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1.
Bioorg Chem ; 125: 105844, 2022 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-35594720

RESUMO

A novel series of carbamate-based N-substituted tryptamine derivatives were designed and synthesized based on functional group combination strategy, and possessed both cholinesterase inhibition and neuroprotective effects. After systematically evaluating the cholinesterase inhibitory activity of 24 synthesized compounds, compound 6H6, bearing n-heptyl residue as carbamate moiety, was highlighted due to its great BChE-selective inhibition (eeAChE IC50 > 100 µM; eqBChE IC50 = 7 nM), neuronal protection, antioxidation and anti-neuroinflammation efficacy. Cytotoxicity and acute toxicity assays confirmed the safety-efficacy profiles of compound 6H6. Besides, pharmacokinetic properties and blood-brain barrier (BBB) permeability of compound 6H6 were favorable and suitable for further study in vivo. The behavioral tests revealed that compound 6H6 could remarkably improve the scop-induced ethological changes and memory impairment, suggesting compound 6H6, as an attractive pleiotropic molecule, had great promise in treating Alzheimer's disease.

2.
Eur J Med Chem ; 229: 114044, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34923430

RESUMO

In this study, we designed, synthesized, and evaluated a series of carbamate derivatives of N-salicyloyl tryptamine as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). After screening the acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitory activities, target compound 1g stood out as a mixed type reversible dual inhibitor of AChE and BChE. In addition, molecular docking studies were conducted to explore the actions on AChE and BChE. The results showed that 1g could decrease the level of pro-inflammatory cytokines NO, iNOS, IL-6, TNF-α, and ROS, increase the level of anti-inflammatory cytokines IL-4, and inhibit the aggregation of Aß1-42. Moreover, the administration of 1g suppressed the activity of AChE in the brain. In a word, the compound 1g is effective for improving learning and memory behavior, blood-brain barrier permeation, pharmacokinetics, ChE inhibition, and anti-neuroinflammation. It may be considered as a promising multi-functional therapeutic agent for further investigation for the treatment of AD.


Assuntos
Carbamatos/química , Desenho de Fármacos , Fármacos Neuroprotetores/síntese química , Triptaminas/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Carbamatos/metabolismo , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Agregados Proteicos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
3.
Healthcare (Basel) ; 9(10)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34683041

RESUMO

The COVID-19 run on medical resources crashed Wuhan's medical care system, a medical disaster duplicated in many countries facing the COVID-19 pandemic. In a novel approach to understanding the run on Wuhan's medical resources, we draw from bank run theory to analyze the causes and consequences of the COVID-19 run on Wuhan's medical resources and recommend policy changes and government actions to attenuate runs on medical resources in the future. Like bank runs, the cause of the COVID-19 medical resource run was rooted in China's local medical resource context and a sudden realignment of expectations, reflecting shortages and misallocations of hospital resources (inadequate liquidity and portfolio composition); high level hospitals siphoning-off patients from lower level health providers (bank moral hazard and adverse selection problem); patients selecting high-level hospitals over lower-level health care (depositor moral hazard problem); inadequate government oversight and uncontrolled risky hospital behavior (inadequate bank regulatory control); biased medical insurance schemes (inadequate depositor insurance); and failure to provide medical resource reserves (failure as lender of last resort). From Wuhan's COVID-19 run on medical resources, we recommend that control and reform by government enlarge medical resource supply, improve the capacity of primary medical care, ensure timely virus information, formulate principles for the allocation of medical resources that suit a country's national conditions, optimize the medical insurance schemes and public health fund allocations and enhance the emergency support of medical resources.

4.
Org Lett ; 23(17): 6956-6960, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34424725

RESUMO

Enantioselective total syntheses of 12 amicoumacin-type natural products are accomplished with a palladium(II)-catalyzed C-H alkylation as the key step to furnish the 3,4-dihydroisocoumarin scaffold. The target chemicals are assembled in a convergent protocol by merging 3,4-dihydroisocoumarin derived amine part with categories of acid segments that are efficiently prepared by chemoselective catalytic oxidation of chiral 1,2-dihydroxyethylfuran-2(5H)-ones. Afterward, the cytotoxicity of amicoumacins on five cancer cell lines and one normal cell line is investigated.


Assuntos
Produtos Biológicos/síntese química , Paládio/química , Alquilação , Produtos Biológicos/química , Catálise , Estrutura Molecular , Oxirredução
5.
Org Lett ; 23(16): 6222-6226, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34369782

RESUMO

The proposed structures of parvistemoamide have been achieved by macrolactamization, but none of the characterization data of synthetic samples matched with those of the natural sample. The transformation of the highly strained 10-membered lactam ring in parvistemoamide into the pyrrolo[1,2-a]-azepine nucleus in stemoamide is accomplished for the first time by either transannular cyclization or Pilli's transformation. This research may promote the total synthesis of other more complex stemoamide-type or medium-sized-ring-containing Stemona alkaloids.


Assuntos
Alcaloides/química , Azepinas/química , Compostos Heterocíclicos com 3 Anéis/síntese química , Lactamas/química , Stemonaceae/química , Ciclização , Estrutura Molecular
6.
Front Psychol ; 12: 747462, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35115981

RESUMO

Bike sharing, as an innovative travel mode featured by mobile internet and sharing, offers a new transport mode for short trips and has a huge positive impact on urban transportation and environmental protection. However, bike-sharing operators face some operational challenges, especially in sustainable development and profitability. Studies show that the customers' willingness to pay is a key factor affecting bike-sharing companies' operating conditions. Based on the theories of perceived value, this study conducts an empirical analysis of factors that affect bike-sharing users' willingness to pay for bike-sharing through measurement scales, user surveys, and structural equation models. We designed a five-point Likert-type scale containing 11 latent variables affecting willingness to pay and a total of 34 measurement items. We investigate bike-sharing users in China's first and second-tier cities, with a total of 502 participants. The results show that perceived value, payment awareness, trust, and environmental awareness constitute key factors that directly affect bike-sharing users' willingness to pay. And perceived usefulness, perceived ease-of-use, perceived cost, and perceived risk indirectly affect bike-sharing users' willingness to pay. However, we found no significant effects of perceived entertainment on perceived value or word of mouth on willingness to pay. Our results are expected to provide theoretical and practical implications for bike-sharing programs.

7.
J Org Chem ; 84(16): 10490-10500, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31333031

RESUMO

A versatile protocol for the direct thiolation of an inert sp2 C-H bond is presented via a catalytic amount of copper catalysis, by switching related Brønsted bases and regulating the reaction time, and the corresponding mono- and dithiolation products can be obtained selectively in moderate to good yields. The reaction exhibits a relatively broad substrate scope and a good functional group tolerance, even with different heterocyclic amides and alkyl thiols.

8.
Org Biomol Chem ; 17(9): 2341-2345, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30758028

RESUMO

Here, we present an unprecedented pathway to α-sulfenylated carbonyl compounds from commercially available thiols and universally employed TEMPO and its analogues, which act as C3 synthons through skeletal rearrangement under simple and metal-free conditions. Mechanism studies suggest that this reaction involves a consecutive radical oxidation and cation coupling process. TEMPO analogues and thiols serve as oxidants and reductive reagents, respectively, along the radical process, while in the coupling process, the former ones afford C3 synthons to couple with related sulfur sources.

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