Parkinson's disease (PD) is a neurodegenerative condition that progresses as age increases, and some of its major symptoms include tremor and postural and movement-related difficulties. To date, the ...treatment of PD remains a challenge because available drugs only treat the symptoms of the disease or possess serious side effects. In light of this, new treatment options are needed; hence, this study investigates the neuroprotective effects of an organic
extract (BHE) and its bioactive compounds using an in vitro model of PD involving the toxin 1-methyl-4-phenylpyridinium (MPP
) and SH-SY5Y neuroblastoma cells. A total of seven compounds were isolated from BHE, viz distichamine (
), 1α,3α-diacetylnerbowdine (
), hippadine (
), stigmast-4-ene-3,6-dione (
), cholest-4-en-3-one (
), tyrosol (
), and 3-hydroxy-1-(4'-hydroxyphenyl)-1-propanone (
). Six compounds (
,
,
,
,
and
) were investigated, and five showed neuroprotection alongside the BHE. This study gives insight into the bioactivity of the non-alkaloidal constituents of Amaryllidaceae, since the isolated compounds and the BHE showed improved cell viability, increased ATP generation in the cells as well as inhibition of MPP
-induced apoptosis. Together, these findings support the claim that the Amaryllidaceae plant family could be a potential reserve of bioactive compounds for the discovery of neuroprotective agents.
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases and affects approximately 6.3 million people worldwide. To date, the treatment of PD remains a challenge, as available ...treatment options are known to be associated with serious side effects; hence, the search for new treatment strategies is critical. Extracts from the Amaryllidaceae plant family as well as their alkaloids have been reported to have neuroprotective potentials. This study, therefore, investigated the biological activities of Crossyne flava and its isolated alkaloids in an in vitro MPP+ (1-methyl-4-phenylpyridinium) PD model using SH-SY5Y cells. The effects of the total extract as well as the four compounds isolated from Crossyne flava (i.e., pancratinine B (1), bufanidrine (2), buphanisine (3), and epibuphanisine (4)) were evaluated for cell viability, neuroprotection, levels of reactive oxygen species (ROS), adenosine triphosphate activity (ATP), and caspase 3/7 activity in SH-SY5Y cells. The results obtained showed that pre-treatment with both the extract and the isolated compounds was effective in protecting the SH-SY5Y cells from MPP+-induced neurotoxicity and inhibited ROS generation, ATP depletion as well as apoptosis induction in the SH-SY5Y cells. The results of this study show that the Amaryllidaceae plant family may be a source of novel compounds for the treatment of neurodegenerative diseases, which validates the reported traditional uses.
The impact of excitotoxicity mediated by
-methyl-D-aspartate (NMDA) receptor overactivation and voltage gated calcium channel (VGCC) depolarization is prominent among the postulated processes ...involved in the development of neurodegenerative disorders. NGP1-01, a polycyclic amine, has been shown to be neuroprotective through modulation of the NMDA receptor and VGCC, and attenuation of MPP
-induced neurotoxicity. Recently, we reported on the calcium modulating effects of tricycloundecene derivatives, structurally similar to NGP1-01, on the NMDA receptor and VGCC of synaptoneurosomes. In the present study, we investigated novel 4-oxatricyclo5.2.1.0
dec-8-ene-3,5-dione derivatives for their cytotoxicity, neuroprotective effects via attenuation of MPP
-induced neurotoxicity and calcium influx inhibition abilities through the NMDA receptor and VGCC using neuroblastoma SH-SY5Y cells. All compounds, in general, showed low or no toxicity against neuroblastoma cells at 10-50 µM concentrations. At 10 µM, all compounds significantly attenuated MPP
-induced neurotoxicity as evident by the enhancement in cell viability between 23.05 ± 3.45% to 53.56 ± 9.29%. In comparison to known active compounds, the derivatives demonstrated mono or dual calcium modulating effect on the NMDA receptor and/or VGCC. Molecular docking studies using the NMDA receptor protein structure indicated that the compounds are able to bind in a comparable manner to the crystallographic pose of MK-801 inside the NMDA ion channel. The biological characteristics, together with results from in silico studies, suggest that these compounds could act as neuroprotective agents for the purpose of halting or slowing down the degenerative processes in neuronal cells.
A medium-throughput screen using
H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. In this initial screen, eleven 7-substituted ...coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at 50 µM. This prompted further exploration of all the 7-substituted coumarins in our library. Four compounds showed promising MIC
values of 8.31-29.70 µM and 44.15-57.17 µM on
H37Rv in independent assays using GAST-Fe and 7H9+OADC media, respectively. These compounds were found to bind to albumin, which may explain the variations in MIC between the two assays. Preliminary data showed that they were able to maintain their activity in fluoroquinolone resistant mycobacteria. Structure-activity relationships indicated that structural modification on position 4 and/or 7 of the coumarin scaffold could direct the selectivity towards either the inhibition of neuronal enzymes or the antimycobacterial effect. Moderate cytotoxicities were observed for these compounds and slight selectivity towards mycobacteria was indicated. Further neuroprotective assays showed significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and neuroprotective agents.
