Multitarget Drug Design Strategy: Quinone\u2013Tacrine Hybrids Designed To Block Amyloid-\u3b2 Aggregation and To Exert Anticholinesterase and Antioxidant Effects

We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-\u3b2 (A\u3b2) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by A\u3b2. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit

Novel Tacrine–Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease: Design, Synthesis, Biological Evaluation, and X‑ray Crystallography

Twenty-six new tacrine–benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer’s disease. Most hybrids exhibited good inhibitory activities on cholinesterases and β-amyloid self-aggregation. Selected compounds displayed significant inhibition of human β-secretase-1 (<i>h</i>BACE-1). Among the 26 hybrids, <b>2e</b> showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (<i>h</i>AChE) (IC₅₀ = 0.86 nM) and a good inhibitor of both β-amyloid aggregation (<i>h</i>AChE- and self-induced, 61.3% and 58.4%, respectively) and <i>h</i>BACE-1 activity (IC₅₀ = 1.35 μM). Kinetic studies showed that <b>2e</b> acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of <b>2e</b> to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (<i>Tc</i>AChE), with significant implications for structure-based drug design. In vivo studies confirmed that <b>2e</b> significantly ameliorates performances of scopolamine-treated ICR mice. Finally, <b>2e</b> administration did not exhibit significant hepatotoxicity

Postmarketing active surveillance of myocarditis and pericarditis following vaccination with COVID-19 mRNA vaccines in persons aged 12 to 39 years in Italy: A multi-database, self-controlled case series study

Myocarditis and pericarditis following the Coronavirus Disease 2019 (COVID-19) mRNA vaccines administration have been reported, but their frequency is still uncertain in the younger population. This study investigated the association between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccines, BNT162b2, and mRNA-1273 and myocarditis/pericarditis in the population of vaccinated persons aged 12 to 39 years in Italy

Multitarget Drug Design Strategy: Quinone–Tacrine Hybrids Designed To Block Amyloid‑β Aggregation and To Exert Anticholinesterase and Antioxidant Effects

We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. <i>In vitro</i>, 15 compounds displayed excellent acetyl­cholin­esterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-β (Aβ) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC₅₀ = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by Aβ. Importantly, they crossed the blood-brain barrier, as demonstrated in <i>ex vivo</i> experiments with rats. When <i>ex vivo</i> results were combined with <i>in vitro</i> studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit