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1.
Bioorg Med Chem Lett ; 74: 128925, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35944852

RESUMO

A series of 1-oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione derivatives containing structural fragments of conjugated dienone have been synthesized previously by our group, however the Michael addition reaction between conjugated dienone and nucleophilic groups in the body may generate harmful and adverse effects. To reduce harmful side effects, the authors started with p-aminophenol to make 1-oxo-4- azaspirodecanedione derivatives, then utilized the Michael addition and cyclopropanation to eliminate α, ß unsaturated olefinic bond and lower the Michael reactivity of the compounds in vivo for optimization. At the same time, heteroatoms are put into the molecules in order to improve the hydrophilicity of the molecules and the binding sites of the molecules and the target molecules, establishing the groundwork for improved antitumor activity. The majority of the compounds had moderate to potent activity against A549 human lung cancer cells, MDA-MB-231 breast cancer cells, and Hela human cervical cancer cells. Among them, the compound 6d showed the strongest effect on A549 cell line with IC50 of 0.26 µM; the compound 8d showed the strongest cytotoxicity on MDA-MB-231 cell line with IC50 of 0.10 µM; and the compound 6b showed the strongest activity on Hela cell line with IC50 of 0.18 µM.


Assuntos
Antineoplásicos , Compostos Aza/farmacologia , Compostos de Espiro/farmacologia , Antineoplásicos/química , Compostos Aza/química , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Compostos de Espiro/síntese química , Relação Estrutura-Atividade
2.
J Agric Food Chem ; 70(35): 10693-10707, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-35998302

RESUMO

Spiro compounds are biologically active organic compounds with unique structures, found in a wide variety of natural products and drugs. They do not readily lead to drug resistance due to their unique mechanisms of action and have, therefore, attracted considerable attention regarding pesticide development. Analyzing structure-activity relationships (SARs) and summarizing the characteristics of spiro compounds with high activity are crucial steps in the design and development of new pesticides. This review mainly summarizes spiro compounds with insecticidal, bactericidal, fungicidal, herbicidal, antiviral, and plant growth regulating functions to provide insight for the creation of new spiro compound pesticides.


Assuntos
Fungicidas Industriais , Inseticidas , Praguicidas , Compostos de Espiro , Desenho de Fármacos , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Praguicidas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
3.
Sci Rep ; 12(1): 13880, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35974029

RESUMO

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.


Assuntos
Antineoplásicos , COVID-19 , Compostos de Espiro , Antineoplásicos/química , COVID-19/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Indóis , Estrutura Molecular , SARS-CoV-2 , Compostos de Espiro/química , Compostos de Espiro/farmacologia
4.
Molecules ; 27(13)2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35807228

RESUMO

Opioids are used to treat pain, but despite their effectiveness, they possess several side effects such as respiratory depression, tolerance and physical dependence. Cebranopadol has been evaluated as a solution to this problem. The compound acts on the mu opioid receptor and the nociceptin/orphanin receptor and these receptors co-activation can reduce opioid side-effects without compromising analgesia. In the present review, we have compiled information on the effects of cebranopadol, its pharmacokinetics, and clinical trials involving cebranopadol, to further explore its promise in pain management.


Assuntos
Compostos de Espiro , Analgésicos Opioides/efeitos adversos , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico
5.
Org Biomol Chem ; 20(29): 5651-5693, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35792116

RESUMO

Spirocyclic frameworks have attracted synthetic practitioners due to their unique three-dimensional assembly, improved metabolic stability, solubility, and increased molecular complexity with regard to planar architectures. A recent surge in the number of spirocyclic oxindoles inhibiting enzymes, moderating unique protein-protein interactions, modulating receptors and transporters is testament to their prevalence. Against this background, the construction of spirocyclic frameworks containing an oxindole moiety as a torsional switch via stereoselective methods is in great demand. Herein we present a summary of the past three years in the progress of metal, organic molecule, nanostructured particle mediated, and even uncatalyzed versions of the highly diastereo- and enantioselective pathways leading to oxindole spirocycles.


