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1.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204857

RESUMO

Phytochemicals belonging to the group of alkaloids are signature specialized metabolites endowed with countless biological activities. Plants are armored with these naturally produced nitrogenous compounds to combat numerous challenging environmental stress conditions. Traditional and modern healthcare systems have harnessed the potential of these organic compounds for the treatment of many ailments. Various chemical entities (functional groups) attached to the central moiety are responsible for their diverse range of biological properties. The development of the characterization of these plant metabolites and the enzymes involved in their biosynthesis is of an utmost priority to deliver enhanced advantages in terms of biological properties and productivity. Further, the incorporation of whole/partial metabolic pathways in the heterologous system and/or the overexpression of biosynthetic steps in homologous systems have both become alternative and lucrative methods over chemical synthesis in recent times. Moreover, in-depth research on alkaloid biosynthetic pathways has revealed numerous chemical modifications that occur during alkaloidal conversions. These chemical reactions involve glycosylation, acylation, reduction, oxidation, and methylation steps, and they are usually responsible for conferring the biological activities possessed by alkaloids. In this review, we aim to discuss the alkaloidal group of plant specialized metabolites and their brief classification covering major categories. We also emphasize the diversity in the basic structures of plant alkaloids arising through enzymatically catalyzed structural modifications in certain plant species, as well as their emerging diverse biological activities. The role of alkaloids in plant defense and their mechanisms of action are also briefly discussed. Moreover, the commercial utilization of plant alkaloids in the marketplace displaying various applications has been enumerated.


Assuntos
Alcaloides/química , Alcaloides/metabolismo , Fenômenos Fisiológicos Vegetais , Plantas/química , Acilação , Alcaloides/farmacologia , Vias Biossintéticas , Glicosilação , Metilação , Estrutura Molecular , Oxirredução , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacologia
2.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204905

RESUMO

Cyclodipeptides (CDPs) or 2,5-diketopiperazines (DKPs) can exert a variety of biological activities and display pronounced resistance against enzymatic hydrolysis as well as a propensity towards self-assembly into gels, relative to the linear-dipeptide counterparts. They have attracted great interest in a variety of fields spanning from functional materials to drug discovery. This concise review will analyze the latest advancements in their synthesis, self-assembly into gels, and their more innovative applications.


Assuntos
Dicetopiperazinas/síntese química , Dipeptídeos/química , Peptídeos Cíclicos/síntese química , Dicetopiperazinas/química , Géis/química , Química Verde , Micro-Ondas , Estrutura Molecular , Peptídeos Cíclicos/química
3.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205002

RESUMO

Numerous chemical compounds of high practical importance, such as drugs, fertilizers, and food additives are being commercialized as racemic mixtures, although in most cases only one of the isomers possesses the desirable properties. As our understanding of the biological actions of chiral compounds has improved, the investigation of the pharmacological and toxicological properties has become more and more important. Chirality has become a major issue in the pharmaceutical industry; therefore, there is a continuous demand to extend the available analytical methods for enantiomeric separations and enhance their efficiency. Direct liquid chromatography methods based on the application of chiral stationary phases have become a very sophisticated field of enantiomeric separations by now. Hundreds of chiral stationary phases have been commercialized so far. Among these, macrocyclic glycopeptide-based chiral selectors have proved to be an exceptionally useful class of chiral selectors for the separation of enantiomers of biological and pharmacological importance. This review focuses on direct liquid chromatography-based enantiomer separations, applying macrocyclic glycopeptide-based chiral selectors. Special attention is paid to the characterization of the physico-chemical properties of these macrocyclic glycopeptide antibiotics providing detailed information on their applications published recently.


