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1.
Comput Biol Chem ; 94: 107565, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34474201

RESUMO

A series of novel urea, sulfamide and N,N-dipropargyl substituted benzylamines were synthesized from dihydrochalcones. The synthesized compounds were evaluated for their cholinesterases and carbonic anhydrase inhibitory actions. The known dihydrochalcones were converted into four new benzylamines via reductive amination. N,N-Dipropargylamines, ureas and sulfamides were synthesized following the reactions of benzylamines with propargyl bromide, N,N-dimethyl sulfamoyl chloride and N,N-dimethyl carbamoyl chloride. The novel substituted benzylamines derived from dihydrochalcones were evaluated against some enzymes such as human erythrocyte carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The novel substituted benzylamines derived from dihydrochalcones exhibited Ki values in the range of 0.121-1.007 nM on hCA I, and 0.077-0.487 nM on hCA II closely related to several pathological processes. On the other hand, Ki values were found in the range of 0.112-0.558 nM on AChE, 0.061-0.388 nM on BChE. As a result, novel substituted benzylamines derived from dihydrochalcones showed potent inhibitory profiles against indicated metabolic enzymes. In addition, Induced-Fit Docking (IFD) simulations and ADME prediction studies have also been carried out to elucidate the inhibition mechanisms and drug-likeness of the synthesized compounds. Therefore, these results can make significant contributions to the treatment of some global diseases, especially Alzheimer's diseases and glaucoma, and the development of new drugs.


Assuntos
Benzilaminas/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Animais , Benzilaminas/síntese química , Benzilaminas/química , Butirilcolinesterase/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Chalconas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
2.
Chem Pharm Bull (Tokyo) ; 69(8): 811-816, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334527

RESUMO

Three new aconitine-type C19-diterpenoid alkaloid namely novolunines A (1), B (2), and C (3), along with fifteen known diterpenoid alkaloids were isolated from the roots of Aconitum novoluridum, whose phytochemical investigations have never been reported before. The structures of three new alkaloids were established on the basis of spectra data (high-resolution electrospray ionization (HR-ESI)-MS, IR, one dimensional (1D)- and 2D-NMR). Noteworthily, novolunines A (1) and B (2) are two diterpenoid alkaloids bearing conformational isomerism. In addition, the diterpenoid alkaloids 1-3 did not show any anti-acetylcholinesterase (AChE) or anti-inflammatory activities.


Assuntos
Acetilcolinesterase/metabolismo , Aconitum/química , Anti-Inflamatórios/farmacologia , Inibidores da Colinesterase/farmacologia , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Electrophorus , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Células RAW 264.7
3.
Sci Rep ; 11(1): 13953, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230570

RESUMO

Among 276 herbal extracts, a methanol extract of Castanopsis cuspidata var. sieboldii stems was selected as an experimental source for novel acetylcholinesterase (AChE) inhibitors. Five compounds were isolated from the extract by activity-guided screening, and their inhibitory activities against butyrylcholinesterase (BChE), monoamine oxidases (MAOs), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE-1) were also evaluated. Of these compounds, 4'-O-(α-L-rhamnopyranosyl)-3,3',4-tri-O-methylellagic acid (3) and 3,3',4-tri-O-methylellagic acid (4) effectively inhibited AChE with IC50 values of 10.1 and 10.7 µM, respectively. Ellagic acid (5) inhibited AChE (IC50 = 41.7 µM) less than 3 and 4. In addition, 3 effectively inhibited MAO-B (IC50 = 7.27 µM) followed by 5 (IC50 = 9.21 µM). All five compounds weakly inhibited BChE and BACE-1. Compounds 3, 4, and 5 reversibly and competitively inhibited AChE, and were slightly or non-toxic to MDCK cells. The binding energies of 3 and 4 (- 8.5 and - 9.2 kcal/mol, respectively) for AChE were greater than that of 5 (- 8.3 kcal/mol), and 3 and 4 formed a hydrogen bond with Tyr124 in AChE. These results suggest 3 is a dual-targeting inhibitor of AChE and MAO-B, and that these compounds should be viewed as potential therapeutics for the treatment of Alzheimer's disease.


