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1.
ACS Infect Dis ; 7(8): 2229-2237, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34339171

RESUMO

SARS-CoV-2 virus has recently given rise to the current COVID-19 pandemic where infected individuals can range from being asymptomatic, yet highly contagious, to dying from acute respiratory distress syndrome. Although the world has mobilized to create antiviral vaccines and therapeutics to combat the scourge, their long-term efficacy remains in question especially with the emergence of new variants. In this work, we exploit a class of compounds that has previously shown success against various viruses. A salicylanilide library was first screened in a SARS-CoV-2 activity assay in Vero cells. The most efficacious derivative was further evaluated in a prophylactic mouse model of SARS-CoV-2 infection unveiling a salicylanilide that can reduce viral loads, modulate key cytokines, and mitigate severe weight loss involved in COVID-19 infections. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and a previously established favorable pharmacokinetic profile for the lead salicylanilide renders salicylanilides in general as promising therapeutics for COVID-19.


Assuntos
COVID-19 , Pandemias , Animais , Chlorocebus aethiops , Citocinas , Humanos , Camundongos , Roedores , SARS-CoV-2 , Salicilanilidas , Células Vero
2.
Bioorg Med Chem ; 40: 116129, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33971488

RESUMO

Over the past few decades, an increasing variety of molecular chaperones have been investigated for their role in tumorigenesis and as potential chemotherapeutic targets; however, the 60 kDa Heat Shock Protein (HSP60), along with its HSP10 co-chaperone, have received little attention in this regard. In the present study, we investigated two series of our previously developed inhibitors of the bacterial homolog of HSP60/10, called GroEL/ES, for their selective cytotoxicity to cancerous over non-cancerous colorectal cells. We further developed a third "hybrid" series of analogs to identify new candidates with superior properties than the two parent scaffolds. Using a series of well-established HSP60/10 biochemical screens and cell-viability assays, we identified 24 inhibitors (14%) that exhibited > 3-fold selectivity for targeting colorectal cancer over non-cancerous cells. Notably, cell viability EC50 results correlated with the relative expression of HSP60 in the mitochondria, suggesting a potential for this HSP60-targeting chemotherapeutic strategy as emerging evidence indicates that HSP60 is up-regulated in colorectal cancer tumors. Further examination of five lead candidates indicated their ability to inhibit the clonogenicity and migration of colorectal cancer cells. These promising results are the most thorough analysis and first reported instance of HSP60/10 inhibitors being able to selectively target colorectal cancer cells and highlight the potential of the HSP60/10 chaperonin system as a viable chemotherapeutic target.


Assuntos
Antineoplásicos/farmacologia , Benzoxazóis/farmacologia , Chaperonina 10/antagonistas & inibidores , Chaperonina 60/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Salicilanilidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzoxazóis/síntese química , Benzoxazóis/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chaperonina 10/metabolismo , Chaperonina 60/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Salicilanilidas/síntese química , Salicilanilidas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
Nat Commun ; 12(1): 3061, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031399

RESUMO

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of Mpro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses.


Assuntos
Azóis/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Compostos Organosselênicos/farmacologia , SARS-CoV-2/enzimologia , Antivirais/farmacologia , Azóis/química , Domínio Catalítico , Proteases 3C de Coronavírus/metabolismo , Cristalografia por Raios X , Cisteína/química , Hidrólise , Isoindóis , Modelos Moleculares , Compostos Organosselênicos/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Padrões de Referência , SARS-CoV-2/efeitos dos fármacos , Salicilanilidas/química , Salicilanilidas/farmacologia , Selênio/metabolismo
4.
BMC Ophthalmol ; 21(1): 158, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33789597