Assuntos
Antibacterianos/química , Glicopeptídeos/química , Compostos Macrocíclicos/química , Cromatografia Líquida , Estrutura Molecular , Fenômenos Físicos , Estereoisomerismo
4.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205043

RESUMO

Glioblastoma (GBM) is the most common and most deadly primary malignant brain tumor. Current therapies are not effective, the average survival of GBM patients after diagnosis being limited to few months. Therefore, the discovery of new treatments for this highly aggressive brain cancer is urgently needed. Chalcones are synthetic and naturally occurring compounds that have been widely investigated as anticancer agents. In this work, three chalcone derivatives were tested regarding their inhibitory activity and selectivity towards GBM cell lines (human and mouse) and a non-cancerous mouse brain cell line. The chalcone 1 showed the most potent and selective cytotoxic effects in the GBM cell lines, being further investigated regarding its ability to reduce critical hallmark features of GBM and to induce apoptosis and cell cycle arrest. This derivative showed to successfully reduce the invasion and proliferation capacity of tumor cells, both key targets for cancer treatment. Moreover, to overcome potential systemic side effects and its poor water solubility, this compound was encapsulated into liposomes. Therapeutic concentrations were incorporated retaining the potent in vitro growth inhibitory effect of the selected compound. In conclusion, our results demonstrated that this new formulation can be a promising starting point for the discovery of new and more effective drug treatments for GBM.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Ciclo Celular/efeitos dos fármacos , Chalconas/farmacologia , Glioblastoma/metabolismo , Animais , Antineoplásicos/química , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Humanos , Lipossomos , Camundongos , Estrutura Molecular , Invasividade Neoplásica
5.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205046

RESUMO

A small organic molecule P was synthesized and characterized as a fluorometric and colorimetric dual-modal probe for Hg2+. The sensing characteristics of the proposed probe for Hg2+ were studied in detail. A fluorescent enhancing property at 583 nm (>30 fold) accompanied with a visible colorimetric change, from colorless to pink, was observed with the addition of Hg2+ to P in an ethanol-water solution (8:2, v/v, 20 mM HEPES, pH 7.0), which would be helpful to fabricate Hg2+-selective probes with "naked-eye" and fluorescent detection. Meanwhile, cellular experimental results demonstrated its low cytotoxicity and good biocompatibility, and the application of P for imaging of Hg2+ in living cells was satisfactory.


Assuntos
Corantes Fluorescentes/química , Mercúrio/química , Rodaminas/química , Bibliotecas de Moléculas Pequenas/síntese química , Colorimetria , Células HeLa , Humanos , Citometria de Varredura a Laser , Limite de Detecção , Imagem Molecular , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química
6.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205060

RESUMO

The medicinal potential and volatile composition of different parts of three cultivars of grapefruit (Citrus paradisi) were evaluated for their toxicity and anti-inflammatory activities. Fresh leaf and fruit peel were separately isolated by hydrodistillation for 4 h. The essential oils were subjected to GC/GC-MS analysis for chemical profile. Toxicity of the essential oils in mice were evaluated using Lorke's method, while an anti-inflammatory assay was performed in a rat model using egg albumin-induced oedema. The oils obtained were light yellow in colour, and odour varied from strong citrus smell to mild. Percentage yield of fresh peel oil (0.34-0.57%) was greater than the fresh leaf oil yield (0.21-0.34%). D-limonene (86.70-89.90%) was the major compound identified in the leaf oil, while ß-phellandrene (90.00-91.01%) dominated the peel oil. At a dosage level of 5000 mg/kg, none of the oils showed mortality in mice. An anti-inflammatory bioassay revealed that all the oils caused a significant (p < 0.05-0.01) reduction in oedema size when compared to the negative control group throughout the 5 h post induction assessment period. The study reveals that the oils are non-toxic and demonstrate significant anti-inflammatory activity. Our findings suggest that the leaf and peel oils obtained from waste parts of grapefruit plants can be useful as flavouring agents, as well as anti-inflammatory agents.


