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Previous evidence has revealed that increase in intracellular levels of calcium promotes cellular senescence. However, whether calcium channel blockers (CCBs) can slow aging and extend lifespan is still unknown. In this study, we showed that verapamil, an L-type calcium channel blocker, extended the Caenorhabditis elegans (C. elegans) lifespan and delayed senescence in human lung fibroblasts. Verapamil treatment also improved healthspan in C. elegans as reflected by several age-related physiological parameters, including locomotion, thrashing, age-associated vulval integrity, and osmotic stress resistance. We also found that verapamil acted on the α1 subunit of an L-type calcium channel in C. elegans. Moreover, verapamil extended worm lifespan by inhibiting calcineurin activity. Furthermore, verapamil significantly promoted autophagy as reflected by the expression levels of LGG-1/LC3 and the mRNA levels of autophagy-related genes. In addition, verapamil could not further induce autophagy when tax-6, calcineurin gene, was knocked down, indicating that verapamilinduced lifespan extension is mediated via promoting autophagy processes downstream of calcineurin. In summary, our study provided mechanistic insights into the anti-aging effect of verapamil in C. elegans.

Multifunctional agents aiming at cholinesterases (ChEs) and monoamine oxidases (MAOs) are promising therapy for Alzheimer's disease (AD). Herein, a series of novel propargylamine-modified pyrimidinylthiourea derivatives (1-4) were designed and synthesized as dual inhibitors of ChEs and MAOs with other functions against AD. Most of these derivatives inhibited ChEs and MAOs with IC values in the micro- or nanomolar ranges. Compound 1c displayed the dual functional profile of targeting the AChE (IC = 0.032 ± 0.007 μM) and MAO-B (IC = 2.117 ± 0.061 μM), along with the improved blood-brain barrier (BBB) permeability, antioxidant ability, and good copper chelating property in vitro. Animal studies showed that compound 1c·HCl could inhibit the cerebral AChE/MAO-B activities and alleviate scopolamine-induced cognitive impairment in mice. Combined with good oral bioavailability ( F = 45.55%), these findings demonstrated that compound 1c may be a potent brain permeable multifunctional candidate for the treatment of AD.

Depression is one of the most frequent psychiatric complications of Alzheimer's disease (AD), affecting up to 50% of the patients. A novel series of hybrid molecules were designed and synthesized by combining the pharmacophoric features of vilazodone and tacrine as potential multitarget-directed ligands for the treatment of AD with depression. In vitro biological assays were conducted to evaluate the compounds; among the 30 hybrids, compound 1e showed relatively balanced profiles between acetylcholinesterase inhibition (IC = 3.319 ± 0.708 μM), 5-HT agonist (EC = 107 ± 37 nM), and 5-HT reuptake inhibition (IC = 76.3 ± 33 nM). Compound 1e displayed tolerable hepatotoxicity and moderate hERG inhibition activity, and could penetrate the blood-brain barrier in vivo. Furthermore, an oral intake of 30 mg/kg 1e·HCl could significantly improve the cognitive function of scopolamine-induced amnesia mice and alleviate the depressive symptom in tail suspension test. The effectivity of 1e validates the rationality of our design strategy.