Assuntos
Inibidores da Colinesterase/farmacologia , Ácido Elágico/isolamento & purificação , Ácido Elágico/farmacologia , Fagaceae/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Animais , Bioensaio , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fracionamento Químico , Inibidores da Colinesterase/farmacocinética , Diálise , Cães , Electrophorus , Ácido Elágico/farmacocinética , Células HL-60 , Humanos , Ligação de Hidrogênio , Cinética , Células Madin Darby de Rim Canino , Metanol , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase/farmacocinética , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química
4.
J Enzyme Inhib Med Chem ; 36(1): 1659-1664, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34294013

RESUMO

The synthesis of four tetra-tacrine clusters where the tacrine binding units are attached to a central scaffold via linkers of variable lengths is described. The multivalent inhibition potencies for the tacrine clusters were investigated for the inhibition of acetylcholinesterase. Two of the tacrine clusters displayed a small but significant multivalent inhibition potency in which the binding affinity of each of the tacrine binding units increased up to 3.2 times when they are connected to the central scaffold.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenvolvimento de Medicamentos , Tacrina/farmacologia , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Estrutura Molecular , Relação Estrutura-Atividade , Tacrina/síntese química , Tacrina/química
5.
Future Med Chem ; 13(13): 1105-1125, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33960203

RESUMO

Background: Alzheimer's disease is a multifactorial neurological disorder seen in elderly people. Loss of cholinergic transmission and unbalanced tryptophan metabolism kynurenine pathway have been demonstrated in neuropsychiatric diseases. Methods & results: Among the two series of synthesized compounds, compounds 5c and 5h were identified as effective dual BChE/IDO1 inhibitors, with well-balanced micromolar activity. Compounds 5c and 5h exhibited promising ability to ameliorate behavioral impairment by Morris water maze. The safety of miconazole analogs was also validated by PC12 and SH-SY5Y cell lines. Conclusion: These results highlight the ability of 5c and 5h to treat Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Miconazol/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Humanos , Masculino , Camundongos , Miconazol/síntese química , Miconazol/química , Modelos Moleculares , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos
6.
Bioorg Med Chem Lett ; 41: 128000, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33798702

RESUMO

(S, S)-1-hydroxy-1-oxo-2-c,5-t-diphenylphospholane or Fiaud's acid is used as a novel and effective chiral organocatalyst for bis α-aminophosphonates synthesis with excellent diastereoselectivity and yields within short reaction time. All synthesized bis α-aminophosphonates revealed a good to excellent antifungal capacity, where the six compounds 4a, 4b, 4e, 4h, 4k and 4l are the best fungicide inhibiting the growth of Fusarium oxysporumandBotrytis cinereaby 65% to 84% with IC50 values <0.02 mg/mL. Similarly, these six products exhibited a strong antioxidant effect, whereas a low inhibition activity was obtained with both AChE and BChE. Furthermore, they displayed a very weak inhibitory activity against tyrosinase except for the compound4l.These findings suggest a possible use of these compounds as synthetic pesticides with less hazardous effects with antioxidant, and anti-tyrosinase properties.


Assuntos
Antifúngicos/farmacologia , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antifúngicos/síntese química , Antifúngicos/química , Antioxidantes/síntese química , Antioxidantes/química , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Botrytis/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Fusarium/efeitos dos fármacos , Cavalos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidores
7.
Bioorg Chem ; 111: 104893, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33882364

RESUMO

To date, Alzheimer's disease is the most alarming neurodegenerative disorder worldwide. This illness is multifactorial in nature and cholinesterase inhibitors have been the ones used in clinical treatments. In this context, many of these drugs selectively inhibit the acetylcholinesterase enzyme interacting in both the active site and the peripheric anionic site. Besides, some agents have exhibited extensive benefits being able to co-inhibit butyrylcholinesterase. In this contribution, a strategy previously explored by numerous authors is reported; the synthesis of hybrid cholinesterase inhibitors. This strategy uses a molecule of recognized high inhibitory activity (tacrine) together with a steroidal alkaloid of natural origin using different connectors. The biological assays demonstrated the improvement in the inhibitory activity compared to the alkaloidal precursor, together with the reinforcement of the interactions in multiple sites of the enzymatic cavity. This strategy should be explored and exploited in this area. Docking and molecular dynamic studies were performed to explain enzyme-ligand interactions, assisting a structure-activity relationship analysis.


