induced Aβ 1–42 aggregation and Cu 2+ ‐induced Aβ 1–42 aggregation by 89.5% and 79.7%, respectively . Mathew et al synthesized two series of fluorinated chalcones containing morpholine or imidazole‐based compounds and evaluated them against recombinant hMAO‐A and ‐B and acetylcholinesterase. This study corroborated the MAO and AChE inhibitory effects of morpholine and imidazole heterocyclic nuclei located at the para position of ring A of fluorinated chalcones.…”

Section: Overview Of Dual‐acting Mao and Che Inhibitorsmentioning

confidence: 99%

Emerging therapeutic potentials of dual‐acting MAO and AChE inhibitors in Alzheimer's and Parkinson's diseases

Mathew

Parambi

Mathew³

et al. 2019

Archiv der Pharmazie

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112

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No drug has been approved to prevent neuronal cell loss in patients suffering from Parkinson's disease (PD) or Alzheimer's disease (AD); despite increased comprehension of the underlying molecular causes, therapies target cognitive functional improvement and motor fluctuation control. Drug design strategies that adopt the "one protein, one target" philosophy fail to address the multifactorial aetiologies of neurodegenerative disorders such as AD and PD optimally. On the contrary, restoring neurotransmitter levels by combined combinatorial inhibition of cholinesterases, monoamine oxidases, and adenosine A 2A A receptors, in conjunction with strategies to counter oxidative stress and beta-amyloid plaque accumulation, would constitute a therapeutically robust, multitarget approach. This extensive review delineates the therapeutic advantages of combining dual-acting molecules that inhibit monoamine oxidases and cholinesterases and/or adenosine A 2A A receptors, and describes the structure-activity relationships of compound classes that include, but are not limited to, alkaloids, coumarins, chalcones, donepezil-propargylamine conjugates, homoisoflavonoids, resveratrol analogs, hydrazones, and pyrazolines. In the wake of recent advances in network biology, in silico approaches, and omics, this review emphasizes the need to consider conceptually informed research strategies for drug discovery, in the context of the mounting burden posed by chronic neurodegenerative diseases with complex aetiologies and pathophysiologies involving multiple signalling pathways and numerous drug targets. K E Y W O R D Sacetylcholinesterase, adenosine antagonist, monoamine oxidase, multitarget

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“…[ 18 ] The FDA approved MAO‐B inhibitors selegiline and rasagiline are currently coadministered with levodopa for the relief of motor fluctuations in early‐stage PD, and selective, reversible type MAO‐B inhibitors safinamide and lazabemide are currently undergoing clinical trials. [ 19,20 ] Many privileged structural scaffolds like chalcones, chromones, coumarins and pyrazolines have been extensively explored as the basis of novel MAO‐B inhibitors, [ 21‐33 ] and thus, new classes of selective, reversible MAO‐B inhibitors are viewed with considerable interest in the contexts of AD and PD.…”

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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Potent and highly selective dual‐targeting monoamine oxidase‐B inhibitors: Fluorinated chalcones of morpholine versus imidazole

Cited by 49 publications

References 48 publications

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Emerging therapeutic potentials of dual‐acting MAO and AChE inhibitors in Alzheimer's and Parkinson's diseases

Design of enamides as new selective monoamine oxidase-B inhibitors

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