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The controversial approval in June 2021 by the Food and Drug Administration (FDA) of aducanumab (marketed as Aduhelm), Biogen's monoclonal antibody for patients with Alzheimer's disease, raises significant concerns for the dementia field and drug approval process, considering its lack of adequate evidence for clinical efficacy, safety issues, and cost. On 15 December 2021, an international group of clinicians, basic science experts, psychological and social science researchers, lay people with lived experience of dementia, and advocates for public health met to discuss making a recommendation for whether aducanumab's approval should be withdrawn. Attendees considered arguments both in favor of and in opposition to withdrawal and voted unanimously to recommend that the FDA withdraw its approval for aducanumab and to support the Right Care Alliance's filing of a formal Citizen Petition to this effect. [ABSTRACT FROM AUTHOR]

U.S. Food and Drug Administration-s (FDA) approval of aducanumab (Aduhelm® in the US) as a treatment for mild cognitive impairment of the Alzheimer type and Alzheimer-s disease has raised such major concerns about efficacy, safety, FDA processes, and regulatory capture that Biogen-s license to market this biologic should be immediately withdrawn. Aducanumab has not demonstrated benefit to patients, failed to meet regulatory guidelines, and is likely to cause both individual and societal harm. [ABSTRACT FROM AUTHOR]

A series of novel Diallyl disulfide (DADS) derivatives were designed, synthesized and evaluated as chemical agents, which target and modulate multiple facets of Alzheimer’s disease (AD). The results showed that the target compounds 5a – l and 7e – m exhibited significant anti-Aβ aggregation activity, considerable acetylcholinesterase (AChE) inhibition, high selectivity towards AChE over butyrylcholinesterase (BuChE), potential antioxidant and metal chelating activities. Specifically, compounds 7k and 7l exhibited highest potency towards self-induced Aβ aggregation (74% and 71.4%, 25 μM) and metal chelating ability. Furthermore, compounds 7k and 7l disaggregated Aβ fibrils generated by Cu 2+ -induced Aβ aggregation by 80.9% and 78.5%, later confirmed by transmission electron microscope (TEM) analysis. Besides, 7k and 7l had the strongest AChE inhibitory activity with IC 50 values of 0.056 μM and 0.121 μM, respectively. Furthermore, molecular modelling studies showed that these compounds were capable of binding simultaneously to catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. All the target compounds displayed moderate to excellent antioxidant activity with ORAC-FL values in the range 0.546–5.86 Trolox equivalents. In addition, absorption, distribution, metabolism and excretion (ADME) profile and toxicity prediction (TOPKAT) of best compounds 7k and 7l revealed that they have drug like properties and possess very low toxic effects. Collectively, the results strongly support our assertion that these compounds could provide good templates for developing new multifunctional agents for AD treatment. [ABSTRACT FROM AUTHOR]

The cholinergic hypothesis associated with Alzheimer's disease has spurred the development of numerous structural classes of compounds with different pharmacological profiles aimed at increasing central cholinergic neurotransmission. In the present study, six synthetic piperazine derivatives D1-D6 were screened for their efficacy as acetylcholinesterase inhibitors (AChEIs) through in silico and in vitro studies. Compound D2 was found to be a potential AChEI with adequate pharmacokinetic properties, as supported by in silico study. Further, in vivo studies were designed to examine the protective effect of piperazine derivative D2 (3 and 5 mg/kg for 6 weeks) in ameliorating the alterations induced by aluminium chloride (AlCl) on behavioural and neurochemical indices. Behavioural tests (Morris water maze and elevated plus maze) revealed significant alterations in the short-term memory and anxiety levels in rats treated with AlCl, which was further improved after D2 treatment. Further, D2 treatment attenuated the neurotoxic effects of AlCl as shown by the improvement in rats performance in Water maze test and in lowering AChE activity. Besides preventing lipid peroxidation and protein damage, changes in the levels of endogenous antioxidant enzymes (GST, GPx, GR and GSH) associated with AlCl administration were also restored upon treatment with D2. Thus, our results support the neuroprotective potential of compound D2, thus validating its use in alleviating toxic effects of aluminium. [ABSTRACT FROM AUTHOR]