RESUMO

BACKGROUND: Closantel is the best-known anti-parasitic medicine for veterinarians, which is contraindicated in humans. After reviewing the literature on ocular toxicity following mistaken usage of Closantel in humans, this report was found as the first complete restoration of visual function after Closantel intoxication. This report could be useful in anticipating the possibility of a further improvement based on a dose-response relationship. An important point of this report is the apparent reversibility of the vision and Electrophysiological parameters after Closantel intoxication and blindness. To conclude, the present case report demonstrates the importance of immediate referral and management in Closantel intoxication to avoid the long-term adverse effects of drug on visual function. CASE PRESENTATION: A 47-year-old man mistakenly took about 20 cc of Closantel 5% (15.87 mg/kg). Four hours after mistaken usage of Closantel, he was transferred to the district hospital due to dizziness and nausea. His stomach was washed out immediately after hospital arrival. He was being hospitalized in that hospital for 3 days. Then, he was referred to our clinic due to progressive vision loss. Methylprednisolone acetate 250 mg was injected once on 5th day after taking Closantel. His vision was reducing gradually so low that he could only detect hand motion (HM) on the 14th day after taking Closantel. ERG test was requested. It showed an exclusive reduction in b-wave amplitude under photopic and scotopic conditions. Later, his vision surprisingly improved gradually and his visual acuity was fully restored on the 28th day after the incident. After 3 years, we checked him again. His visual acuity was 20/20 in both eyes and the patient did not have any problem and his ERG report was completely normal. CONCLUSIONS: In low dose of Closantel and immediate referral, ocular toxicity could be resolved.


Assuntos
Cegueira , Salicilanilidas , Cegueira/induzido quimicamente , Eletrorretinografia , Olho , Humanos , Masculino , Pessoa de Meia-Idade , Acuidade Visual
5.
J Chromatogr Sci ; 59(5): 445-451, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33709144

RESUMO

A rapid and accurate high-performance liquid chromatographic method was developed for the determination of both abamectin and closantel in the veterinary formulation. The chromatographic separation was conducted on an Agilent 1200 with a UV detector using Waters C18 (4.6 mm × 50 mm; 2.7 µm). The mobile phase consisted of acetonitrile:water (80:20 v/v) adjusts pH 3.0 using diluted phosphoric acid. The flow rate of 1.5 mL min-1 was used. An injection volume of 10 µL was used The calibration curve of abamectin B1b was linear with a correlation coefficient (r2) = 0.9996; over a concentration range of 2.0-8.0 µg/mL, abamectin B1a was linear with a correlation coefficient (r2) = 0.9997; over a concentration range of 8.0-32.0 µg/mL; with a retention time of 2.18 and 3.72 minutes for avermectin B1b and avermectin B1a, respectively. While the calibration curve of closantel was linear with a correlation coefficient (r2) = 0.99929; over a concentration range of 250.0-1,000.0 µg/mL for; with a retention time of 5.84 minutes. Correlation coefficient was r2 ≥ 0.999. The relative standard deviation was found to be ≤ 2. The proposed method was validated and successfully applied for the simultaneous determination of abamectin and closantel in the veterinary formulation.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ivermectina/análogos & derivados , Salicilanilidas/análise , Drogas Veterinárias/análise , Ivermectina/análise , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes
6.
Toxicol In Vitro ; 72: 105096, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33460737

RESUMO

Inhibition of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzymatic step in de novo pyrimidine synthesis, has broad immunosuppressive effects in vivo and shows promise as a therapeutic target for the treatment of malignancies, viral infections and auto-immune diseases. Whilst there are numerous DHODH inhibitors under development, leflunomide and teriflunomide are the only FDA approved compounds on the market, each of which have been issued with black-box warnings for hepatotoxicity. Mitochondrial dysfunction is a putative mechanism by which teriflunomide and leflunomide elicit their hepatotoxic effects, however it is as yet unclear whether this is shared by other nascent DHODH inhibitors. The present study aimed to evaluate the propensity for DHODH inhibitors to mediate mitochondrial dysfunction in two hepatic in vitro models. Initial comparisons of cytotoxicity and ATP content in HepaRG® cells primed for oxidative metabolism, in tandem with mechanistic evaluations by extracellular flux analysis identified multifactorial toxicity and moderate indications of respiratory chain dysfunction or uncoupling. Further investigations using HepG2 cells, a hepatic line with limited capability for phase I xenobiotic metabolism, identified leflunomide and brequinar as positive mitochondrial toxicants. Taken together, biotransformation of some DHODH inhibitor species may play a role in mediating or masking hepatic mitochondrial liabilities.