Assuntos
Anti-Inflamatórios/administração & dosagem , Citrus paradisi/química , Edema/tratamento farmacológico , Óleos Voláteis/administração & dosagem , Ovalbumina/efeitos adversos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Monoterpenos Cicloexânicos/análise , Modelos Animais de Doenças , Edema/induzido quimicamente , Frutas/química , Cromatografia Gasosa-Espectrometria de Massas , Limoneno/análise , Camundongos , Estrutura Molecular , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Folhas de Planta/química , Óleos Vegetais/análise , Óleos Vegetais/química , Ratos , África do Sul
7.
Molecules ; 26(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209381

RESUMO

Hydantoins and their hybrids with other molecules represent a very important group of heterocycles because they exhibit diverse biological and pharmacological activities in medicinal and agrochemical applications. They also serve as key precursors in the chemical or enzymatic synthesis of significant nonnatural α-amino acids and their conjugates with medical potential. This review provides a comprehensive treatment of the synthesis of hydantoins via the Bucherer-Bergs reaction including the Hoyer modification but limited to free carbonyl compounds or carbonyl compounds protected as acetals (ketals) and cyanohydrins used as starting reaction components. In this respect, the Bucherer-Bergs reaction provides an efficient and simple method in the synthesis of important natural products as well as for the preparation of new organic compounds applicable as potential therapeutics. The scope and limitations, as well as a comparison with some other methods for preparing hydantoins, are also discussed.


Assuntos
Agroquímicos/química , Agroquímicos/síntese química , Técnicas de Química Sintética , Hidantoínas/química , Hidantoínas/síntese química , Estrutura Molecular
8.
J Asian Nat Prod Res ; 23(8): 724-730, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34253100

RESUMO

Three new flavonoid glycosides, embeliaflavosides A-C (1-3), together with eight known flavonoid glycosides (4-11), were isolated from the fruits of Embelia ribes. Their structures were established based on the analyses of spectroscopic data. Compounds 1-11 were evaluated for antioxidant and α-glucosidase inhibitory activities. The results revealed that compounds 1-11 owned significant ABTS radical scavenging activity with IC50 values of 2.52-9.78 µM, and DPPH scavenging activity with IC50 values of 7.56-26.47 µM, respectively. However, α-glucosidase inhibition assay indicated that all the isolates were inactive.[Formula: see text].


Assuntos
Embelia , Ribes , Antioxidantes/farmacologia , Embelia/metabolismo , Flavonoides/farmacologia , Frutas , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeos/farmacologia , Estrutura Molecular , Extratos Vegetais , Ribes/metabolismo , alfa-Glucosidases/metabolismo
9.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203564

RESUMO

The work is devoted to the study of the complementarity of the electronic structures of the ligands and SARS-CoV-2 RNA-dependent RNA polymerase. The research methodology was based on determining of 3D maps of electron densities of complexes using an original quantum free-orbital AlteQ approach. We observed a positive relationship between the parameters of the electronic structure of the enzyme and ligands. A complementarity factor of the enzyme-ligand complexes has been proposed. The console applications of the AlteQ complementarity assessment for Windows and Linux (alteq_map_enzyme_ligand_4_win.exe and alteq_map_enzyme_ligand_4_linux) are available for free at the ChemoSophia webpage.


Assuntos
RNA-Polimerase RNA-Dependente de Coronavírus/química , Elétrons , SARS-CoV-2/enzimologia , Algoritmos , Amidas/química , Antivirais/química , Ligantes , Estrutura Molecular , Ligação Proteica , Pirazinas/química , Ribonucleosídeos/química
10.
Int J Mol Sci ; 22(12)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34203049