Holamine and funtumine, steroidal alkaloids with strong and diverse pharmacological activities are commonly found in the Apocynaceae family of
. The selective anti-proliferative and cell cycle arrest ...effects of holamine and funtumine on cancer cells have been previously reported. The present study evaluated the anti-proliferative mechanism of action of these two steroidal alkaloids on cancer cell lines (HT-29, MCF-7 and HeLa) by exploring the mitochondrial depolarization effects, reactive oxygen species (ROS) induction, apoptosis, F-actin perturbation, and inhibition of topoisomerase-I. The apoptosis-inducing effects of the compounds were studied by flow cytometry using the APOPercentage
dye and Caspase-3/7 Glo assay kit. The two compounds showed a significantly greater cytotoxicity in cancer cells compared to non-cancer (normal) fibroblasts. The observed antiproliferative effects of the two alkaloids presumably are facilitated through the stimulation of apoptosis. The apoptotic effect was elicited through the modulation of mitochondrial function, elevated ROS production, and caspase-3/7 activation. Both compounds also induced F-actin disorganization and inhibited topoisomerase-I activity. Although holamine and funtumine appear to have translational potential for the development of novel anticancer agents, further mechanistic and molecular studies are recommended to fully understand their anticancer effects.
Multitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer’s disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their ...inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD’s complex pathophysiology. A preliminary series of 3,7-substituted coumarin derivatives were synthesised and evaluated for enzyme inhibitory activity, cytotoxicity as well as neuroprotective ability. The results indicated that the compounds are weak cholinesterase inhibitors with five compounds demonstrating relatively potent inhibition and selectivity towards MAO-B with IC
50
values between 0.014 and 0.498 hx00B5;µM. Significant neuroprotective effects towards MPP
+
-compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 µM for all compounds. The overall results demonstrated that substitution of the phenylethyloxy moiety at the 7-position imparted superior general activity to the derivatives, with the propargylamine substitution at the 3-position, in particular, displaying the best MAO-B selectivity and neuroprotection.
The neuroprotective effects of closed polycyclic cage molecules such as NGP1-01, memantine and amantadine have been extensively explored. These effects are mostly linked to the antagonism of the ...N-methyl-d-aspartate (NMDA) receptor- and the blockage of voltage gated calcium channels (VGCC). The synthesis of structurally related open and rearranged cage derivatives has been studied in depth. However, very little is known on their neuroprotective effects. In this study, a series of open and rearranged polycyclic cage molecules containing a norbornane derived scaffold were synthesised and evaluated for cytotoxicity, neuroprotection and calcium blocking effects via the NMDA receptor and VGCC on neuroblastoma cells at a 10 μM concentration. All compounds showed negligible cytotoxicity and were able to significantly attenuate MPP+-induced neurotoxicity between 26.07 ± 12.50% to 48.42 ± 0.76%, with compound 14 showing the best neuroprotective effect. In comparison to known NMDA receptor antagonists, all compounds demonstrated moderate to excellent calcium blocking effects of 26.50 ± 2.28 to 72.95 ± 3.38%. Docking studies suggest that these compounds are able to show significant NMDA receptor channel blocking ability since they bind in a comparable manner to the crystallographic pose of MK-801 inside the NMDAR ion channel. Some compounds were also able to attenuate calcium influx through VGCC channels between 21.28 ± 3.69% to 50.34 ± 7.67%. Compound 4 and 15 showed the highest inhibition of calcium influx at the VGCC and NMDA receptor, respectively. The compounds exhibiting good cytotoxicity-, neuroprotective- and calcium blocking profiles could potentially act as neuroprotective agents to clinically benefit people suffering from neurodegenerative disorders.
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•Synthesis of open- and rearranged polycyclic cage molecules are reported.•All compounds (1–15) showed minimal toxicity towards neuroblastoma cells at 10 μM.•The compounds were able to attenuate MPP+-induced neurotoxicity.•Significant attenuation of calcium influx at the NMDA receptor and VGCCs observed.•A number of compounds displayed multifunctional neuroprotective abilities similar to NGP1-01.
The multifactorial pathophysiology of neurodegenerative disorders remains one of the main challenges in the design of a single molecule that may ultimately prevent the progression of these disorders ...in affected patients. In this article, we report on twelve novel polycyclic amine cage derivatives, synthesized with or without a propargylamine function, designed to possess inherent multifunctional neuroprotective activity. The MTT cytotoxicity assay results showed the SH-SY5Y human neuroblastoma cells to be viable with the twelve compounds, particularly at concentrations less than 10 μM. The compounds also showed significant neuroprotective activity, ranging from 31% to 61% at 1 μM, when assayed on SH-SY5Y human neuroblastoma cells in which neurodegeneration was induced by MPP+. Calcium regulation assays conducted on the same cell line showed the compounds to be significant VGCC blockers with activity ranging from 26.6% to 51.3% at 10 μM; as well as significant NMDAr antagonists with compound 5 showing the best activity of 88.3% at 10 μM. When assayed on human MAO isoenzymes, most of the compounds showed significant inhibitory activity, with compound 5 showing the best activity (MAO-B: IC50 = 1.70 μM). Generally, the compounds were about 3–52 times more selective to the MAO-B isoenzyme than the MAO-A isoenzyme. Based on the time-dependency studies conducted, the compounds can be defined as reversible MAO inhibitors. Several structure activity relationships were derived from the various assays conducted, and the compounds' possible putative binding modes within the MAO-B enzyme cavity were assessed in silico.