Assuntos
Antineoplásicos/toxicidade , Imunossupressores/toxicidade , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Compostos de Bifenilo/toxicidade , Linhagem Celular , Respiração Celular/efeitos dos fármacos , Crotonatos/toxicidade , Ácidos Dicarboxílicos/toxicidade , Humanos , Hidroxibutiratos/toxicidade , Leflunomida/toxicidade , Fígado/metabolismo , Mitocôndrias/metabolismo , Modelos Biológicos , Nitrilas/toxicidade , Salicilanilidas/toxicidade , Toluidinas/toxicidade , Triazóis/toxicidade
7.
Sci Total Environ ; 769: 144960, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33477039

RESUMO

This article studies the ecotoxicity of 3,3',4',5-tetrachlorosalicylanilide (TCSA) using different bioassays and examines its fate in activated sludge batch experiments. Despite of the common use of TCSA as chemical uncoupler in wastewater treatment systems and as preservative in several products, limited data has been published for its ecotoxicity, while no information is available for its biodegradation. Among different bioassays, the highest toxicity of TSCA was noticed for Daphna magna (48-h LC50: 0.054 mg L-1), followed by Vibrio fischeri (15-min EC50: 0.392 mg L-1), Lemna minor, (7-d EC50: 5.74 mg L-1) and activated sludge respiration rate (3-h EC50: 31.1 mg L-1). The half-life of TSCA was equal to 7.3 h in biodegradation experiments with activated sludge, while use of mass balances showed that 90% of this compound is expected to be removed in an aerobic activated sludge system, mainly due to biodegradation. A preliminary risk assessment of TSCA using the Risk Quotient methodology showed possible ecological threat in rivers where wastewater is diluted up to 100-fold. Comparison with the structurally similar 5-chloro-2-(2,4-dichlorophenoxy)phenol (triclosan, TCS) showed that both compounds have similar biodegradation potential and seem to cause analogous toxicity to Vibrio fischeri and activated sludge. Specifically, TCS was biodegraded quite rapidly by activated sludge (half-life: 6.2 h), while EC50 values equal to 0.134 mg L-1 and 39.9 mg L-1 were calculated for Vibrio fischeri, and activated sludge respiration rate. Future research should focus on monitoring of TSCA concentrations in the environment and study its effects in long-term toxicity and bioaccumulation tests.


Assuntos
Triclosan , Poluentes Químicos da Água , Biodegradação Ambiental , Salicilanilidas , Esgotos , Triclosan/análise , Triclosan/toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
8.
Front Immunol ; 11: 586572, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324406

RESUMO

COVID-19 pandemic has infected millions of people with mortality exceeding >1 million. There is an urgent need to find therapeutic agents that can help clear the virus to prevent severe disease and death. Identifying effective and safer drugs can provide more options to treat COVID-19 infections either alone or in combination. Here, we performed a high throughput screening of approximately 1,700 US FDA-approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 20 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, and thioridazine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating a wide therapeutic window compared to hydroxychloroquine which had a safety index of 22 in similar experiments. Mechanistically, five of the effective compounds (fendiline HCl, monensin sodium salt, vortioxetine, sertraline HCl, and salifungin) were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA-approved compounds can provide much needed therapeutic options that we urgently need during the midst of the pandemic.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Ensaios de Triagem em Larga Escala/métodos , Pandemias/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/epidemiologia , COVID-19/virologia , Linhagem Celular , Reposicionamento de Medicamentos/métodos , Fendilina/uso terapêutico , Células HEK293 , Humanos , Monensin/uso terapêutico , SARS-CoV-2/fisiologia , Salicilanilidas/uso terapêutico , Sertralina/uso terapêutico , Vortioxetina/uso terapêutico
10.
mBio ; 11(5)2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934086

