Polycyclic propargylamine and acetylene derivatives as multifunctional neuroprotective agents

Zindo, Frank T.; Barber, Quinton Raymond; Joubert, Jacques; Bergh, Jacobus J.; Petzer, Jacobus P.; Malan, Sarel F.

doi:10.1016/j.ejmech.2014.04.039

Cited by 33 publications

(20 citation statements)

References 43 publications

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“…The compounds selected for our design strategy includes isatin, selegeline, rasagiline and isatin sulfonamide derivatives. [29][30][31][32] Substituting the isatin moiety at the N-position with a propargylamine moiety might thus increase the MAO inhibitory-and antiapoptotic activity of isatin. 22 Previous studies have shown that isatin is located in the substrate cavity of MAO-B in close proximity to the flavin adenine dinucleotide (FAD) co-factor.…”

Section: Introductionmentioning

confidence: 99%

“…Although these compounds did not show good caspase-3 activity, they should be tested for general anti-apoptotic activity because the propargylamine functional group in these compounds might act in a completely different manner than what was tested for in this assay [28][29][30][31][32]. The role of the fluorophenylamine moiety in the synthesized compounds was significant for their multifunctional activity as shown by compounds 4 and 5 having good inhibitory activity towards MAO-A, MAO-Band also excellent inhibitory activity against caspase-3 making them ideal candidates for further anti-apoptotic studies, lead compound development and multifunctional drug design.…”

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confidence: 99%

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Design, synthesis, biological evaluation and docking studies of sulfonyl isatin derivatives as monoamine oxidase and caspase-3 inhibitors

2016

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The aim of this study was to design novel multifunctional neuroprotective agents that would slow down or halt neurodegeneration through inhibition of MAO-A, MAO-B and caspase-3. We focused on pharmacophoric groups of known MAO-inhibitors including selegiline (propargylamine moiety) and safinamide (fluorobenzyl moiety), and isatin sulfonamide caspase-3 inhibitors. The synthesised compounds consisted of the isatin nucleus conjugated to a fluorophenylsulfonyl moiety at position 5 and on selected compounds a propargylamine moiety was introduced at the Nposition of isatin. All the compounds showed promising MAO-A inhibitory activity (IC 50 : 4 -22 µM). The compounds without the propargylamine moiety showed better MAO-B inhibition (IC 50 : 5 -8 µM) and caspase-3 inhibition (IC 50 : 25 -29 µM). The fluorophenylsulfonyl moiety in the synthesized compounds was significant for their multifunctional activity. In general the active compounds showed similar or improved inhibitory activities when compared to the reference compounds isatin (MAO-A and -B) and Z-VAD-FMK (caspase-3). Possible binding orientations of selected isatin analogues within the active site cavities of MAO-A, -B and caspase-3 are proposed and in silico ADMET studies were also done. N-[(3-Fluorophenyl)methyl]-N -methyl-2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonamide (4) and N-[(4fluorophenyl)methyl]-N-methyl-2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonamide (5) showed the best multifunctional neuroprotective potential and can be considered as new lead compounds for the development of alternative treatment options for neurodegenerative disorders such as AD, PD and HD.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Design, synthesis, biological evaluation and docking studies of sulfonyl isatin derivatives as monoamine oxidase and caspase-3 inhibitors

2016

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“…[32] The relative change in calcium flux, as indicated by change in fluorescencei ntensity,t hrough synaptoneuromesa fter NMDA/ glycine-induced receptor stimulation was used to evaluate the NMDA receptor inhibition of the reference compounds (amantadine, MK-801,and NGP1-01) and tricycloundecane derivatives 3-12.T he ratiometric fluorescence indicator Fura-2 AM was used to monitort hese changes. The results, average inhibition of three experiments on different murines ynaptoneurosomes, represent the inhibitory effects at 100 mm (Table1).…”

Section: Nmda Receptor and Vgcc Activitymentioning

confidence: 99%

“…[32] The ratiometric fluorescencei ndicator Fura-2 AM was used to monitor the change in intracellular calcium ion concentration after depolarisation of the VGCC with ah igh-concentration KCl (140 mm)s olution. Ther atio of the calcium-bound andu nbound fluorescence intensities of test compounds, relative to control (100 %influx), gives an estimate of the degree of inhibition produced by the reference and test compounds 3-12.T he reference compounds were nimodipine, amantadine, and NGP1-01.…”