Assuntos
Alcaloides/farmacologia , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Esteroides/farmacologia , Acetilcolinesterase/metabolismo , Alcaloides/síntese química , Alcaloides/química , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Estrutura Molecular , Esteroides/síntese química , Esteroides/química , Relação Estrutura-Atividade
8.
Bioorg Chem ; 111: 104895, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33887586

RESUMO

A series of 4-aminoalkyl-1(2H)-phthalazinone derivatives was designed and synthesized as potential multifunctional agents for Alzheimer's disease (AD) treatment. In vitro biological assay results demonstrated that most synthesized compounds exhibited significant AChE inhibition, moderate to high MAOs inhibitory potencies and good anti-platelet aggregation abilities. Among them, compound 15b exhibited the highest inhibitory potencies towards MAO-B and MAO-A (IC50 = 0.7 µM and 6.4 µM respectively), moderate inhibition towards AChE (IC50 = 8.2 µM), and good activities against self- and Cu2+-induced Aß1-42 aggregation and platelet aggregation. Moreover, 15b also displayed antioxidant capacity, neuroprotective potency, anti-neuroinflammation and BBB permeability. These excellent results indicated that compound 15b could be worthy of further studies to be considered as a promising multifunctional candidate for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Ftalazinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Ftalazinas/síntese química , Ftalazinas/química , Agregação Plaquetária/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
9.
Chem Biodivers ; 18(6): e2000924, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33861892

RESUMO

A novel series of tacrine based cyclopentapyranopyridine- and tetrahydropyranoquinoline-kojic acid derivatives were designed, synthesized, and evaluated as anti-cholinesterase agents. The chemical structures of all target compounds were characterized by 1 H-NMR, 13 C-NMR, and elemental analyses. The synthesized compounds mostly inhibited acetylcholinesterase enzyme (AChE) with IC50 values of 4.18-48.71 µM rather than butyrylcholinesterase enzyme (BChE) with IC50 values of >100 µM. Among them, cyclopentapyranopyridine-kojic acid derivatives showed slightly better AChE inhibitory activity compared to tetrahydropyranoquinoline-kojic acid. The compound 10-amino-2-(hydroxymethyl)-11-(4-isopropylphenyl)-7,8,9,11-tetrahydro-4H-cyclopenta[b]pyrano[2',3' : 5,6]pyrano[3,2-e]pyridin-4-one (6f) bearing 4-isopropylphenyl moiety and cyclopentane ring exhibited the highest anti-AChE activity with IC50 value of 4.18 µM. The kinetic study indicated that the compound 6f acts as a mixed inhibitor and the molecular docking studies also illustrated that the compound 6f binds to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE. The compound 6f showed moderate neuroprotective properties against H2 O2 -induced cytotoxicity in PC12 cells. The theoretical ADME study also predicted good drug-likeness for the compound 6f. Based on these results, the compound 6f seems to be a very promising AChE inhibitor for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Pironas/síntese química , Pironas/química , Pironas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Ratos , Tacrina/análogos & derivados , Tacrina/química
10.
Sci Rep ; 11(1): 6193, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737620

RESUMO

The electric eel is a unique species that has evolved three electric organs. Since the 1950s, electric eels have generally been assumed to use these three organs to generate two forms of electric organ discharge (EOD): high-voltage EOD for predation and defense and low-voltage EOD for electrolocation and communication. However, why electric eels evolved three electric organs to generate two forms of EOD and how these three organs work together to generate these two forms of EOD have not been clear until now. Here, we present the third form of independent EOD of electric eels: middle-voltage EOD. We suggest that every form of EOD is generated by one electric organ independently and reveal the typical discharge order of the three electric organs. We also discuss hybrid EODs, which are combinations of these three independent EODs. This new finding indicates that the electric eel discharge behavior and physiology and the evolutionary purpose of the three electric organs are more complex than previously assumed. The purpose of the middle-voltage EOD still requires clarification.


Assuntos
Comunicação Animal , Evolução Biológica , Órgão Elétrico/fisiologia , Electrophorus/fisiologia , Animais , Órgão Elétrico/anatomia & histologia , Eletricidade , Eletrodos , Electrophorus/classificação , Filogenia
11.
Org Biomol Chem ; 19(10): 2322-2337, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33645607

RESUMO

We have used the Cu(i)-catalyzed azide-alkyne Huisgen cycloaddition reaction to obtain two families of bivalent heterodimers where tacrine is connected to an azasugar or iminosugar, respectively, via linkers of variable length. The heterodimers were investigated as cholinesterase inhibitors and it was found that their activity increased with the length of the linker. Two of the heterodimers were significantly stronger acetylcholinesterase inhibitors than the monomeric tacrine. Molecular modelling indicated that the longer heterodimers fitted better into the active gorge of acetylcholinesterase than the shorter counterparts and the former provided more efficient simultaneous interaction with the tryptophan residues in the catalytic anionic binding site (CAS) and the peripheral anionic binding site (PAS).


