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Sarglamides A–E (1−5), representing the first example of heterodimers of a trans-N-cinnamoylindolidinoid and an α-phelladrene derivatives, were isolated from Sarcandra glabra subsp. brachystachys. Particularly, compounds 4 and 5 possess unprecedented cage-like 6/6/5/6/5- and 6/6/6/6/5-fused pentacyclic scaffolds, respectively. Their structures were established by spectroscopic analysis, X-ray crystallography, quantum chemical calculations, and chemical conversions. Plausible biosynthetic pathways of 1−5, involving the co-isolated enantiomers 6a and 6b were proposed. Compounds 3–7 showed inhibitory activity against lipopolysaccharide (LPS) induced inflammation in BV-2 microglial cells.

A novel norditerpenoid, sinusiaetone A (1), featuring an uncommon bicyclo[11.3.0]hexadecane carbon skeleton, and four polyoxygenated cembranoids (2-5) were isolated from the Hainan soft coral Sinularia siaesensis. Their structures were established by spectroscopic analysis, X-ray diffraction, quantum chemical computational approaches, and/or a modified Mosher's method. A plausible biosynthetic pathway of 1 and its biogenetic relationship with 2-5 were proposed. New compounds 1-3 displayed an interesting inhibitory activity against lipopolysaccharide-induced inflammation in BV-2 microglial cells.

Two eudesmane-guaiane/lindenane heterocoupled sesquiterpenoid dimers, horienoids A (1) and B (2) with new carbon skeletons, from Hedyosmum orientale were characterized by a combined method. Compound 1 featured a unique 2,10-dioxabicyclo[6.2.1]undecane core moiety with an anti-Bredt bridgehead double bond. Their biogenetic pathways were proposed to involve Diels-Alder and cascade rearrangement reactions as the key steps. Compound 2 exhibited a potent anti-inflammatory effect on LPS-induced BV-2 microglial cells.

The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.

The chemical investigation of the South China Sea soft coral Sinularia humilis has resulted in the isolation of a library of diverse diterpenoids, including four new cembranoids, namely, humilisins A-D (1-4), two new uncommon diterpenoids possessing a tetradecahydrocyclopenta[3',4']cyclobuta[1',2':4,5]cyclonona[1,2-b]oxirene ring system, namely, humilisins E and F (5 and 6), and eight known related compounds (7-14). Humilisin A (1) is the first cembranoid with an ether linkage between C-3 and C-7. The structures and absolute configurations of 1-8 were determined by extensive spectroscopic data analyses, chemical reactions, and a series of quantum chemical calculations including quantum mechanical-nuclear magnetic resonance (QM-NMR), time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD), and optical rotatory dispersion (ORD) methods. In bioassay, compound 6 displayed anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells.

Three new dimeric diarylheptanoids, taccachanfurans A-C (1-3), a new monomeric diarylheptanoid, taccachannoid A (4), and four known diarylheptanoids (5-8) were isolated from the EtOH extract of the rhizomes of Tacca chantrieri. Their structures were established on the basis of comprehensive spectroscopic data analysis. The absolute configuration of taccachanfuran A (1) was confirmed by single-crystal X-ray diffraction. All the diarylheptanoid dimers contain a ditetrahydrofuran moiety, which has not been described previously for diarylheptanoid compounds. A plausible biosynthetic pathway for the diarylheptanoid dimers is proposed. Compounds 2-4 showed significant neuroprotective activity against Aβ25-35-induced damage in SH-SY5Y cells at the concentrations of 10 and 1 μM. Compounds 3, 4, 6, 7, and 8 showed anti-inflammatory activity in LPS-stimulated murine microglial BV-2 cells at the concentrations of 10 and 1 μM.

Our previous study had identified ciclopirox (CPX) as a promising lead compound for treatment of ischemic stroke. To find better neuroprotective agents, a series of N-hydroxypyridone derivatives based on CPX were designed, synthesized, and evaluated in this study. Among these derivatives, compound 11 exhibits significant neuroprotection against oxygen glucose deprivation and oxidative stress-induced injuries in neuronal cells. Moreover, compound 11 possesses good blood-brain barrier permeability and superior antioxidant capability. In addition, a complex of compound 11 with olamine-11·Ola possesses good water solubility, negligible hERG inhibition, and superior metabolic stability. The in vivo experiment demonstrates that 11·Ola significantly reduces brain infarction and alleviates neurological deficits in middle cerebral artery occlusion rats. Hence, compound 11·Ola is identified in our research as a prospective prototype in the innovation of stroke treatment.

Twenty-one dihydro-β-agarofuran derivatives were purified from the seeds of Euonymus maackii, and eight compounds (1-8) were identified as new natural products. Their structures were deduced by extensive spectroscopic analysis, X-ray diffraction studies, and comparison of observed and reported NMR data. Compounds 10, 12, 17, and 18 significantly increased the cell viability of Aβ25-35-treated SH-SY5Y cells with effects similar to that of epigallocatechin gallate (EGCG). In addition, the abundant compound 9 reduced the seizure-like locomotor activity of zebrafish at 10 μM compared with a pentylenetetrazol-treated group.