RESUMO

One avenue to combat multidrug-resistant Gram-negative bacteria is the coadministration of multiple drugs (combination therapy), which can be particularly promising if drugs synergize. The identification of synergistic drug combinations, however, is challenging. Detailed understanding of antibiotic mechanisms can address this issue by facilitating the rational design of improved combination therapies. Here, using diverse biochemical and genetic assays, we examine the molecular mechanisms of niclosamide, a clinically approved salicylanilide compound, and demonstrate its potential for Gram-negative combination therapies. We discovered that Gram-negative bacteria possess two innate resistance mechanisms that reduce their niclosamide susceptibility: a primary mechanism mediated by multidrug efflux pumps and a secondary mechanism of nitroreduction. When efflux was compromised, niclosamide became a potent antibiotic, dissipating the proton motive force (PMF), increasing oxidative stress, and reducing ATP production to cause cell death. These insights guided the identification of diverse compounds that synergized with salicylanilides when coadministered (efflux inhibitors, membrane permeabilizers, and antibiotics that are expelled by PMF-dependent efflux), thus suggesting that salicylanilide compounds may have broad utility in combination therapies. We validate these findings in vivo using a murine abscess model, where we show that niclosamide synergizes with the membrane permeabilizing antibiotic colistin against high-density infections of multidrug-resistant Gram-negative clinical isolates. We further demonstrate that enhanced nitroreductase activity is a potential route to adaptive niclosamide resistance but show that this causes collateral susceptibility to clinical nitro-prodrug antibiotics. Thus, we highlight how mechanistic understanding of mode of action, innate/adaptive resistance, and synergy can rationally guide the discovery, development, and stewardship of novel combination therapies.IMPORTANCE There is a critical need for more-effective treatments to combat multidrug-resistant Gram-negative infections. Combination therapies are a promising strategy, especially when these enable existing clinical drugs to be repurposed as antibiotics. We examined the mechanisms of action and basis of innate Gram-negative resistance for the anthelmintic drug niclosamide and subsequently exploited this information to demonstrate that niclosamide and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide in vitro against a diverse range of recalcitrant Gram-negative clinical isolates and in vivo in a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to niclosamide but show that evolution of these enzymes for enhanced niclosamide resistance confers a collateral sensitivity to other clinical antibiotics. Our results highlight how detailed mechanistic understanding can accelerate the evaluation and implementation of new combination therapies.


Assuntos
Antibacterianos/farmacologia , Sinergismo Farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Salicilanilidas/metabolismo , Salicilanilidas/farmacologia , Animais , Desenho de Fármacos , Reposicionamento de Medicamentos , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada/métodos , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Niclosamida/metabolismo , Niclosamida/farmacologia
11.
Int J Radiat Oncol Biol Phys ; 108(5): 1368-1379, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32763454

RESUMO

PURPOSE: Esophageal cancer (EC) is an aggressive malignancy and is often resistant to currently available therapies. Inhibition of ribonucleotide reductase small subunit M2 (RRM2) in tumors is speculated to mediate chemosensitization. Previous studies have reported that Osalmid could act as an RRM2 inhibitor. We explored whether RRM2 was involved in radioresistance and the antitumor effects of Osalmid in EC. METHODS AND MATERIALS: RRM2 expression was detected by immunohistochemistry in EC tissues. The effects of Osalmid on cell proliferation, apoptosis, and cell cycle were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphhenyl tetrazolium, colony formation, and flow cytometry assays. DNA damage, cell apoptosis, and senescence induced by Osalmid or ionizing radiation (IR) alone, or both, were detected with immunofluorescence, flow cytometry, Western blot, and ß-galactosidase staining. A xenograft mouse model of EC was used to investigate the potential synergistic effects of Osalmid and IR in vivo. RESULTS: The expression of RRM2 in treatment-resistant EC tissues is much higher than in treatment-sensitive EC, and strong staining of RRM2 was correlated with shorter overall survival. We observed direct cytotoxicity of Osalmid in EC cells. Osalmid also produced inhibition of the ERK1/2 signal transduction pathway and substantially enhanced IR-induced DNA damage, apoptosis, and senescence. Furthermore, treatment with Osalmid and IR significantly suppressed tumor growth in xenograft EC models without additional toxicity to the hematologic system and internal organs. CONCLUSIONS: Our study revealed that RRM2 played a vital role in radioresistance in EC, and Osalmid synergized with IR to exert its antitumor effects both in vitro and in vivo.


Assuntos
Neoplasias Esofágicas/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Ribonucleosídeo Difosfato Redutase/antagonistas & inibidores , Salicilanilidas/farmacologia , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Dano ao DNA , Desoxirribonucleosídeos/análise , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Feminino , Técnicas de Silenciamento de Genes , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fosforilação , Ribonucleosídeo Difosfato Redutase/metabolismo
12.
Biomed Pharmacother ; 130: 110556, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32763815

