Search

[Display omitted] • PROTAC has been considered as a promising strategy for drug discovery in the field of neurodegenerative diseases. • This review provides a summary of aberrant pathogenic proteins involved in NDD, and their degraders reported from 2016. • The listed PROTAC molecules were categorized based on their protein targets associated with various types of NDD. • PROTAC-based approaches offer potential therapeutic benefits for treating neurodegenerative diseases. Neurodegenerative diseases (NDD) are characterized by the gradual deterioration of neuronal function and integrity, resulting in an overall decline in brain function. The existing therapeutic options for NDD, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, fall short of meeting the clinical demand. A prominent pathological hallmark observed in numerous neurodegenerative disorders is the aggregation and misfolding of proteins both within and outside neurons. These abnormal proteins play a pivotal role in the pathogenesis of neurodegenerative diseases. Targeted degradation of irregular proteins offers a promising avenue for NDD treatment. Proteolysis-targeting chimeras (PROTACs) function via the ubiquitin–proteasome system and have emerged as a novel and efficacious approach in drug discovery. PROTACs can catalytically degrade "undruggable" proteins even at exceptionally low concentrations, allowing for precise quantitative control of aberrant protein levels. In this review, we present a compilation of reported PROTAC structures and their corresponding biological activities aimed at addressing NDD. Spanning from 2016 to present, this review provides an up-to-date overview of PROTAC-based therapeutic interventions. Currently, most protein degraders intended for NDD treatment remain in the preclinical research phase. Overcoming several challenges is imperative, including enhancing oral bioavailability and permeability across the blood–brain barrier, before these compounds can progress to clinical research or eventually reach the market. However, armed with an enhanced comprehension of the underlying pathological mechanisms and the emergence of innovative scaffolds for protein degraders, along with further structural optimization, we are confident that PROTAC possesses the potential to make substantial breakthroughs in the field of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Twenty-eight coumarin-dithiocarbamate hybrids were designed and synthesized. • 8g was identified as a potent and balanced inhibitor for AChE and MAO-B. • 8g showed no acute toxicity in mice and could penetrate the BBB. • 8g could significantly reverse scopolamine-induced memory deficit in vivo. Abstract A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC 50 values of 0.0068 μM and 0.0089 μM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 µM for hAChE; 0.101 µM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel melatonin-based compounds were designed and synthesized. • 5 displayed potent inhibitory activity and the excellentive selectivity against BuChE. • 5 could scavenge free radicals and induce expression of the Nrf2. • 5 displayed the good abilities to penetrate BBB. Here, we have designed and synthesized a series of melatonin-alkylbenzylamine hybrids as multitarget agents for the treatment of Alzheimer's disease (AD). Most of them exhibited a potent multifunctional profile involving cholinesterase inhibition and antioxidant effects. Among these compounds, compound 5 was most the potent antioxidant (ORAC = 5.13) and also an excellent selective inhibitor of BuChE (hu BuChE IC 50 = 1.20 μM, hu AChE IC 50 = 177.49 μM, SI = 147.91). Moreover, kinetic study indicated compound 5 was a mixed-type inhibitor for hu BuChE. Furthermore, it could induce expression of the Nrf2 as well as its downstream markers at the protein level in cells. More importantly, compound 5 display no acute toxicity in mice at doses up to 2500 mg/kg. And we found compound 5 could improve memory function of scopolamine-induced amnesia mice. These results highlighted compound 5 as a possible hit molecule for further investigation of new anti-AD drugs. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) possessed intricate pathogenesis. Currently, multi-targeted drugs were considered to have the potential to against AD by simultaneously triggering molecules in functionally complementary pathways. Hence, a series of molecules based on the pharmacophoric features of Dimethyl fumarate, Tranilast, and Dithiocarbate were designed and synthesized. These compounds showed significant AChE inhibitory activity in vitro. Among them, compound 4c 2 displayed the mighty inhibitory activity to hAChE (IC 50 = 0.053 μM) and held the ability to cross the BBB. Kinetic study and molecular docking pointed out that 4c 2 bound well into the active sites of hAChE, forming steady and sturdy interactions with key residues in hAChE. Additionally, 4c 2 as an Nrf2 activator could promote the nuclear translocation of Nrf2 protein and induce the expressions of Nrf2-dependent enzymes HO-1, NQO1, and GPX4. Moreover, 4c 2 rescued BV-2 cells from H 2 O 2 -induced injury and inhibited ROS accumulation. For the anti-neuroinflammatory potential of 4c 2 , we observed that 4c 2 could lower the levels of pro-inflammatory cytokines (NO, IL-6 and TNF-α) and suppressed the expressions of iNOS and COX-2. In particular, 4c 2 was well tolerated in mice (2500 mg/kg, p.o.) and efficaciously recovered the memory impairment in a Scopolamine-induced mouse model. Overall, these results highlighted that 4c 2 was a promising multi-targeted agent for treating AD. [Display omitted] • A series of dual-target compounds were designed and synthesized. • 4c 2 was the most potent AChE inhibitor and could penetrate the BBB. • 4c 2 exerted anti-oxidative stress and anti-inflammatory effects as an Nrf2 activator. • 4c 2 could reverse Scopolamine-induced memory deficit in mice. [ABSTRACT FROM AUTHOR]