Fluorescent imaging of β-amyloid (Aβ) is one of the most promising methods for Alzheimer's disease diagnosis. Several fluorescent probes have been reported to detect Aβ both in vitro and in vivo. However, highly sensitive and highly selective probes with low background signals are still greatly needed. Herein, we rationally designed and synthesized a PIET quenched near-infrared probe QAD-1 to detect Aβ. This probe contains BODIPY as fluorophore and tetrahydroquinoxaline as the quenching group. QAD-1 exhibited significant fluorescent switch-on after binding to soluble and insoluble Aβ species, and the probe had the benefit of low background signal to stain Aβ plaques without the need of wash-out procedures in vitro, which was specially found by the fluorescence off-on probe. QAD-1 could identify the overproduced Aβ in transgenic (APPSWE/PSEN 1dE9) AD mice as early as 6 months old in vivo, which indicated that QAD-1 may be a potential probe for monitoring Aβ species at an early stage of AD.

Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 μM, SI196; 5t, IC50 = 0.067 μM, SI597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Aβ aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.

Three novel 7,8-seco-lycopodane-derived 8,5-lactones (annotinolides A-C, 1-3) were isolated from Lycopodium annotinum. Their structures were elucidated by spectroscopic methods and single-crystal X-ray diffraction. Compound 1 possesses an unusual cyclopropane ring constructed through a hitherto unknown C-6/C-12 bond. Compound 2 represents the first 7,8-seco-lycopodane-derived alkaloid with a rare cyclobutane ring formed by a new C-12/C-15 linkage, while the C-8/C-15 bond remains. Compound 3 contains an unprecedented 12-spiro-9,12-γ-lactone moiety. Their plausible biosynthetic pathways and antiaggregation effects on amyloid-β1-42 are also presented.

Alzheimer's disease (AD) is an irreversible, multifaceted, and progressive neurodegenerative disorder. Over the past 30 years, the search for anti-AD drugs has been primarily based on the cholinergic deficiency hypothesis and/or the β-amyloid (Aβ) cascade hypothesis. In this study, we report the identification of 16 new and 38 known β-dihydroagarofuran-type sesquiterpenoids from Celastrus flagellaris and Celastrus angulatus. The β-dihydroagarofuran-type sesquiterpenoids 58, 59, 61, and 63 significantly attenuated scopolamine-induced prolonged escape latency and increased number of errors compared with the control group. At 10 μM, 21 of the 62 tested β-dihydroagarofuran-type sesquiterpenoids rescued Aβ25-35-induced SH-SY5Y cells from viability reduction, which increased the cell viability from 64.6% for the model to more than 74.0%. The majority of the β-dihydroagarofuran-type sesquiterpenoids with ester groups exhibited stronger activity than those with free hydroxy groups or without substituents at the same positions. These results identified a new chemical skeleton as drug lead for the investigation of novel therapeutic agents against AD.

(M)-Bicelaphanol A (1) and (P)-bicelaphanol A (2), two unprecedented dimeric trinorditerpenes existing as atropisomers, together with their monomer celaphanol A (3), were isolated from the root bark of Celastrus orbiculatus. The structures and absolute configurations of 1 and 2 were determined by spectroscopic and single-crystal X-ray diffraction analyses. Compound 1 exhibited a significant in vitro neuroprotective effect against a hydrogen peroxide-induced cell viability decrease in PC12 cells at 1 μM, while compounds 2 and 3 showed such effects at 10 μM.

Eleven new dibenzocyclooctadiene lignans, polysperlignans A-K (1-11), and eight known analogues (12-19) were isolated from the stems of Kadsura polysperma. Their structures and absolute configurations were established using a combination of MS, NMR, CD, and single-crystal X-ray diffraction techniques. Selected compounds were evaluated for activity against beta-amyloid- or hydrogen peroxide-induced neurotoxicity on PC12 cells, and 1, 2, 4, 5, 13, and 16 showed statistically significant neuroprotective effects in these in vitro assays.

Fourteen new dibenzocyclooctadiene lignans, ananolignans A-N (1-14), together with five known compounds, were isolated from the seeds of Kadsura ana iosma. The structures and absolute configurations of 1-14 were established using a combination of spectroscopic methods including 1D- and 2D-NMR and CD techniques. The biological activity of the isolated lignans was evaluated, and ananolignan F (6) and ananolignan L (12) showed significant neuroprotective effects in an in vitro assay.

A dinuclear samarium(III) complex [Sm(p-ClBA)3bipy·H2O]2 [p-ClBA = p-chlorobenzoate; bipy = 2,2′-bipyridine] has been synthesized and characterized by elemental analysis, molar conductance, UV and ...

Four new merrillianin-type sesquiterpenes, oligandrumins A-D (1-4), two new seco-prezizaane-type sesquiterpenes, veranisatins D and E (5 and 6), and a new phenylpropane glycoside, oligandrumin E (7), were isolated from the ethanol extract of pericarps of Illicium oligandrum, together with six known sesquiterpenoids and two phenylpropanoids. Their structures were established on the basis of extensive spectroscopic analyses. The structures of 1 and 2 were further confirmed by single-crystal X-ray diffraction experiments. Anislactone B (13) and the erythro form of anethole glycol (14) were shown to attenuate the damage induced by H(2)O(2) in SH-SY5Y cells.

Walsucochins A (1) and B (2) with an unprecedented skeleton were isolated from Walsura cochinchinensis. Their structures including absolute configuration were elucidated by spectral methods. A biosynthetic pathway of 1 and 2 was postulated. Both 1 and 2 exhibited significant cell protecting activities against H2O2-induced PC12 cell damage.