Assuntos
Inibidores da Colinesterase/química , Imino Açúcares/química , Tacrina/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Electrophorus , Ensaios Enzimáticos , Cavalos , Imino Açúcares/síntese química , Imino Açúcares/metabolismo , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Tacrina/síntese química , Tacrina/metabolismo , Termodinâmica
12.
Bioorg Med Chem ; 35: 116074, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33640707

RESUMO

To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC50 = 9.18 × 10-5 and 6.16 × 10-4 µM, respectively), good MAO-B inhibitory activity (IC50 = 5.88 µM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu2+-induced Aß1-42 aggregation inhibitory potency, disaggregation ability on Aß1-42 fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/farmacologia , Compostos de Benzilideno/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes , Benzofuranos/síntese química , Benzofuranos/química , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cobre/farmacologia , Relação Dose-Resposta a Droga , Electrophorus , Feminino , Humanos , Masculino , Bases de Mannich/síntese química , Bases de Mannich/química , Bases de Mannich/farmacologia , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
13.
Chem Biodivers ; 18(3): e2000834, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33594810

RESUMO

The Libellus de Medicinalibus Indorum Herbis (Booklet of Indian Medicinal Plants) is the first book of medicinal plants written in the American continent. It was first published in 1939 as 'An Aztec Herbal'. One of the depicted plants is Huetzcanixochitl (laughing flower) interpreted as Zephyranthes fosteri (Amaryllidaceae). No chemical or pharmacological studies are reported for this species; so, we decide to investigate it. The GC/MS of the bulbs and aerial parts extracts indicated that they contain Amaryllidaceae alkaloids, among them: lycorine, 3-O-acetylpowelline, and norlycoramine. An unknown major alkaloid was isolated and identified by 1 H, 13 C-NMR and MS, as 3'-demethoxy-6-epimesembranol (1). The methanolic extract, the alkaloid fraction, and compound 1 inhibited acetylcholinesterase in vitro. Mesembrine alkaloids are found in Sceletium species (Aizoaceae). Several are known as serotonin recapture inhibitors and have been proposed as potential antidepressant drugs. The presence of 1 suggests that Z. fosteri was probably used in pre-Columbian times in Mexico as a 'stimulant and euphoriant', alike Sceletium tortuosum by several ethnic groups in South Africa.


Assuntos
Alcaloides/farmacologia , Amaryllidaceae/química , Inibidores da Colinesterase/farmacologia , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Acetilcolinesterase/metabolismo , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Relação Dose-Resposta a Droga , Electrophorus , México , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Estereoisomerismo , Relação Estrutura-Atividade
14.
J Enzyme Inhib Med Chem ; 36(1): 618-626, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33557639

RESUMO

Feijoa sellowiana leaves and fruits have been investigated as a source of diverse bioactive metabolites. Extract and eight metabolites isolated from F. sellowiana leaves were evaluated for their enzymatic inhibitory activity against α-glucosidase, amylase, tyrosinase, acetylcholinestrerase and butyrylcholinesterase both in vitro and in silico. Feijoa leaves' extract showed strong antioxidant activity and variable levels of inhibitions against target enzymes with a strong anti-tyrosinase activity (115.85 mg Kojic acid equivalent/g). Additionally, α-tocopherol emerged as a potent inhibitor of AChE and BChE (5.40 & 10.38 mmol galantamine equivalent/g, respectively). Which was further investigated through molecular docking and found to develop key enzymatic interactions in AChE and BChE active sites. Also, primetin showed good anti BChE (11.70 mmol galantamine equivalent/g) and anti-tyrosinase inhibition (90.06 mmol Kojic acid equivalent/g) which was also investigated by molecular docking studies. Highlights Isolation of eight bioactive constituents from Feijoa sellowiana leaves. In vitro assays using different enzymatic drug targets were investigated. In silico study was performed to define compound interactions with target proteins. Feijoa leaf is an excellent source of anti-AChE and antityrosinase bioactives.