RESUMO

BACKGROUNDS: Ribonucleotide reductase (RR) catalyzes the essential step in the formation of all four deoxynucleotides. Upregulated activity of RR plays an active role in tumor progression. As the regulatory subunit of RR, ribonucleotide reductase subunit M2 (RRM2) is regarded as one of the effective therapeutic targets for DNA replication-dependent diseases, such as cancers. Recent studies have revealed that osalmid significantly inhibits the activity of RRM2, but the metabolic profile of osalmid remains unknown. OBJECTIVE: The aim of this study was to clarify the metabolic profile including metabolites, isoenzymes and metabolic pathways of osalmid. The anti-human hepatocellular carcinoma activity and mechanism of metabolites were further investigated. MATERIALS AND METHODS: Ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) was used for identifying metabolites and for characterizing phase I and phase II metabolic pathways with recombinant enzymes or in human liver microsomes of osalmid. The eHiTS docking system was used for potential RRM2 inhibitor screening among metabolites. Cytotoxicity assays were performed for evaluating cell proliferation inhibitory activity of metabolites. Cell cycle assays and cell apoptosis assays were assessed by flow cytometry. Western blotting analysis of RRM2, cyclin D1, p21, p53, phosphorylated p53, Bcl-2 and Bax was performed to explore the anti-hepatocellular carcinoma mechanism of the active metabolites. RESULTS: Ten metabolites of osalmid were identified, and none of them have been reported previously. Hydroxylation, glucuronidation, sulfonation, acetylation and degradation were recognized as the main metabolic processes of osalmid. Isozymes of CYP1A2, CYP2C9, UGT1A1, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 were involved in phase I and phase II metabolism of osalmid. Metabolites M7, M8 and M10 showed higher binding affinities with the RRM2 active site than osalmid. Metabolite M7 exhibited potent inhibitory activity to hepatocellular carcinoma cell lines by both competitive inhibition and down-regulation of RRM2. Moreover, M7 significantly induced cell cycle arrest and apoptosis by activating p53-related pathways. CONCLUSIONS: The metabolic profile of osalmid was identified. M7 significantly inhibited human hepatocellular carcinoma progression by inhibiting RRM2 activity. Furthermore, M7 induced cell cycle arrest and apoptosis by activating p53-related signaling pathways.


Assuntos
Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Salicilanilidas/metabolismo , Salicilanilidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biotransformação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Ribonucleosídeo Difosfato Redutase/antagonistas & inibidores , Proteína Supressora de Tumor p53/efeitos dos fármacos
13.
Spectrochim Acta A Mol Biomol Spectrosc ; 243: 118779, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32810780

RESUMO

A molecularly imprinted polymer (MIP) for the selective solid-phase extraction (SPE) was prepared applying polymerization of pyrrole monomer in the presence of closantel (CLS) as a template molecule. The quantitative measurements were carried out using UV-Vis spectrophotometry. Several important parameters control the performance of polypyrrole sorbent. The influence of seven factors including loading time, polymerization time, amount of sorbent, stirring rate, desorption time, initiator concentration and monomer to template ratio were investigated. The optimization of parameters was performed using Plackett-Burman design (PBD), central composite design (CCD), artificial neural network (ANN) and genetic algorithm (GA). The Pareto plot showed that the effects of loading time, reaction time and amount of sorbent are most important to the process. These significant factors were investigated using CCD and the obtained data were used to train the ANN. The predicted model obtained from the trained ANN was introduced to GA as the fitness function to be optimized. The calibration curve demonstrated linearity over a concentration range of 0.010-10 mM with a correlation coefficient (R2) of 0.9833 under optimal condition. The synthesized MIP sorbent showed a good selectivity and sensitivity toward CLS. The limit of detection (LOD) for CLS was obtained 1.0 µM. The real sample analysis was performed to determine CLS in pharmaceutical and human serum samples.


Assuntos
Impressão Molecular , Polímeros , Humanos , Redes Neurais de Computação , Pirróis , Salicilanilidas , Extração em Fase Sólida , Espectrofotometria
14.
Int J Mol Sci ; 21(14)2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32668817

RESUMO

Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics-a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine-have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system.