RESUMO

The present study aims to determine the neuroprotective effect of Bergenin against spatial memory deficit associated with neurodegeneration. Preliminarily, the protective effect of Bergenin was observed against H2O2-induced oxidative stress in HT-22 and PC-12 cells. Further studies were performed in 5xFAD Tg mouse model by administering Bergenin (1, 30 and 60 mg/kg; orally), whereas Bergenin (60 mg/kg) significantly attenuated the memory deficit observed in the Y-maze and Morris water maze (MWM) test. Fourier transform-infrared (FT-IR) spectroscopy displayed restoration of lipids, proteins and their derivatives compared to the 5xFAD Tg mice group. The differential scanning calorimeter (DSC) suggested an absence of amyloid beta (Aß) aggregation in Bergenin-treated mice. The immunohistochemistry (IHC) analysis suggested the neuroprotective effect of Bergenin by increasing Reelin signaling (Reelin/Dab-1) and attenuated Aß (1-42) aggregation in hippocampal regions of mouse brains. Furthermore, IHC and western blot results suggested antioxidant (Keap-1/Nrf-2/HO-1), anti-inflammatory (TLR-4/NF-kB) and anti-apoptotic (Bcl-2/Bax/Caspase-3) effect of Bergenin. Moreover, a decrease in Annexin V/PI-stained hippocampal cells suggested its effect against neurodegeneration. The histopathological changes were reversed significantly by Bergenin. In addition, a remarkable increase in antioxidant level with suppression of pro-inflammatory cytokines, oxidative stress and nitric oxide production were observed in specific regions of the mouse brains.


Assuntos
Benzopiranos/farmacologia , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Benzopiranos/química , Biomarcadores , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Ligação de Hidrogênio , Mediadores da Inflamação/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/diagnóstico , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade , Resultado do Tratamento
11.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205930

RESUMO

BACKGROUND: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. OBJECTIVE: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. METHODS: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. RESULTS: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of "open field" and "elevated plus maze" (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of "forced swimming" (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABAA receptor with a value of the scoring function that estimates free energy of binding (ΔG) at -7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT1A receptor. CONCLUSIONS: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.


Assuntos
Azepinas/administração & dosagem , Azepinas/síntese química , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Convulsões/tratamento farmacológico , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/farmacologia , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Azepinas/química , Azepinas/farmacologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Pentilenotetrazol/efeitos adversos , Pirimidinas/química , Pirimidinas/farmacologia , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Ratos , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
12.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206005

RESUMO

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood-brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.


Assuntos
Alcaloides/química , Antineoplásicos/síntese química , Indóis/química , Indolizinas/química , Fenantrenos/química , Fenantrolinas/química , Pró-Fármacos/síntese química , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células CHO , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Células MCF-7 , Estrutura Molecular , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Compostos de Amônio Quaternário/química , Relação Estrutura-Atividade
13.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198817

RESUMO

Despite the serious public health problem represented by the diseases caused by dengue (DENV), Zika (ZIKV) and chikungunya (CHIKV) viruses, there are still no specific licensed antivirals available for their treatment. Here, we examined the potential anti-arbovirus activity of ten di-halogenated compounds derived from L-tyrosine with modifications in amine and carboxyl groups. The activity of compounds on VERO cell line infection and the possible mechanism of action of the most promising compounds were evaluated. Finally, molecular docking between the compounds and viral and cellular proteins was evaluated in silico with Autodock Vina®, and the molecular dynamic with Gromacs®. Only two compounds (TDC-2M-ME and TDB-2M-ME) inhibited both ZIKV and CHIKV. Within the possible mechanism, in CHIKV, the two compounds decreased the number of genome copies and in the pre-treatment strategy the infectious viral particles. In the ZIKV model, only TDB-2M-ME inhibited the viral protein and demonstrate a virucidal effect. Moreover, in the U937 cell line infected with CHIKV, both compounds inhibited the viral protein and TDB-2M-ME inhibited the viral genome too. Finally, the in silico results showed a favorable binding energy between the compounds and the helicases of both viral models, the NSP3 of CHIKV and cellular proteins DDC and ß2 adrenoreceptor.