Assuntos
Antioxidantes/farmacologia , Inibidores Enzimáticos/farmacologia , Feijoa/química , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Extratos Vegetais/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Butirilcolinesterase/metabolismo , Relação Dose-Resposta a Droga , Electrophorus , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Cavalos , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Picratos/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidores , Suínos , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
15.
J Enzyme Inhib Med Chem ; 36(1): 627-639, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33557647

RESUMO

A new series of 3-O-substituted xanthone derivatives were synthesised and evaluated for their anti-cholinergic activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results indicated that the xanthone derivatives possessed good AChE inhibitory activity with eleven of them (5, 8, 11, 17, 19, 21-23, 26-28) exhibited significant effects with the IC50 values ranged 0.88 to 1.28 µM. The AChE enzyme kinetic study of 3-(4-phenylbutoxy)-9H-xanthen-9-one (23) and ethyl 2-((9-oxo-9H-xanthen-3-yl)oxy)acetate (28) showed a mixed inhibition mechanism. Molecular docking study showed that 23 binds to the active site of AChE and interacts via extensive π-π stacking with the indole and phenol side chains of Trp86 and Tyr337, besides the hydrogen bonding with the hydration site and π-π interaction with the phenol side chain of Y72. This study revealed that 3-O-alkoxyl substituted xanthone derivatives are potential lead structures, especially 23 and 28 which can be further developed into potent AChE inhibitors.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Xantonas/farmacologia , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Xantonas/síntese química , Xantonas/química
16.
Bioorg Med Chem ; 32: 115991, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33440318

RESUMO

A novel series of arylcarbamate-N-acylhydrazones derivatives have been designed and synthesized as potential anti-cholinesterase agents. In vitro studies revealed that these compounds demonstrated selective for butyrylcholinesterase (BuChE) with potent inhibitory activity. The compounds 10a-d, 12b and 12d were the most potent BuChE inhibitors with IC50 values of 0.07-2.07 µM, highlighting the compound 10c (IC50 = 0.07 µM) which showed inhibitory activity 50 times greater than the reference drug donepezil (IC50 = 3.54 µM). The activity data indicates that the position of the carbamate group in the aromatic ring has a greater influence on the inhibitory activity of the derivatives. The enzyme kinetics studies indicate that the compound 10c has a non-competitive inhibition against BuChE with Ki value of 0.097 mM. Molecular modeling studies corroborated the in vitro inhibitory mode of interaction and show that compound 10c is stabilized into hBuChE by strong hydrogen bond interaction with Tyr128, π-π stacking interaction with Trp82 and CH⋯O interactions with His438, Gly121 and Glu197. Based on these data, compound10cwas identified as low-cost promising candidate for a drug prototype for AD treatment.


Assuntos
Carbamatos/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Hidrazonas/farmacologia , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Carbamatos/síntese química , Carbamatos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Hidrazonas/síntese química , Hidrazonas/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
17.
Bioorg Chem ; 108: 104643, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33486370

RESUMO

Acetylcholinesterase (AChE) inhibitor and telomerase reverse transcriptase (TERT) potentiator phytochemicals are highly targeted as anti-Alzheimerꞌs disease and as an anti-ageing process. A phytochemical study of Thunbergia erecta aerial parts resulted in the isolation of ten compounds (1-10). Their structures were identified based on spectral data and comparison with literature values. The activity of our pure isolates on AChE and TERT enzymes by documented in vitro assay methods were evaluated. The results indicated that apigenin (2), vanillic acid (4), and acacetin-7-O-ß-D-glucoside (7) exhibited potent inhibition of AChE (IC50 37.33, 30.80 and 49.57 ng/mL, respectively), compared to the standard drug donepezil (IC50 31.25 ng/mL). In the TERT enzyme assay, compound 7 triggered a 1.66­fold increase in telomerase activity at the concentration of 2.85 ng/ml. This is the first study that demonstrates that compound 7 isolated from T. erecta can lead to such telomerase activity relative to control cells. Virtual screening studies including docking, rapid overlay chemical structure (ROCS), and calculated structure-property relationships (SPR) were implemented in this work. Molecular docking studies supported the binding of compounds 2, 4, and 7 through hydrogen bonds (HBs) formation to essential amino acid residues namely ARG:24 A, SER:347 A, LYS:51 A, PHE:346 A, and GLY:345 A of acetylcholinesterase. ROCS and SPR analyses realized compound 2 as a possible treatment of Alzheimer's disease and as a lead compound for drug development process through applying semisynthetic modifications.