Assuntos
Anti-Helmínticos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias do Sistema Digestório/tratamento farmacológico , Reposicionamento de Medicamentos , Anti-Helmínticos/efeitos adversos , Anti-Helmínticos/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Ensaios Clínicos como Assunto , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Salicilanilidas/efeitos adversos , Salicilanilidas/farmacologia , Salicilanilidas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
16.
J Med Chem ; 63(13): 6898-6908, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32482070

RESUMO

Clostridioides difficile infection (CDI) causes serious and sometimes fatal symptoms like diarrhea and pseudomembranous colitis. Although antibiotics for CDI exist, they are either expensive or cause recurrence of the infection due to their altering the colonic microbiota, which is necessary to suppress the infection. Here, we leverage a class of known membrane-targeting compounds that we previously showed to have broad inhibitory activity across multiple Clostridioides difficile strains while preserving the microbiome to develop an efficacious agent. A new series of salicylanilides was synthesized, and the most potent analog was selected through an in vitro inhibitory assay to evaluate its pharmacokinetic parameters and potency in a CDI mouse model. The results revealed reduced recurrence of CDI and diminished disturbance of the microbiota in mice compared to standard-of-care vancomycin, thus paving the way for novel therapy that can potentially target the cell membrane of C. difficile to minimize relapse in the recovering patient.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Clostridioides difficile/fisiologia , Infecções por Clostridium/tratamento farmacológico , Salicilanilidas/química , Salicilanilidas/farmacologia , Animais , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Clostridioides difficile/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Recidiva , Segurança , Salicilanilidas/farmacocinética , Salicilanilidas/uso terapêutico , Distribuição Tecidual
17.
Acta Trop ; 210: 105580, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32533936

RESUMO

Oncomelania hupensis is the intermediate host of Schistosoma japonicum, one of the Schistosoma species that can cause human schistosomiasis. Molluscicidal treatment remains the primary means to control snail. Niclosamide is the only molluscicide recommended by the World Health Organization, and it has been used throughout schistosomiasis-endemic areas in China for almost 30 years. In our previous studies on transcriptomics, morphology, and enzymology of snails after molluscicidal treatment, two effective molluscicides were used, 50% wettable powder of niclosamide ethanolamine salt (WPN) and a new molluscicide derived from niclosamide, the salt of quinoid-2', 5-dichloro-4'-nitro-salicylanilide (LDS, simplified for Liu Dai Shui Yang An). Genes involved in cell structure mintenance, inhibition of neurohumoral transmission, and energy metabolism showed significant differential expression after molluscicide treatments. Damages in the structure of liver and muscle cells were accompanied by inhibited activities of enzymes related to carbohydrate metabolism and energy supply. This study was designed to clarify the dynamic metabolic process by metabonomics, together with the previous transcriptomic and enzymological profiles, to identify potential metabolite markers and metabolism pathways that related to the toxic mechanism of the molluscicide. In total, 56 metabolites were identified for O. hupensis, and 75% of these metabolites consisted of amino acids and derivatives, organic acids, and nucleic acid components. The concentration of glucose, maltose, succinate, choline, and alanine changed significantly after molluscicide treatments. These changes in metabolites mainly occurred in the process of carbohydrate metabolism, energy metabolism, and amino acid metabolism, primarily related to glycolysis/gluconeogenesis, oxidative phosphorylation, and transamination by KEGG pathway identification. Most of the identified pathways were also related to those differentially expressed unigenes and observed enzymes from our previous studies. Inhibited aerobic respiration and oxidative phosphorylation, and energy deficiency were implied further to be the leading causes of the final death of snails after molluscicide treatments. The hypothesised mathematical model in this study identified the rational hysteresis to explain the inconsistency of responses of unigenes, enzymes, and metabolites to molluscicide treatments. This study contributes to the comprehensive understanding of the molluscicidal mechanism in the metabolic process and this could assist in improving existing molluscicide formulations or development of new molluscicides.


Assuntos
Metabolismo dos Carboidratos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Moluscocidas/farmacologia , Caramujos/efeitos dos fármacos , Animais , Niclosamida/farmacologia , Salicilanilidas/farmacologia , Esquistossomose Japônica/transmissão , Caramujos/metabolismo
18.
Int J Mol Sci ; 21(10)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408543

RESUMO

Ring-substituted 1-hydroxynaphthalene-2-carboxanilides were previously investigated for their antimycobacterial properties. In our study, we have shown their antiproliferative and cell death-inducing effects in cancer cell lines. Cell proliferation and viability were assessed by WST-1 assay and a dye exclusion test, respectively. Cell cycle distribution, phosphatidylserine externalization, levels of reactive oxygen or nitrogen species (RONS), mitochondrial membrane depolarization, and release of cytochrome c were estimated by flow cytometry. Levels of regulatory proteins were determined by Western blotting. Our data suggest that the ability to inhibit the proliferation of THP-1 or MCF-7 cells might be referred to meta- or para-substituted derivatives with electron-withdrawing groups -F, -Br, or -CF3 at anilide moiety. This effect was accompanied by accumulation of cells in G1 phase. Compound 10 also induced apoptosis in THP-1 cells in association with a loss of mitochondrial membrane potential and production of mitochondrial superoxide. Our study provides a new insight into the action of salicylanilide derivatives, hydroxynaphthalene carboxamides, in cancer cells. Thus, their structure merits further investigation as a model moiety of new small-molecule compounds with potential anticancer properties.