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•In silico studies guided the design of twelve new polycyclic cage compounds.•All compounds showed significant neuroprotection between 31% and 61% at 1 μM.•The compounds have VGCC and NMDAr Ca2+ regulatory potential similar to or better than NGP1-01.•In vitro and in-silico studies suggest the compounds to be reversible MAO-B inhibitors.•The inclusion of the propargylamine led to multi-mechanistic neuroprotective agents.
A series of indole derivatives was designed and synthesised to improve on activity and circumvent pharmacokinetic limitations experienced with the structurally related compound, ladostigil. The ...compounds consisted of a propargylamine moiety (a known MAO inhibitor and neuroprotector) at the
N
1 position and a ChE inhibiting diethyl-carbamate/urea moiety at the 5 or 6 position of the indole ring. In order to prevent or slow down the
in vivo
hydrolysis and deactivation associated with the carbamate function of ladostigil, a urea moeity was incorporated into selected compounds to obtain more metabolically stable structures. The majority of the synthesised compounds showed improved MAO-A inhibitory activity compared to ladostigil. The compounds possessing the propargylamine moiety showed good MAO-B inhibitory activity with
6
and
8
portraying IC
50
values between 14-20 fold better than ladostigil. The ChE assay results indicated that the compounds have non-selective inhibitory activities on eeAChE and eqBuChE regardless of the type or position of substitution (IC
50
: 2-5 μM). MAO-A and MAO-B docking results showed that the propargylamine moiety was positioned in close proximity to the FAD cofactor suggesting that the good inhibitory activity may be attributed to the propargylamine moiety and irreversible inhibition as confirmed in the reversibility studies. Docking results also indicated that the compounds have interactions with important amino acids in the AChE and BuChE catalytic sites. Compound
6
was the most potent multifunctional agent showing better inhibitory activity than ladostigil
in vitro
on all enzymes tested (hMAO-A IC
50
= 4.31 μM, hMAO-B IC
50
= 2.62 μM, eeAChE IC
50
= 3.70 μM, eqBuChE IC
50
= 2.82 μM). Chemical stability tests confirmed the diethyl-urea containing compound
6
to be more stable than its diethyl-carbamate containing counterpart compound
8
. Compound
6
also exerted significant neuroprotection (52.62% at 1 μM) against MPP
+
insult to SH-SY5Y neural cells and has good
in silico
predicted ADMET properties. The favourable neuronal enzyme inhibitory activity, likely improved pharmacokinetic properties
in vivo
and the potent neuroprotective ability of compound
6
make it a promising compound for further development.
Novel indole derivatives as multi-target directed ligands with neuroprotective abilities. X = NH or O.
•Two chalcones were successfully isolated and identified from H.foetidum.•The activities of the total extract and the chalcones were explored for the bio-reduction of gold in green synthesis gold ...nanoparticles.•Physicochemical characterisation and stability were performed for the green synthesised gold nanoparticles in different biogenic media.•In vitro evaluation of all samples for the amelioration of diabetes was conducted.
Searching for new natural bioactive capping agents represent an urgent priority in the green synthesis of metal nanoparticles. Additionaly, the biosaftey of metal nanparticles is a major concern especially in medical applications. Recently, the use of pharmacollogicaly active natural products as capping agents has been deployed to avoid toxic effects during the nanoparticles preparation and to enhance their drugability compared with convential drugs. Helichrysum foetidum is a South African medicinal plant used in folk medicine for the treatment of different human pathologies, and it is known to contain a variety of bioactive compounds. Herein, the total extract and two pure chalcones, helichrysetin and helichrysin, isolated from the same plant were successfully used to synthesize quasi-monodispersed gold nanoparticles in the size range of 2–12 nm. The bio-evaluation of samples indicated that the AuNP/capping agent conjugates are biostable, and have different biological profiles from the total extract/pure compounds. The enzymatic inhibition assays showed significant inhibition by the total extract, helichrysetin and their gold nanoparticles. Interestingly, a similar activity was observed for glucose uptake in HEK293 treated cells. On the other hand, all the tested samples relatively demonstrated no cytotoxicity when tested against the HaCaT keratinocytes. In conclusion, the study demonstrated potential enhancement of glucose uptake in mammalian kidney cells, and inhibition of carbohydrate-hydrolysing enzymes by green synthesized gold nanoparticles of H. foetidum. It also provides a therapeutic appraisal of AuNPs/chalcones conjugate towards the development of antidiabetes drugs derived from H. foetidum and its gold nanoparticles.
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