Assuntos
Acanthaceae/química , Acetilcolinesterase/metabolismo , Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Linhagem Celular , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
18.
Bioorg Chem ; 108: 104649, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33517001

RESUMO

Five new examples of 9,10-chloro(bromo)-7-amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes] - in which cycloalkanes = cyclopentane, cyclohexane, and cycloheptane - were synthesized at yields of 42-56%, using a sequential one-pot two-step cyclocondensation reaction of three different scaffolds of 2-aminobenzonitriles and the respective spiro[chroman-2,1'-cycloalkan]-4-ones, and using AlCl3 as the catalyst in a solvent-free method. Subsequently, the five new spirochromeno-quinolines and nine quinolines previously published by us (14 modified tacrine scaffolds) were subjected to AChE and BChE inhibitory activity evaluation. The molecule containing a spirocyclopentane derivative had the highest AChE and BChE inhibitory activity (IC50 = 3.60 and 4.40 µM, respectively), and in general, the non-halogenated compounds were better inhibitors of AChE and BChE than the halogenated molecules. However, the inhibitory potency of compounds 3a-n was weaker than that of tacrine. By molecular docking simulations, it was found that the size of the spirocarbocyclic moieties is inversely proportional to the inhibitory activity of the cholinesterases, probably because an increase in the size of the spirocyclic component sterically hindered the interaction of tacrine derivatives with the active site of tested cholinesterases. The findings obtained here may help in the design and development of new anticholinesterase drugs.


Assuntos
Inibidores da Colinesterase/farmacologia , Colinesterases/metabolismo , Cicloparafinas/farmacologia , Quinolinas/farmacologia , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cicloparafinas/síntese química , Cicloparafinas/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
19.
Toxins (Basel) ; 13(1)2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435184

RESUMO

In this paper, I draw an analogy between the use of electricity by electric eels (Electrophorus electricus) to paralyze prey muscles and the use of venoms that paralyze prey by disrupting the neuromuscular junction. The eel's strategy depends on the recently discovered ability of eels to activate prey motor neuron efferents with high-voltage pulses. Usually, eels use high voltage to cause brief, whole-body tetanus, thus preventing escape while swallowing prey whole. However, when eels struggle with large prey, or with prey held precariously, they often curl to bring their tail to the opposite side. This more than doubles the strength of the electric field within shocked prey, ensuring maximal stimulation of motor neuron efferents. Eels then deliver repeated volleys of high-voltage pulses at a rate of approximately 100 Hz. This causes muscle fatigue that attenuates prey movement, thus preventing both escape and defense while the eel manipulates and swallows the helpless animal. Presumably, the evolution of enough electrical power to remotely activate ion channels in prey efferents sets the stage for the selection of eel behaviors that functionally "poison" prey muscles.


Assuntos
Electrophorus/fisiologia , Fenômenos Eletrofisiológicos , Comportamento Predatório , Peçonhas/toxicidade , Animais
20.
Chem Biodivers ; 18(3): e2000935, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33502110

RESUMO

Perennial plant Mentha pulegium L. (pennyroyal, Lamiaceae) can be found in Europe and Mediterranean. In areas where it thrives, M. pulegium is used in nutrition and as medicinal plant. Essential oil of M. pulegium is also a frequent constituent of foods and fragrances, because of mint-like odor. Regarding the use of M. pulegium in traditional medicine and nutrition, as well as fact that essential oils are potential sources of bioactive components, this study was conducted to examine the chemical composition of essential oil of M. pulegium wild growing in Bosnia and Herzegovina and its biological activity. The chemical profile testing was made using GC/MS and GC/FID technique. Potential of cholinesterase inhibition was tested by Ellman's assay. The antioxidant activity was tested by DPPH and FRAP assay. The dominant components in analyzed oil were pulegone 54.4 %, p-menthone 14.0 % and piperitenone 12.8 %. Good antioxidant activity and moderate cholinesterase inhibition potential of tested essential oil indicates to possibility of its use in treatment of diseases related to free radicals, Alzheimer disease and as lipid protecting antioxidant.


Assuntos
Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Mentha pulegium/química , Óleos Voláteis/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Estrutura Molecular , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Picratos/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade
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