A novel series of donepezil based multi-functional agents “( E )-5,6-dimethoxy-2-(4-(4-substituted piperazin-1-yl)benzylidene)-2,3-dihydro-1 H -inden-1-ones” have been designed and synthesized as potential anti-Alzheimer's agents. In-vitro studies revealed that these compounds demonstrated moderate to good AChE and Aβ aggregation inhibitory activity. These derivatives are also endowed with admirable antioxidant activity. Among the entire series compounds IP-9 , IP-13 and IP-15 appeared as most active multi-functional agents and displayed marked AChE inhibitory, Aβ disaggregation and antioxidant activity. Studies indicate that IP-13 and IP-15 showed better AChE inhibitory activity than the standard drug donepezil and IP-9 , IP-13 as well as IP-15 exhibited better Aβ aggregation inhibitory activity than curcumin. These compounds ( IP-9 , IP-13 and IP-15 ) successfully diminished H 2 O 2 induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H 2 O 2 as well as Aβ induced toxicity in SH-SY5Y cells in a concentration dependent manner. Moreover, these derivatives did not exert any significant toxicity in neuronal SH-SY5Y cells in cytotoxicity assay. To elucidate the plausible binding mode of the compounds IP-9 , IP-13 and IP-15 , molecular docking studies and molecular dynamics (MD) simulation studies were also performed and the results indicate their significant interactions with the active sites of AChE as well as Aβ 1-42 peptide. Thus, the present study evidently showed that IP-9 , IP-13 and IP-15 are potent multi-functional agents against Alzheimer's disease and might serve as promising lead candidates for anti-Alzheimer drug development. [ABSTRACT FROM AUTHOR]

A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)-1 H -indene-1,3(2 H )-diones were designed, synthesized and appraised as multifunctional anti-Alzheimer agents. In vitro studies of compounds 27 – 38 showed that these compounds exhibit moderate to excellent AChE, BuChE and Aβ aggregation inhibitory activity. Notably, compounds 34 and 38 appeared as most active multifunctional agents in the entire series and exhibited excellent inhibition against AChE (IC 50 = 0.048 μM: 34 ; 0.036 μM: 38 ), Aβ aggregation (max% inhibition 82.2%, IC 50 = 9.2 μM: 34 ; max% inhibition 80.9%, IC 50 = 10.11 μM: 38 ) and displayed significant antioxidant potential in ORAC-FL assay. Both compounds also successfully diminished H 2 O 2 induced oxidative stress in SH-SY5Y cells. Fascinatingly, compounds 34 and 38 showed admirable neuroprotective effects against H 2 O 2 and Aβ induced toxicity in SH-SY5Y cells. Additionally, both derivatives showed no considerable toxicity in neuronal cell viability assay and represented drug likeness properties in the primarily pharmacokinetics study. All these results together, propelled out that compounds 34 and 38 might serve as promising multi-functional lead candidates for treatment of AD in the future. [ABSTRACT FROM AUTHOR]

A series of new cyanopyridine–triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimer’s agents. These molecules were designed while using computational techniques and were synthesized via a feasible concurrent synthetic route. Inhibition potencies of synthetic compounds 4a – 4h against cholinesterases, Aβ 1–42 disaggregation, oxidative stress, cytotoxicity, and neuroprotection against Aβ 1–42 -induced toxicity of the synthesized compounds were evaluated. Compounds 4d and 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC 50 values 0.059 and 0.080 μM, respectively, along with good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modelling studies revealed that these compounds interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The mixed type inhibition of compound 4d further confirmed their dual binding nature in kinetic studies. Furthermore, the results from neuroprotection studies of most potent compounds 4d and 4h indicate that these derivatives can reduce neuronal death induced by H 2 O 2 -mediated oxidative stress and Aβ 1–42 induced cytotoxicity. In addition, in silico analysis of absorption, distribution, metabolism and excretion (ADME) profile of best compounds 4d and 4h revealed that they have drug like properties. Overall, these cyanopyridine–triazine hybrids can be considered as a candidate with potential impact for further pharmacological development in Alzheimer’s therapy. [ABSTRACT FROM AUTHOR]