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1.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206076

RESUMO

Novel symmetrical bis-pyrrolo[2,3-d]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-d]pyrimidine monomer 5f with 4,4'-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC50 = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-d]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.


Assuntos
Antineoplásicos/síntese química , Pirimidinas/síntese química , Pirróis/síntese química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reação de Cicloadição , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia
2.
Int J Biol Sci ; 17(9): 2348-2355, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239361

RESUMO

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to more than 150 million infections and about 3.1 million deaths up to date. Currently, drugs screened are urgently aiming to block the infection of SARS-CoV-2. Here, we explored the interaction networks of kinase and COVID-19 crosstalk, and identified phosphoinositide 3-kinase (PI3K)/AKT pathway as the most important kinase signal pathway involving COVID-19. Further, we found a PI3K/AKT signal pathway inhibitor capivasertib restricted the entry of SARS-CoV-2 into cells under non-cytotoxic concentrations. Lastly, the signal axis PI3K/AKT/FYVE finger-containing phosphoinositide kinase (PIKfyve)/PtdIns(3,5)P2 was revealed to play a key role during the cellular entry of viruses including SARS-CoV-2, possibly providing potential antiviral targets. Altogether, our study suggests that the PI3K/AKT kinase inhibitor drugs may be a promising anti-SARS-CoV-2 strategy for clinical application, especially for managing cancer patients with COVID-19 in the pandemic era.


Assuntos
COVID-19/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , COVID-19/enzimologia , Chlorocebus aethiops , Simulação por Computador , Humanos , Neoplasias/enzimologia , Neoplasias/mortalidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor Cross-Talk , Células Vero
3.
Aging (Albany NY) ; 13(12): 16425-16444, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34156352

RESUMO

To identify novel prognostic and therapeutic targets for osteosarcoma patients, we compared the gene expression profiles of osteosarcoma and control tissues from the GSE42352 dataset in the Gene Expression Omnibus. Differentially expressed genes were subjected to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment and protein-protein interaction network analyses. Survival curve analyses indicated that osteosarcoma patients with lower mRNA levels of cyclin-dependent kinase 1 (CDK1) and topoisomerase II alpha had better prognoses. Various computer-aided techniques were used to identify potential CDK1 inhibitors for osteosarcoma patients, and PHA-793887 was predicted to be a safe drug with a high binding affinity for CDK1. In vitro, MTT and colony formation assays demonstrated that PHA-793887 reduced the viability and clonogenicity of osteosarcoma cells, while a scratch assay suggested that PHA-793887 impaired the migration of these cells. Flow cytometry experiments revealed that PHA-793887 dose-dependently induced apoptosis in osteosarcoma cells. Western blotting and enzyme-linked immunosorbent assays indicated that CDK1 expression in osteosarcoma cells declined with increasing PHA-793887 concentrations. These results suggest that PHA-793887 could be a promising new treatment for osteosarcoma.


Assuntos
Biologia Computacional , Simulação de Acoplamento Molecular , Osteossarcoma/tratamento farmacológico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Sítios de Ligação , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Ligantes , Osteossarcoma/genética , Osteossarcoma/patologia , Mapas de Interação de Proteínas/genética , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Pirróis/química , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Sobrevida
4.
Colloids Surf B Biointerfaces ; 204: 111804, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33940521

RESUMO

In this study, pot and field experiments showed that S903, Hasten and Gemini-31511 can significantly enhanced the control efficacy of fludioxonil on cucumber anthracnose. Then by studying the deposition and penetration interaction between active ingredients and cucumber leaves to revealed how the adjuvants influence the interaction process between pesticide active ingredients and target plants to improve the control efficacy. By analysis the effect of fludioxonil deposition to synergism of adjuvants, indicated that fludioxonil active ingredient deposition caused by adjuvants was not the main factor for the adjuvants synergistic effect. Fludioxonil + S903 yielded the lowest surface tension and contact angle, which also implying the best wetting ability. The mean diameters in Hasten + fludioxonil group were much smaller than those in only fludioxonil group (5.39 µm-90 g a.i. ha-1, 5.50 µm-180 g a.i. ha-1), the average particle size only had 3.45 µm (90 g a.i. ha-1) and 3.94 µm (180 g a.i. ha-1). And the result of spray droplets was consistent with the particles of fludioxonil crystals observed on glass slides and cucumber leaves. Therefore, S903 improved the penetrability of fludioxonil in the target plants by improving the wetting and dispersion of active ingredients on the target interface. Meantime, Hasten improved the penetrability of fludioxonil in the target plants by decreasing the particle size of active ingredients.