Assuntos
Anilidas/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Naftóis/química , Anilidas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Salicilanilidas/química , Salicilanilidas/farmacologia , Relação Estrutura-Atividade , Superóxidos/metabolismo , Células THP-1
19.
Acta Biochim Biophys Sin (Shanghai) ; 52(4): 401-410, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32259210

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common category and disease entity of non-Hodgkin lymphoma. Osalmide and pterostilbene are natural products with anticancer activities via different mechanism. In this study, using a new synthetic strategy for the two natural products, we obtained the compound DCZ0801, which was previously found to have anti-multiple myeloma activity. We performed both in vitro and in vivo assays to investigate its bioactivity and explore its underlying mechanism against DLBCL cells. The results showed that DCZ0801 treatment gave rise to a dose- and time-dependent inhibition of cell viability as determined by CCK-8 assay and flow cytometry assay. Western blot analysis results showed that the expression of caspase-3, caspase-8, caspase-9 and Bax was increased, while BCL-2 and BCL-XL levels were decreased, which suggested that DCZ0801 inhibited cell proliferation and promoted intrinsic apoptosis. In addition, DCZ0801 induced G0/G1 phase arrest by downregulating the protein expression levels of CDK4, CDK6 and cyclin D1. Furthermore, DCZ0801 exerted an anti-tumor effect by down-regulating the expressions of p-PI3K and p-AKT. There also existed a trend that the expression of p-JNK and p-P38 was restrained. Intraperitoneal injection of DCZ0801 suppressed tumor development in xenograft mouse models. The preliminary metabolic study showed that DCZ0801 displayed a rapid metabolism within 30 min. These results demonstrated that DCZ0801 may be a new potential anti-DLBCL agent in DLBCL therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Ciclofosfamida/química , Ciclofosfamida/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Salicilanilidas/química , Salicilanilidas/farmacologia , Estilbenos/química , Estilbenos/farmacologia
20.
J Med Chem ; 63(11): 6164-6178, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32345019

RESUMO

Antagonists for the ATP-gated ion channel receptor P2X1 have potential as antithrombotics and for treating hyperactive bladder and inflammation. In this study, salicylanilide derivatives were synthesized based on a screening hit. P2X1 antagonistic potency was assessed in 1321N1 astrocytoma cells stably transfected with the human P2X1 receptor by measuring inhibition of the ATP-induced calcium influx. Structure-activity relationships were analyzed, and selectivity versus other P2X receptor subtypes was assessed. The most potent compounds, N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (1, IC50 0.0192 µM) and N-[3,5-bis(trifluoromethyl)phenyl]-4-chloro-2-hydroxybenzamide (14, IC50 0.0231 µM), displayed >500-fold selectivity versus P2X2 and P2X3, and 10-fold selectivity versus P2X4 and P2X7 receptors, and inhibited collagen-induced platelet aggregation. They behaved as negative allosteric modulators, and molecular modeling studies suggested an extracellular binding site. Besides selective P2X1 antagonists, compounds with ancillary P2X4 and/or P2X7 receptor inhibition were discovered. These compounds represent the first potent, non-acidic, allosteric P2X1 receptor antagonists reported to date.


Assuntos
Antagonistas do Receptor Purinérgico P2X/química , Receptores Purinérgicos P2X1/metabolismo , Salicilanilidas/química , Regulação Alostérica/efeitos dos fármacos , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Sítios de Ligação , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Cálcio/metabolismo , Linhagem Celular , Colágeno , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Dinâmica Molecular , Agregação Plaquetária/efeitos dos fármacos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Antagonistas do Receptor Purinérgico P2X/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X1/química , Salicilanilidas/metabolismo , Salicilanilidas/farmacologia , Relação Estrutura-Atividade
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