Section: Nmda Receptor and Vgcc Activitymentioning

confidence: 99%

“…The preparation of synaptoneurosomes, solutions, and experimental techniques were similar to those of published studies. [32,41] All data analysis, calculation, and graphs were done using Prism 6.0 (GraphPad, La Jolla, CA, USA). Data analysis was carried out using the Student Newman-Keuls multiple range test, and the level of significance was accepted at p < 0.05.…”

Section: Generalp Rocedures For the Nmda Receptor And Vgcc Assaysmentioning

confidence: 99%

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Tricycloundecane Derivatives as Potential N‐Methyl‐D‐aspartate (NMDA) Receptor and Voltage‐Gated Calcium Channel Modulators

2015

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Neurodegenerative disorders are debilitating conditions characterised by progressive dysfunction and death of neuronal cells. Amidst the proposed mechanisms of neurodegeneration, the effects of excitotoxicity via N-methyl-D-aspartate (NMDA) receptor stimulation and activation of voltage-gated calcium channels (VGCC) on neuronal cells are prominent. This has led to the development of polycyclic cage molecules such as NGP1-01, which exhibit neuroprotective properties through NMDA receptor and VGCC modulation. The medicinal potential of structurally related tricycloundecanes that are open-cage or rearranged polycyclic moieties has not been explored. This study is therefore focused on the synthesis of a series of novel tricycloundecane derivatives and their ability to inhibit NMDA receptors and VGCC. Significant NMDA receptor inhibition was observed for tricyclo[6.2.1.0(2,7) ]undec-9-ene-3,6-dione (4, 78%) and 6-hydroxytricyclo[6.2.1.0(2,7) ]undec-9-en-3-one (5, >95%) at a concentration of 100 μM. The highest inhibitory activity was observed for 6-(benzylimino)tricyclo[6.2.1.0(2,7) ]undec-9-en-3-one (9, >95%), which is in the same range as the inhibitory activity of MK-801 (dizocilpine). In the VGCC inhibition assay, 6-(benzylamino)tricyclo[6.2.1.0(2,7) ]undeca-4,9-dien-3-one (8, 34%), 9 (38%) and 2-(benzylamino)-3,6-epoxytricyclo[6.2.1.0(5,10) ]undecan-9-ol (12, 40%) showed statistically significant (p<0.05) VGCC inhibition.

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Grignard Reagents and Their N‐analogues in the Synthesis of Tricyclic and Tetracyclic Cage‐like Lactams

Tkachenko

Tarabara

Omelchenko

et al. 2018

Journal of Heterocyclic Chem

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A convenient method is reported for the synthesis of 34 novel tricyclic and tetracyclic cage‐like lactams in high to excellent yields. The method involves treatment of easily available exo‐2,3‐epoxy(or Ts‐aziridino)bicyclo[2.2.1]heptan‐endo‐5,6‐dicarboximides by Grignard reagents, their N‐analogues, or phenyl lithium in tetrahydrofuran. In silico screening of biological activity spectrum showed high probability levels of glyceryl‐ether monooxygenase inhibitory, testosterone 17β‐dehydrogenase (NADP+) inhibitory, bilirubin oxidase inhibitory, and anti‐ischemic activity for tetracyclic derivatives.

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Polycyclic propargylamine and acetylene derivatives as multifunctional neuroprotective agents

Cited by 33 publications

References 43 publications

Design, synthesis, biological evaluation and docking studies of sulfonyl isatin derivatives as monoamine oxidase and caspase-3 inhibitors

Design, synthesis, biological evaluation and docking studies of sulfonyl isatin derivatives as monoamine oxidase and caspase-3 inhibitors

Tricycloundecane Derivatives as Potential N‐Methyl‐D‐aspartate (NMDA) Receptor and Voltage‐Gated Calcium Channel Modulators

Grignard Reagents and Their N‐analogues in the Synthesis of Tricyclic and Tetracyclic Cage‐like Lactams

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