Development of Fluorinated Thienylchalcones as Monoamine Oxidase-B Inhibitors: Design, Synthesis, Biological Evaluation and Molecular Docking Studies

Mathew, Bijo; Uçar, Gülberk; Yabanogclu-Ciftci, Samiye; Baysal, İpek; Suresh, Jerad; Mathew, Githa Elizabeth; Vilapurathu, Jobin Kunjumon; Nadeena, A. M.; Nabeela, P.; Lakshmi, Vijaya M.; Haridas, Abitha; Fathima, Fajeelath

doi:10.2174/1570178612666150903213416

Cited by 44 publications

(29 citation statements)

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“…Among them, (2 E )‐1‐(4‐methoxyphenyl)‐3‐[4‐(trifluoromethyl)phenyl]prop‐2‐en‐1‐one and ( 2E )‐1‐(thiophen‐2‐yl)‐3‐[4‐(trifluoromethyl)phenyl]prop‐2‐en‐1‐one exhibited a K i value of 0.22 ± 0.01 and 0.90 ± 0.05 μ m , respectively, towards hMAO‐B. The study mainly highlighted the effect of orientation of F and CF 3 groups at the ring B of chalcone on the inhibition of hMAO . The ability of chalcone scaffolds to act on the central nervous system (CNS) mainly associated with its low polar surface area that can help to cross the blood–brain barrier easily.…”

Section: Introductionmentioning

confidence: 86%

“…This clearly shows the effect of electronegativity on biological activity. When thiophene is replaced with a p ‐methoxyphenyl moiety, the position of F and CF 3 has shown a great difference in potency in inhibiting both hMAO‐A and hMAO‐B . Chalcones having F substitution at ortho ‐ and para ‐positions were found to inhibit hMAO‐B potently in comparison with their meta ‐counterpart, whereas the reverse has been observed for hMAO‐A.…”

Section: Introductionmentioning

confidence: 99%

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Potent and Selective Monoamine Oxidase‐B Inhibitory Activity: Fluoro‐ vs. Trifluoromethyl‐4‐hydroxylated Chalcone Derivatives

Mathew

Mathew²,

Uçar³

et al. 2016

Chemistry & Biodiversity

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For various neurodegenerative disorders like Alzheimer's and Parkinson's diseases, selective and reversible MAO-B inhibitors have a great therapeutic value. In our previous study, we have shown that a series of methoxylated chalcones with F functional group exhibited high binding affinity toward human monoamine oxidase-B (hMAO-B). In continuation of our earlier study and to extend the understanding of the structure-activity relationships, a series of five new chalcones were studied for their inhibition of hMAO. The results demonstrated that these compounds are reversible and selective hMAO-B inhibitors with a competitive mode of inhibition. The most active compound, (2E)-1-(4-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one, exhibited a Ki value of 0.33 ± 0.01 μm toward hMAO-B with a selectivity index of 26.36. A molecular docking study revealed that the presence of a H-bond network in hydroxylated chalcone with the N(5) atom of FAD is crucial for MAO-B selectivity and potency.

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Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Potent and Selective Monoamine Oxidase‐B Inhibitory Activity: Fluoro‐ vs. Trifluoromethyl‐4‐hydroxylated Chalcone Derivatives

Mathew

Mathew²,

Uçar³

et al. 2016

Chemistry & Biodiversity

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“…We have recently demonstrated the utility of thiophene hybrid structures incorporating para substituted phenyl nucleus by means of α, β‐unsaturated carbonyl unit for the discovery of potent, selective and reversible hMAO−B inhibitors . To further investigate these structure–activity relationships (SAR), in the present study, we have synthesized C2‐and C5‐chlorosubstituted thiophene based chalcone analogues and evaluated them as inhibitors of recombinant human MAO−A and MAO−B.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Thienylchalcones as hMAO‐B Inhibitors: Synthesis, Biochemistry and Molecular Dynamics Studies

et al. 2017

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The design of selective, reversible and non‐toxic hMAO−B inhibitors has received increasing attention due to their perceived utility in targeting of neurological disorders like Alzheimer's and Parkinson's diseases. For this purpose, herein, we report the inhibitory studies on monoamine oxidase of a series of (2E)‐1‐(2, 5‐dichlorothiophen‐3‐yl)‐3‐(4‐substitutedphenyl) prop‐2‐en‐1‐ones (S1‐S9). All the compounds were found to be competitive, selective, and reversible inhibitors of hMAO−B except (2E)‐1‐(2, 4‐dichlorothiophen‐3‐yl)‐3‐(4‐nitrophenyl) prop‐2‐en‐1‐one (S6) which is found to be non‐selective MAO inhibitor. The potent hMAO−B inhibitor, (2E)‐1‐(2, 4‐dichlorothiophen‐3‐yl)‐3‐[4‐(dimethylamino) phenyl] prop‐2‐en‐1‐one (S4), showed a Ki value of 0.041 μM better than the standard drug, selegiline (hMAO−B with Ki= 0.302 μM). Moreover, S4, was nontoxic in cultured hepatic cells at 5 and 25 μM, with 94.44 and 88.00% viable cells, respectively. Molecular docking and molecular dynamics simulation studies were carried out using Autodock‐vina and Amber 14 to understand the molecular level interaction and energy relation of MAO isoforms with selective MAO−B inhibitor, S4.

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“…In another study, the same group (2016) synthesized a series of thienyl chalcones with fluoro and trifluoromethyl derivatives and evaluated their capability to inhibit hMAO‐B (Figure ) . The results documented that the compounds revealed moderate to good inhibitory activities toward MAO‐B.…”

Section: Discovery and Development Of Mao‐b Inhibitors (2015‐2018)mentioning

confidence: 99%

“…Fluorinated methoxylated chalcones ( 10a ‐ e ) and fluorinated thienyl chalcones ( 11 ) . hMAO, human monoamine oxidase; SI, selectivity index…”

Section: Discovery and Development Of Mao‐b Inhibitors (2015‐2018)mentioning

confidence: 99%

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

Tripathi

Ayyannan

2019

Medicinal Research Reviews

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Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO‐A/MAO‐B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO‐B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO‐B inhibitors (MAO‐BIs) belonging to diverse chemical scaffolds, arising from intensive chemical‐mechanistic and computational studies documented during past 3 years (2015‐2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO‐BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO‐BIs with superior activity profiles and critical discussions will inflict more caution in the decision‐making process in the MAOIs discovery.

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Development of Fluorinated Thienylchalcones as Monoamine Oxidase-B Inhibitors: Design, Synthesis, Biological Evaluation and Molecular Docking Studies

Cited by 44 publications

References 29 publications

Potent and Selective Monoamine Oxidase‐B Inhibitory Activity: Fluoro‐ vs. Trifluoromethyl‐4‐hydroxylated Chalcone Derivatives

Potent and Selective Monoamine Oxidase‐B Inhibitory Activity: Fluoro‐ vs. Trifluoromethyl‐4‐hydroxylated Chalcone Derivatives

Characterization of Thienylchalcones as hMAO‐B Inhibitors: Synthesis, Biochemistry and Molecular Dynamics Studies

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

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