Assuntos
Antivirais/síntese química , Vírus Chikungunya/efeitos dos fármacos , Vírus da Dengue/efeitos dos fármacos , Fenóis/síntese química , Tirosina/análogos & derivados , Zika virus/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Vírus Chikungunya/genética , Vírus Chikungunya/metabolismo , Chlorocebus aethiops , Vírus da Dengue/genética , Genoma Viral/efeitos dos fármacos , Halogenação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Fenóis/química , Fenóis/farmacologia , Células Vero , Zika virus/genética , Zika virus/metabolismo
14.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198892

RESUMO

This study investigated the antioxidant activity DPPH, ABTS, and Folin-Ciocalteu methods of betulin (compound 1) and its derivatives (compounds 2-11). Skin permeability and accumulation associated with compounds 1 and 8 were also examined. Identification of the obtained products (compound 2-11) and betulin isolated from plant material was based on the analysis of 1H- NMR and 13C-NMR spectra. The partition coefficient was calculated to determine the lipophilicity of all compounds. In the next stage, the penetration through pig skin and its accumulation in the skin were evaluated of ethanol vehicles containing compound 8 (at a concentration of 0.226 mmol/dm3), which was characterized by the highest antioxidant activity. For comparison, penetration studies of betulin itself were also carried out. Poor solubility and the bioavailability of pure compounds are major constraints in combination therapy. However, we observed that the ethanol vehicle was an enhancer of skin permeation for both the initial betulin and compound 8. The betulin 8 derivative showed increased permeability through biological membranes compared to the parent betulin. The paper presents the transformation of polycyclic compounds to produce novel derivatives with marked antioxidant activities and as valuable intermediates for the pharmaceutical industry. Moreover, the compounds contained in the vehicles, due to their mechanism of action, can have a beneficial effect on the balance between oxidants and antioxidants in the body, minimizing the effects of oxidative stress. The results of this work may contribute to knowledge regarding vehicles with antioxidant potential. The use of vehicles for this type of research is therefore justified.


Assuntos
Antioxidantes/farmacologia , Pele/química , Triterpenos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacocinética , Disponibilidade Biológica , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Absorção Cutânea , Solubilidade , Suínos , Triterpenos/química , Triterpenos/farmacocinética
15.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198914

RESUMO

The five-membered heterocyclic group of pyrazoles/pyrazolines plays important role in drug discovery. Pyrazoles and pyrazolines present a wide range of biological activities. The synthesis of the pyrazolines and pyrazole derivatives was accomplished via the condensation of the appropriate substituted aldehydes and acetophenones, suitable chalcones and hydrazine hydrate in absolute ethanol in the presence of drops of glacial acetic acid. The compounds are obtained in good yields 68-99% and their structure was confirmed using IR, 1H-NMR, 13C-NMR and elemental analysis. The novel derivatives were studied in vitro for their antioxidant, anti-lipid peroxidation (AAPH) activities and inhibitory activity of lipoxygenase. Both classes strongly inhibit lipid peroxidation. Compound 2g was the most potent lipoxygenase inhibitor (IC50 = 80 µM). The inhibition of the carrageenin-induced paw edema (CPE) and nociception was also determined, with compounds 2d and 2e being the most potent. Compound 2e inhibited nociception higher than 2d. Pyrazoline 2d was found to be active in a preliminary test, for the investigation of anti-adjuvant-induced disease (AID) activity. Pyrazoline derivatives were found to be more potent than pyrazoles. Docking studies of the most potent LOX inhibitor 2g highlight hydrophobic interactions with VAL126, PHE143, VAL520 and LYS526 and a halogen bond between the chlorine atom and ARG182.