Assuntos
Compostos de Espiro , Indóis/farmacologia , Compostos de Espiro/farmacologia , Estereoisomerismo
6.
Bioorg Chem ; 124: 105830, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35500504

RESUMO

In the present study an efficient synthetic pathway has been developed for the library synthesis of diversely functionalized spiro indolinone-dihydroquinazolinones from easily available isatins and 2-aminobenzamides by acid catalyzed condensation at 70 °C in ethanol. The outcome of the ROS scavenging analysis over the synthesized spiro compounds displays significant variation in their respective antioxidant properties with the change of substituent at different positions. Noteworthy, the spiro compounds substituted with phenyl ring at nitrogen atom either in indolinone or dihydroquinazolinone moiety show a promising defensive capability towards OH (≈ 83% at 80 µM against control) and O2- (≈ 78% at 20 µM against epinephrine auto-oxidation). Almost every single spiro compound exhibits substantial reducing power, especially compounds containing dihydroquinazolinone moiety substituted with aromatic ring at amide nitrogen (N-3) exhibit remarkable reducing property. IC50 and TEAC (Trolox Equivalent Antioxidant Capacity) values reveal that the spiro compound substituted with phenyl ring to indolic nitrogen (N-1) possesses significant antioxidant potency (IC50 ≈ 22.67 µM) and substantial OH scavenging ability (TEAC ≈ 0.82) comparable to highly potent antioxidant Trolox.


Assuntos
Antioxidantes , Compostos de Espiro , Antioxidantes/farmacologia , Nitrogênio , Oxindóis , Compostos de Espiro/farmacologia
7.
Int J Mol Sci ; 23(9)2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35563059

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive heme enzyme for its significant function in cancer immunotherapy. Potent IDO1 inhibitors have been discovered for decades, whereas no clinical drugs are used for cancer treatment up to now. With the goal of developing medically valuable IDO inhibitors, we performed a systematic study of SAR405838 analogs with a spiro-oxindole skeleton in this study. Based on the expression and purification of human IDO1, the inhibitory activity of spiro-oxindole skeleton compounds to IDO1 was evaluated by IC50 and Ki values. The results demonstrated that inhibitor 3 exhibited the highest IDO1 inhibitory activity with IC50 at 7.9 µM among all inhibitors, which is ~six-fold of the positive control (4-PI). Moreover, inhibitor 3 was found to have the most effective inhibition of IDO1 in MCF-7 cancer cells without toxic effects. Molecular docking analysis revealed that the hydrophobic interaction stabilized the binding of inhibitor 3 to the IDO1 active site and made an explanation for the uncompetitive mode of inhibitors. Therefore, this study provides valuable insights into the screen of more potent IDO1 inhibitors for cancer immunotherapy.


Assuntos
Inibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenase , Oxindóis , Compostos de Espiro , Inibidores Enzimáticos/química , Humanos , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indóis , Simulação de Acoplamento Molecular , Oxindóis/farmacologia , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
8.
Biochem Biophys Res Commun ; 608: 39-44, 2022 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-35381427

RESUMO

Pre-mRNA splicing is one of the most important mechanisms in gene expression in eukaryotes, and therefore splicing inhibition affects various cellular functions. We previously reported that the potent splicing inhibitor spliceostatin A (SSA) causes cell cycle arrest at G1 and G2/M phases. Upregulation of the p27 cyclin dependent kinase inhibitor, encoded by the CDKN1B gene, is one of the reasons for G1 phase arrest caused by SSA treatment. However, the molecular mechanism of p27 upregulation by SSA remains unknown. In this study, we found that SSA treatment caused stabilization of the p27 protein and increase of CDKN1B mRNA. SSA did not affect transcription of CDKN1B gene, but stabilized CDKN1B mRNA. Finally, we revealed that the 3' untranslated region of CDKN1B mRNA was involved in the stabilization. These results suggest that stabilization of CDKN1B mRNA is one of the reasons of upregulation of the p27 protein by SSA.


Assuntos
Piranos , Compostos de Espiro , Regiões 3' não Traduzidas/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Piranos/farmacologia , RNA Mensageiro/genética , Compostos de Espiro/farmacologia
9.
Expert Opin Drug Discov ; 17(6): 603-618, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35333138

RESUMO

INTRODUCTION: Spirocyclic scaffolds are an exceptional tool in drug design, allowing fine-tuning of a molecule's conformational and physicochemical properties. As it expands and diversifies, so does the number of therapeutics that contain this core. Several spirocyclic drugs are already marketed, and considerably more have shown promising results. AREAS COVERED: This review addresses recent in vivo studies (2017-2021) on applying spirocyclic compounds to treat various diseases, mainly grouped within neurological, infectious, and metabolic diseases and cancer. An emphasis is given on the influence of the spiro-structure on activity and consequent structure-activity study. In vivo results and their significance in the future progression towards clinical trials are also presented. EXPERT OPINION: Spirocyclic compounds present an exciting opportunity as an unexplored chemical space in medicinal chemistry. However, their development is hindered by their complexity and synthesis challenges. Furthermore, a clear preference is still seen for readily available spirocyclic compounds involving amine or amide bonds. Nevertheless, these are temporary as high-throughput synthesis, and computational techniques allow fast optimization studies. In our opinion, the field of spirocyclic chemistry will continue to thrive and contribute to drug development, improving activity and selectivity on emergent ailments, such as cancer, metabolic, infectious, and neurological diseases.


