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Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible huAChE (IC 50  = 0.87 μM) and huBuChE (IC 50  = 3.3 μM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-α production, and significantly inhibited self-mediated Aβ 1-42 aggregation (60.6%) and huAChE-mediated induced Aβ 1-40 aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on Aβ 1-42 -induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [ 11 C]10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations., (Copyright © 2022. Published by Elsevier Inc.)

Herein, combining 1,2,3,4-tetrahydroisoquinoline and benzylpiperidine groups into cinnamic acid derivatives, a series of novel cinnamic acid hybrids was rationally designed, synthesized and evaluated by the multi-target-directed ligands (MTDLs) strategy. Hybrid 4e was the most promising one among these hybrids with a reversible huBuChE inhibitor (IC 50  = 2.5 μM) and good MAO-B inhibition activity (IC 50  = 1.3 μM) and antioxidant potency (ORAC = 0.4 eq). Moreover, compound 4e significantly inhibited self-mediated Aβ 1-42 aggregation (65.2% inhibition rate). Compound 4e exhibited remarkable anti-inflammatory propery and neuroprotective effect. Furthermore, compound 4e displayed favourable blood-brain barrier penetration via parallel artificial membrane permeation assay (PAMPA). The obtained results also revealed that compound 4e significantly improved dyskinesia recovery rate and response efficiency on AD model zebrafish. Further, 4e did not show obvious acute toxicity at dose up to 1500 mg/kg in vivo and improved scopolamine-induced memory impairment. Importantly, compound 4e showed good stability in both artificial gastric fluid and artificial intestinal fluid. Therefore, compound 4e presented a promising multi-targeted active molecule for treating AD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The multi-target-directed ligands have been regarded as the promising multifunctional agents for the treatment of Alzheimer's disease (AD). Based on our previous work, a series of genistein-O-alkylamines derivatives was developed to further explore the structure-activity-relationship. The results showed that compound 7d indicated reversible and highly selective hAChE inhibitory activity with IC 50 value of 0.53 μM. Compound 7d also displayed good antioxidant activity (ORAC = 1.1 eq.), promising neuroprotective effect and selective metal chelation property. Moreover, compound 7d significantly inhibited self-induced, hAChE-induced and Cu 2+ -induced Aβ aggregation with 39.8%, 42.1% and 74.1%, respectively, and disaggregated Cu 2+ -induced Aβ 1-42 aggregation (67.3%). In addition, compound 7d was a potential autophagy inducer and improved the levels of GPX4 protein. Furthermore, compound 7d presented good blood-brain-barrier permeability in vitro. More importantly, compound 7d did not show any acute toxicity at doses of up to 1000 mg/kg and presented good precognitive effect on scopolamine-induced memory impairment. Therefore, compound 7d was a promising multifunctional agent for the development of anti-AD drugs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chinese water chestnut, the bulb of Heleocharis dulcis, has been widely consumed as fruit or vegetable in China since ancient times. It exhibits health-promoting properties that leads to an extensive study of their active components. Successive chromatography of active fragments of H. dulcis resulted in isolation of five new chalcone-flavonone heterodimers (1-3, 6, 9), four new diverse flavonoids (4, 5, 7, 8), and sixteen known flavonoids derivatives (10-25) were elucidated on the basis of their IR, UV, NMR, MS spectrometry data analysis and references from H. dulcis for the first time. Among these isolates, compounds 4, 7, 9, 12, 13, and 17 showed moderate neuroprotective activity, which increased the cell survival rate from 49.23 ± 3.68% for the model to 67.75 ± 2.75%, 57.83 ± 2.46%, 67.98 ± 2.74%, 58.65 ± 3.43%, 56.14 ± 1.99%, and 56.70 ± 1.38% at 10 μM, respectively. Moreover, compounds 1-3, 15, 16, 18, and 20 were found to moderately improve the HepG2 cell survival rates from 39.53% (APAP, 10 mM) to 45.53-53.44%. The outcome of the study provided crucial information regarding the structural diversity and health benefits of the edible bulbs of H. dulcis., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Four new phenylpropanoid derivatives (1-4), together with eleven known analogues (5-15) were isolated and identified by comparison with their references and extensive spectroscopic methods from Murraya koenigii for the first time. Compounds (1-15) were assayed for their inhibitory activities by measuring IL-6-induced STAT3 promoter activities in HepG2 cells, and found compounds 1, 2, 6, and 15 showed inhibitory effects with IC 50 values of 11.5, 18.7, 8.9, and 22.7 μM, respectively. The inhibitory activities of compounds (1-15) were screened against NO production in lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells, and found compounds 3, 4, 9, 11, and 14 exhibited inhibitions against LPS-induced NO production in RAW264.7 macrophages, with IC 50 values of 32.7, 7.9, 42.1, 58.9, and 62.4 μM, respectively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6-fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)-1H-pyrrole-3-carboxylate was found to display inhibitory effects against H 37 Ra with an MIC value of 77 µM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis, a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated forin vitrostudies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)-N-((1-(2-chloro-6-fluorophenyl)-2, 5-dimethyl-1H- pyrrolyl)methyl)ethan-1-aminehydrochloride 7d, ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13i, ethyl 1-(4-chlorophenyl)-4-(((2-fluorophenethyl)amino)methyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 µM against Mtb H 37 Ra, respectively., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Two new carbazole alkaloids 1 and 2, and eleven known congeners 3-13 were isolated and identified from Clausena sanki for the first time. Their structures were elucidated on the basis of extensive UV, IR, MS, NMR spectroscopic data and comparison with literatures. The compounds 1-13 were evaluated by MTT assay to determine whether they decreased VEGF-mediated cell proliferation in HUVECs with Axitinib as positive control. Among them, compounds 1, 2, 6, 8, and 13 (μM) exhibited moderate antiangiogenic activities, which inhibited VEGF-induced HUVEC proliferation in vitro with IC 50 values of 12.1 (C.I. 8.2-15.2), 58.1 (C.I. 56.3-63.4), 13.7 (C.I. 9.2-15.4), 16.0 (C.I. 9.5-16.4), and 63.2 (C.I. 57.8-65.7) μM, respectively. Moreover, the antiangiogenic activities of compounds 1-13 were evidenced in vivo in the zebrafish embryo model. As a result, compounds 1, 2, 6, 8, and 13 showed effectively suppress angiogenesis. These research results may guide the search for new natural products with antiangiogenic attributes., (Copyright © 2018 Elsevier Inc. All rights reserved.)