Assuntos
Anti-Inflamatórios/síntese química , Inibidores de Lipoxigenase/síntese química , Lipoxigenase/química , Pirazóis/síntese química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Concentração Inibidora 50 , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Pirazóis/química , Pirazóis/farmacologia , Ratos
16.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198944

RESUMO

Single crystal of furazolidone (FZL) has been successfully obtained, and its crystal structure has been determined. Common and distinctive features of furazolidone and nitrofurantoin (NFT) crystal packing have been discussed. Combined use of QTAIMC and Hirshfeld surface analysis allowed characterizing the non-covalent interactions in both crystals. Thermophysical characteristics and decomposition of NFT and FZL have been studied by differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and mass-spectrometry. The saturated vapor pressures of the compounds have been measured using the transpiration method, and the standard thermodynamic functions of sublimation were calculated. It was revealed that the sublimation enthalpy and Gibbs energy of NFT are both higher than those for FZL, but a gain in the crystal lattice energy of NFT is leveled by an entropy increase. The solubility processes of the studied compounds in buffer solutions with pH 2.0, 7.4 and in 1-octanol was investigated at four temperatures from 298.15 to 313.15 K by the saturation shake-flask method. The thermodynamic functions of the dissolution and solvation processes of the studied compounds have been calculated based on the experimental data. Due to the fact that NFT is unstable in buffer solutions and undergoes a solution-mediated transformation from an anhydrate form to monohydrate in the solid state, the thermophysical characteristics and dissolution thermodynamics of the monohydrate were also investigated. It was demonstrated that a combination of experimental and theoretical methods allows performing an in-depth study of the relationships between the molecular and crystal structure and pharmaceutically relevant properties of nitrofuran antibiotics.


Assuntos
Antibacterianos/química , Furazolidona/química , Nitrofurantoína/química , Antibacterianos/farmacocinética , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Teoria da Densidade Funcional , Furazolidona/farmacocinética , Espectrometria de Massas , Estrutura Molecular , Nitrofurantoína/farmacocinética , Solubilidade , Termodinâmica , Termogravimetria
17.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206444

RESUMO

The alarming raise of multi-drug resistance among human microbial pathogens makes the development of novel therapeutics a priority task. In contrast to conventional antibiotics, antimicrobial peptides (AMPs), besides evoking a broad spectrum of activity against microorganisms, could offer additional benefits, such as the ability to neutralize toxins, modulate inflammatory response, eradicate bacterial and fungal biofilms or prevent their development. The latter properties are of special interest, as most antibiotics available on the market have limited ability to diffuse through rigid structures of biofilms. Lipidation of AMPs is considered as an effective approach for enhancement of their antimicrobial potential and in vivo stability; however, it could also have undesired impact on selectivity, solubility or the aggregation state of the modified peptides. In the present work, we describe the results of structural modifications of compounds designed based on cationic antimicrobial peptides DK5 and CAR-PEG-DK5, derivatized at their N-terminal part with fatty acids with different lengths of carbon chain. The proposed modifications substantially improved antimicrobial properties of the final compounds and their effectiveness in inhibition of biofilm development as well as eradication of pre-formed 24 h old biofilms of Candida albicans and Staphylococcus aureus. The most active compounds (C5-DK5, C12-DK5 and C12-CAR-PEG-DK5) were also potent against multi-drug resistant Staphylococcus aureus USA300 strain and clinical isolates of Pseudomonas aeruginosa. Both experimental and in silico methods revealed strong correlation between the length of fatty acid attached to the peptides and their final membranolytic properties, tendency to self-assemble and cytotoxicity.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Estabilidade de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade , Termodinâmica
18.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206572