Assuntos
Compostos de Espiro , Química Farmacêutica , Desenho de Fármacos , Descoberta de Drogas/métodos , Humanos , Conformação Molecular , Compostos de Espiro/química , Compostos de Espiro/farmacologia
10.
Cephalalgia ; 42(9): 933-943, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35332801

RESUMO

BACKGROUND: This study investigated the mechanism of action of atogepant, a small-molecule CGRP receptor antagonist recently approved for the preventive treatment of episodic migraine, by assessing its effect on activation of mechanosensitive C- and Aδ-meningeal nociceptors following cortical spreading depression. METHODS: Single-unit recordings of trigeminal ganglion neurons (32 Aδ and 20 C-fibers) innervating the dura was used to document effects of orally administered atogepant (5 mg/kg) or vehicle on cortical spreading depression-induced activation in anesthetized male rats. RESULTS: Bayesian analysis of time effects found that atogepant did not completely prevent the activation of nociceptors at the tested dose, but it significantly reduced response amplitude and probability of response in both the C- and the Aδ-fibers at different time intervals following cortical spreading depression induction. For C-fibers, the reduction in responses was significant in the early phase (first hour), but not delayed phase of activation, whereas in Aδ-fibers, significant reduction in activation was apparent in the delayed phase (second and third hours) but not early phase of activation. CONCLUSIONS: These findings identify differences between the actions of atogepant, a small molecule CGRP antagonist (partially inhibiting both Aδ and C-fibers) and those found previously for fremanezumab, a CGRP-targeted antibody (inhibiting Aδ fibers only) and onabotulinumtoxinA (inhibiting C-fibers only)- suggesting that these agents differ in their mechanisms for the preventive treatment of migraine.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Transtornos de Enxaqueca , Nociceptores , Animais , Teorema de Bayes , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Masculino , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Fibras Nervosas Amielínicas , Piperidinas/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Compostos de Espiro/farmacologia
11.
Bioorg Med Chem Lett ; 63: 128666, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35276360

RESUMO

The development of RAF inhibitors targeting cancers with wild type RAF kinase and/or RAS mutation has been challenging due to the paradoxical activation of the RAS-RAF-MEK-ERK cascade following RAF inhibitor treatment. Herein is the discovery and optimization of a series of RAF inhibitors with a novel spiro structure. The most potent spiro molecule 9 showed excellent in vitro potency against b/c RAF enzymes and RAS mutant H358 cancer cells with minimal paradoxical RAF signaling activation. Compound 9 also exhibited good drug-like properties as demonstrated by in vitro cytochrome P450 (CYP), liver microsome stability (LMS) data and moderate oral pharmacokinetics (PK) profiles in rat and mouse.


Assuntos
Neoplasias , Compostos de Espiro , Animais , Linhagem Celular Tumoral , Sistema de Sinalização das MAP Quinases , Camundongos , Mutação , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas p21(ras)/genética , Ratos , Compostos de Espiro/farmacologia
12.
Org Biomol Chem ; 20(15): 3183-3200, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35348173

RESUMO

A practical divergent synthetic approach is reported for the library of regio- and stereoisomers of glutamic acid analogs built on the spiro[3.3]heptane scaffold. Formation of the spirocyclic scaffold was achieved starting from a common precursor - an O-silylated 2-(hydroxymethyl)cyclobutanone derivative. Its olefination required using the titanium-based Tebbe protocol since the standard Wittig reaction did not work with this particular substrate. The construction of the second cyclobutane ring of the spirocyclic system was achieved through either subsequent dichloroketene addition or Meinwald oxirane rearrangement as the key synthetic steps, depending on the substitution patterns in the target compounds (1,6- or 1,5-, respectively). Further modified Strecker reaction of the resulting racemic spirocyclic ketones with the Ellman's sulfinamide as a chiral auxiliary had low to moderate diastereoselectivity; nevertheless, all stereoisomers were isolated in pure form via chromatographic separation, and their absolute configuration was confirmed by X-ray crystallography. Members of the library were tested for the inhibitory activity against H. pylori glutamate racemase.