• Novel pyrazolone-based compounds were designed and synthesized. • The pyrazolone structure was found a selective BuChE pharmacophore. • 5i displayed potent inhibitory activity and the highest selectivity against BuChE. • 5i could scavenge free radicals and cross the BBB. The butyrylcholinesterase (BuChE) has been a potent target for the treatment of the Alzheimer's disease (AD), but the selective BuChE inhibitor is still lacking in the market. In this study, the pyrazolone structure was found to be a promising pharmacophore targeting BuChE. Thus, a series of pyrazolone-based compounds 5a-p were designed, synthesized and evaluated in vitro for BuChE inhibitory activities, antioxidant activities and blood-brain barrier (BBB) permeabilities. Besides, the compounds 5g, 5h, 5i and 5o with submicromolar IC 50 values as well as good BuChE selectivity were chosen to assess their cytotoxicity in PC12 cells. Among them, compound 5i was the most selective BuChE inhibitor (SI: >200) and showed the good abilities to penetrate BBB, scavenge free radicals (1.04 trolox equivalent). Based on above results, compound 5i was selected for molecular docking studies to explain the BuChE selectivity and was considered as a promising lead compound for further investigation in the treatment of AD. [Display omitted] [ABSTRACT FROM AUTHOR]

In this study, a series of multifunctional hybrids against Alzheimer's disease were designed and obtained by conjugating the pharmacophores of xanthone and alkylbenzylamine through the alkyl linker. Biological activity results demonstrated that compound 4j was the most potent and balanced dual ChEs inhibitor with IC 50 values 0.85 μM and 0.59 μM for eeAChE and eqBuChE, respectively. Kinetic analysis and docking study indicated that compound 4j was a mixed-type inhibitor for both AChE and BuChE. Additionally, it exhibited good abilities to penetrate BBB, scavenge free radicals (4.6 trolox equivalent) and selectively chelate with Cu2+ and Al3+ at a 1:1.4 ligand/metal molar ratio. Importantly, after assessments of cytotoxic and acute toxicity, we found compound 4j could improve memory function of scopolamine-induced amnesia mice. Hence, the compound 4j can be considered as a promising lead compound for further investigation in the treatment of AD. Image 1 • Novel xanthone-alkylbenzylamine hybrids were designed and synthesized. • 4j displayed potent and balanced inhibition for both AChE and BuChE. • 4j could selectively chelate with Cu2+ and Al3+, and scavenge free radicals. • 4j could cross the BBB and reverse the scopolamine-induced memory deficit in vivo. [ABSTRACT FROM AUTHOR]