RESUMO

Lipophilicity of 15 derivatives of sodium cholate, defined by the octan-1-ol/water partition coefficient (log P), has been theoretically determined by the Virtual log P method. These derivatives bear highly hydrophobic or highly hydrophilic substituents at the C3 position of the steroid nucleus, being linked to it through an amide bond. The difference between the maximum value of log P and the minimum one is enlarged to 3.5. The partition coefficient and the critical micelle concentration (cmc) are tightly related by a double-logarithm relationship (VirtuallogP=-(1.00±0.09)log(cmcmM)+(2.79±0.09)), meaning that the Gibbs free energies for the transfer of a bile anion from water to either a micelle or to octan-1-ol differ by a constant. The equation also means that cmc can be used as a measurement of lipophilicity. The demicellization of the aggregates formed by three derivatives of sodium cholate bearing bulky hydrophobic substituents has been studied by surface tension and isothermal titration calorimetry. Aggregation numbers, enthalpies, free energies, entropies, and heat capacities, ΔCP,demic, were obtained. ΔCP,demic, being positive, means that the interior of the aggregates is hydrophobic.


Assuntos
Ácidos e Sais Biliares/química , Interações Hidrofóbicas e Hidrofílicas , Algoritmos , Calorimetria , Fenômenos Químicos , Micelas , Modelos Teóricos , Estrutura Molecular , Termodinâmica
19.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206574

RESUMO

Sorafenib (Sor) is an oral multi-kinase inhibitor, but its water solubility is very low. To improve its solubility, sorafenib hydrochloride hydrate, sorafenib hydrobromide and sorafenib hydrobromide hydrate were prepared in the mixed solvent of the corresponding acid solution, and tetrahydrofuran (THF). The crystal structures of sorafenib hydrochloride trihydrate (Sor·HCl.3H2O), 4-(4-{3-[4-chloro-3-(trifluoro-methyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl) pyridinium hydrochloride trihydrate, C21H17ClF3N4O3+·Cl-.3H2O (I), sorafenib hydrochloride monohydrate (Sor·HCl.H2O), C21H17ClF3N4O3+·Cl-.H2O (II), its solvated form (sorafenib hydrochloride monohydrate monotetrahydrofuran (Sor·HCl.H2O.THF), C21H17ClF3N4O3+·Cl-.H2O.C4H8O (III)), sorafenib hydrobromide (Sor·HBr), 4-(4-{3-[4-chloro-3-(trifluoro-methyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl) pyridinium hydrobromide, C21H17ClF3N4O3+·Br- (IV) and sorafenib hydrobromide monohydrate (Sor·HBr.H2O), C21H17ClF3N4O3+·Br-.H2O (V) were analysed. Their hydrogen bond systems and topologies were investigated. The results showed the distinct roles of water molecules in stabilizing their crystal structures. Moreover, (II) and (V) were isomorphous crystal structures with the same space group P21/n, and similar unit cell dimensions. The predicted morphologies of these forms based on the BFDH model matched well with experimental morphologies. The energy frameworks showed that (I), and (IV) might have better tabletability than (II) and (V). Moreover, the solubility and dissolution rate data exhibited an improvement in the solubility of these salts compared with the free drug.


Assuntos
Antineoplásicos/química , Ligação de Hidrogênio , Inibidores de Proteínas Quinases/química , Sorafenibe/química , Antineoplásicos/farmacologia , Cristalografia por Raios X , Cristais Líquidos/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Solubilidade , Sorafenibe/farmacologia , Análise Espectral
20.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206582

RESUMO

Two new pyrazole derivatives, namely compound 1 and compound 2, have been synthesized, and their biological activity has been evaluated. Monocrystals of the obtained compounds were thoroughly investigated using single-crystal X-ray diffraction analysis, FTIR spectroscopy, and NMR spectroscopy. The results gathered from all three techniques are in good agreement, provide complete information about the structures of 1 and 2, and confirm their high purity. Thermal properties were studied using thermogravimetric analysis; both 1 and 2 are stable at room temperature. In order to better characterize 1 and 2, some physicochemical and biological properties have been evaluated using ADMET analysis. The cytotoxic activity of both compounds was determined using the MTT assay on the A549 cell line in comparison with etoposide. It was determined that compound 2 was effective in the inhibition of human lung adenocarcinoma cell growth and may be a promising compound for the treatment of lung cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Células A549 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Químicos , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade
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