Assuntos
Ácido Glutâmico , Compostos de Espiro , Cristalografia por Raios X , Cetonas/química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo
13.
Pharmacol Rep ; 74(3): 545-554, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35297003

RESUMO

BACKGROUND: Acridine compounds have been described as promising anticancer agents. Previous studies showed that (E)-1'-((4-chlorobenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-06), a spiro-acridine compound, has antitumor activity on Ehrlich tumor and low toxicity. Herein, we investigated its antitumor effect against human cells in vitro. METHODS: MTT assay was used to assess cytotoxicity of AMTAC-06 (3.125-200 µM) against tumor and non-tumor cells, and the half-maximal inhibitory concentration (IC50) and the selectivity index (SI) were calculated. The effects on the cell cycle (propidium iodide-PI-staining), apoptosis (Annexin V-FITC/PI double staining by flow cytometry), and production of reactive oxygen species, ROS (DCFH assay) were also evaluated. Statistical analysis was achieved using ANOVA followed by Tukey's post-test. RESULTS: AMTAC-06 showed higher cytotoxicity against colorectal carcinoma HCT-116 cells (IC50: 12.62 µM). The SI showed that AMTAC-06 was more selective for HCT-116 cells (HaCaT SI: 1.41; PBMC SI: 0.62) than doxorubicin (HaCaT SI: 0.10; PBMC SI: 0.01). AMTAC-06 (15 and 30 µM) induced an increase in the sub-G1 peak (p < 0.000001) and cell cycle arrest in S phase (p = 0.003547). Moreover, treatment with this compound (15 and 30 µM) resulted in increased early (p < 0.000001) and late apoptotic cells (p < 0.000001). In addition, there was a reduction on ROS production (p < 0.000001). CONCLUSIONS: AMTAC-06 presents anticancer activity against HCT-116 cells by regulating the cell cycle, inducing apoptosis and an antioxidant action.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Compostos de Espiro , Acridinas/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Células HCT116 , Humanos , Leucócitos Mononucleares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Compostos de Espiro/farmacologia
14.
Bioorg Med Chem ; 59: 116686, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35228069

RESUMO

Necroptosis, a key form of programmed lytic cell death, has gained recognition as an important driver in various inflammatory diseases. Inhibition of kinase activity of receptor interaction protein kinase 1 (RIPK1), which block the activation of the necroptosis pathway has shown therapeutic potential in many human diseases. In order to find new chemotypes of RIPK1 inhibitors, a virtual screening workflow was performed and led to the discovery of 8-benzoyl-3-benzyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (compound 8) as a hit compound. Further structural optimization identified a series of 2,8-diazaspiro[4.5]decan-1-one derivatives as potent RIPK1 inhibitors. Among them, compound 41 exhibited prominent inhibitory activity against RIPK1 with an IC50 value of 92 nM. Meanwhile, compound 41 showed a significant anti-necroptotic effect in a necroptosis model in U937 cells. Therefore, compound 41 could be employed as a lead compound of RIPK1 inhibitors for further structural optimization.


Assuntos
Compostos Aza/farmacologia , Inibidores de Proteínas Quinases , Proteína Serina-Treonina Quinases de Interação com Receptores , Compostos de Espiro/farmacologia , Apoptose , Compostos Aza/química , Humanos , Necroptose , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/farmacologia , Compostos de Espiro/química
15.
Molecules ; 27(3)2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-35164343

RESUMO

Since the efficiency in the transcription of the HIV genome contributes to the success of viral replication and infectivity, we investigated the downregulating effects of the spirobisindole alkaloids globospiramine (1), deoxyvobtusine (2), and vobtusine lactone (3) from the endemic Philippine medicinal plant, Voacanga globosa, during HIV gene transcription. Alkaloids 1-3 were explored for their inhibitory activity on TNF-α-induced viral replication in two latently HIV-infected cell lines, OM10.1 and J-Lat. The induction of HIV replication from OM10.1 and J-Lat cells elicited by TNF-α was blocked by globospiramine (1) within noncytotoxic concentrations. Furthermore, globospiramine (1) was found to target the NF-ĸB activation cascade in a dose-dependent manner when the transcriptional step at which inhibitory activity is exerted was examined in TNF-α-induced 293 human cells using transient reporter (luciferase) gene expression systems (HIV LTR-luc, ĸB-luc, and mutant ĸB-luc). Interrogation through molecular docking against the NF-ĸB p50/p65 heterodimer and target sites of the subunits comprising the IKK complex revealed high binding affinities of globospiramine (1) against the S281 pocket of the p65 subunit (BE = -9.2 kcal/mol) and the IKKα activation loop (BE = -9.1 kcal/mol). These findings suggest globospiramine (1) as a molecular inspiration to discover new alkaloid-based anti-HIV derivatives.


Assuntos
Alcaloides/farmacologia , Infecções por HIV/metabolismo , HIV-1/fisiologia , Quinase I-kappa B/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Fator de Transcrição RelA/metabolismo , Voacanga/química , Alcaloides/química , Linhagem Celular , Relação Dose-Resposta a Droga , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Células HL-60 , Humanos , Quinase I-kappa B/química , Alcaloides Indólicos/farmacologia , Modelos Biológicos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/química , Extratos Vegetais/química , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/farmacologia , Fator de Transcrição RelA/química , Fator de Necrose Tumoral alfa/farmacologia , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
16.
Mar Drugs ; 20(2)2022 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-35200640

RESUMO

Schistosomiasis has been controlled for more than 40 years with a single drug, praziquantel, and only one molluscicide, niclosamide, raising concern of the possibility of the emergence of resistant strains. However, the molecular targets for both agents are thus far unknown. Consequently, the search for lead compounds from natural sources has been encouraged due to their diverse structure and function. Our search for natural compounds with potential use in schistosomiasis control led to the identification of an algal species, Laurencia dendroidea, whose extracts demonstrated significant activity toward both Schistosoma mansoni parasites and their intermediate host snails Biomphalaria glabrata. In the present study, three seaweed-derived halogenated sesquiterpenes, (-)-elatol, rogiolol, and obtusol are proposed as potential lead compounds for the development of anthelminthic drugs for the treatment of and pesticides for the environmental control of schistosomiasis. The three compounds were screened for their antischistosomal and molluscicidal activities. The screening revealed that rogiolol exhibits significant activity toward the survival of adult worms, and that all three compounds showed activity against S. mansoni cercariae and B. glabrata embryos. Biomonitored fractioning of L. dendroidea extracts indicated elatol as the most active compound toward cercariae larvae and snail embryos.


Assuntos
Anti-Helmínticos/farmacologia , Laurencia/química , Moluscocidas/farmacologia , Sesquiterpenos/farmacologia , Animais , Anti-Helmínticos/isolamento & purificação , Larva , Moluscocidas/isolamento & purificação , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose/tratamento farmacológico , Sesquiterpenos/isolamento & purificação , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia
17.
Drug Alcohol Depend ; 231: 109255, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34998256

RESUMO

RATIONALE AND OBJECTIVE: One objective of the National Institutes of Health Helping to End Addiction Long-term (HEAL) initiative is to accelerate research on safer and more effective medications for both pain and opioid use disorder. Ligands that activate the nociceptin opioid peptide receptor (NOP) constitute one class of candidate drugs for both applications. The present preclinical study determined the effectiveness of the NOP agonist Ro 64-6198 to produce antinociception in a pain-depressed behavior procedure and attenuate opioid self-administration in a heroin-vs-food choice procedure. METHODS: In Experiment 1, Adult Sprague-Dawley rats were equipped with microelectrodes and trained to respond for electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. The potency, time course, and receptor mechanism of effects produced by R0 64-6198 alone (0.32-3.2 mg/kg) on ICSS were examined, followed by evaluation of 0.32-1.0 mg/kg Ro 64-6198 effectiveness to block lactic acid-induced depression of ICSS. In Experiment 2, rats self-administered heroin under a heroin-vs-food choice procedure during a regimen of repeated, daily intraperitoneal administration of vehicle or Ro 64-6198 (1-3.2 mg/kg/day). RESULTS: Ro 64-6198 produced dose- and time-dependent ICSS depression that was blocked by the selective NOP antagonist SB612111 but not by naltrexone. Ro 64-6198 failed to block acid-induced depression of ICSS. Repeated Ro 64-6198 pretreatment also failed to attenuate heroin-vs-food choice up to doses that significantly decreased operant behavior. CONCLUSIONS: These results do not support the utility of Ro 64-6198 as a stand-alone medication for either acute pain or opioid use disorder.


Assuntos
Dor Aguda , Heroína , Imidazóis/farmacologia , Peptídeos Opioides/agonistas , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Compostos de Espiro/farmacologia , Dor Aguda/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Peptídeos Opioides/farmacologia , Ratos , Ratos Sprague-Dawley
18.
Bioorg Med Chem Lett ; 59: 128550, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35041942

RESUMO

The five-membered D-ring nalfurafine (d-nor-nalfurafine) derivatives with a 16-sulfonamide group were synthesized. Conversion of the 16-cyclopropylmethyl group to the 16-benzenesulfonamide group in the d-nor-nalfurafine derivatives drastically improved the orexin 1 receptor (OX1R) antagonist activities. The intramolecular hydrogen bond between the 14-hydroxy and the 16-sulfonamide groups may play an important role in increasing the probability that the 6-amide group would be located at the lower side of the C-ring, leading to an active conformation for OX1R. The assay results and the conformational analyses of the 14-OH, 14-H, and 14-dehydrated d-nor-nalfurafine derivatives suggested that the 14- and 16-substituents of the d-nor-nalfurafine derivatives had a greater effect on the affinities for the OX1R than did the 14- and 17-substituents of nalfurafine derivatives.


Assuntos
Morfinanos/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Compostos de Espiro/farmacologia , Sulfonamidas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Morfinanos/química , Antagonistas dos Receptores de Orexina/química , Compostos de Espiro/química , Relação Estrutura-Atividade , Sulfonamidas/química
19.
Biochem Biophys Res Commun ; 595: 7-13, 2022 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-35091109

RESUMO

The intestinal tract is an essential component of the body's immune system, and is extremely sensitive to exposure of ionizing radiation. While ionizing radiation can effectively induce multiple forms of cell death, whether it can also promote ferroptosis in intestinal cells and the possible interrelationship between ferroptosis and intestinal immune function has not been reported so far. Here, we found that radiation-induced major ultrastructural changes in mitochondria of small intestinal epithelial cells and the changes induced in iron content and MDA levels in the small intestine were consistent with that observed during cellular ferroptosis, thus suggesting occurrence of ferroptosis in radiation-induced intestinal damage. Moreover, radiation caused a substantial increase in the expression of ferroptosis-related factors such as LPCAT3 and ALOX15 mRNA, augmented the levels of immune-related factors INF-γ and TGF-ß mRNA, and decreased the levels of IL-17 mRNA thereby indicating that ionizing radiation induced ferroptosis and impairment of intestinal immune function. Liproxstatin-1 is a ferroptosis inhibitor that was found to ameliorate radiation-induced ferroptosis and promote the recovery from immune imbalances. These findings supported the role of ferroptosis in radiation-induced intestinal immune injury and provide novel strategies for protection against radiation injury through regulation of the ferroptosis pathway.


Assuntos
Ferroptose/fisiologia , Intestinos/patologia , Quinoxalinas/farmacologia , Lesões Experimentais por Radiação/prevenção & controle , Radiação Ionizante , Compostos de Espiro/farmacologia , 1-Acilglicerofosfocolina O-Aciltransferase/genética , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Animais , Araquidonato 12-Lipoxigenase/genética , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/metabolismo , Ferroptose/efeitos dos fármacos , Ferroptose/efeitos da radiação , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos da radiação , Glutationa/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/efeitos da radiação , Intestinos/efeitos dos fármacos , Intestinos/efeitos da radiação , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/efeitos da radiação , Mitocôndrias/ultraestrutura , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/fisiopatologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/metabolismo
20.
Bioorg Med Chem ; 57: 116629, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35091169

RESUMO

Malaria is a prevalent and lethal disease. The fast emergence and spread of resistance to current therapies is a major concern and the development of a novel line of therapy that could overcome, the problem of drug resistance, is imperative. Screening of a set of compounds with drug/natural product-based sub-structural motifs led to the identification of spirocyclic chroman-4-one 1 with promising antimalarial activity against the chloroquine-resistant Dd2 and chloroquine-sensitive 3D7 strains of the parasite. Extensive structure-activity and structure-property relationship studies were conducted to identify the essential features necessary for its activity and properties.


Assuntos
Antimaláricos/farmacologia , Cromanos/farmacologia , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Compostos de Espiro/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Sobrevivência Celular/efeitos dos fármacos , Cromanos/síntese química , Cromanos/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
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