Assuntos
Cucumis sativus , Dioxóis/farmacologia , Folhas de Planta , Pirróis/farmacologia
5.
Appl Microbiol Biotechnol ; 105(8): 3315-3325, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33797573

RESUMO

BACKGROUND: Conducting polymer based nanocomposites are known to be effective against pathogens. Herein, we report the antimicrobial properties of multifunctional polypyrrole-cobalt oxide-silver nanocomposite (PPy-Co3O4-AgNPs) for the first time. Antibacterial activities were tested against multi-drug-resistant Gram-negative Escherichia coli (E. coli) and Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) bacteria, while antiamoebic effects were assessed against opportunistic protist Acanthamoeba castellanii (A. castellanii). RESULTS: The ternary nanocomposite containing conducting polymer polypyrrole, cobalt oxide, and silver nanoparticles showed potent antimicrobial effects against these pathogens. The antibacterial assay showed that PPy-Co3O4-AgNPs exhibited significant bactericidal activity against neuropathogenic E. coli K1 at only 8 µg/mL as compared to individual components of the nanocomposite, whereas a 70 % inhibition of A. castellanii viability was observed at 50 µg/mL. Moreover, PPy-Co3O4-AgNPs were found to have minimal cytotoxicity against human keratinocytes HaCaT cells in vitro even at higher concentration (50 µg/mL), and also reduced the microbes-mediated cytopathogenicity against host cells. CONCLUSION: These results demonstrate that PPy-Co3O4-AgNPs hold promise in the development of novel antimicrobial nanomaterials for biomedical applications. KEY POINTS: •Synthesis of polypyrrole-cobalt oxide-silver (PPy-Co3O4-AgNPs) nanocomposite. •Antimicrobial activity of nanocomposite. •PPy-Co3O4-AgNPs hold promise for biomedical applications.


Assuntos
Anti-Infecciosos , Nanopartículas Metálicas , Staphylococcus aureus Resistente à Meticilina , Nanocompostos , Parasitos , Animais , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Bactérias , Cobalto , Escherichia coli , Humanos , Testes de Sensibilidade Microbiana , Óxidos , Polímeros , Pirróis/farmacologia , Prata/farmacologia
6.
Molecules ; 26(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918322

RESUMO

In this article, we showed the synthesis of new polycyclic aromatic compounds, such as thienotriazolopyrimidinones, N-(thienotriazolopyrimidine) acetamide, 2-mercapto-thienotriazolo-pyrimidinones, 2-(((thieno-triazolopyrimidine) methyl) thio) thieno-triazolopyrimidines, thieno-pyrimidotriazolo-thiazines, pyrrolo-triazolo-thienopyrimidines, thienopyrimido-triazolopyrrolo-quinoxalines, thienopyrimido-triazolo-pyrrolo-oxathiino-quinoxalinones, 1,4-oxathiino-pyrrolo- triazolothienopyrimidinones, imidazopyrrolotriazolothienopyrimidines and 1,2,4-triazoloimidazo- pyrrolotriazolothienopyrimidindiones, based on the starting material 2,3-diamino-6-benzoyl-5- methylthieno[2,3-d]pyrimidin-4(3H)-one (3). The chemical structures were confirmed using many spectroscopic ways (IR, 1H, 13C, -NMR and MS) and elemental analyses. A series of thiazine, imidazole, pyrrole, thienotriazolopyrimidine derivatives were synthesized and evaluated for their antiproliferative activity against four human cancer cell lines, i.e., CNE2 (nasopharyngeal), KB (oral), MCF-7 (breast) and MGC-803 (gastric) carcinoma cells. The compounds 20, 19, 17, 16 and 11 showed significant cytotoxicity against types of human cancer cell lines.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Imidazóis/síntese química , Pirimidinas/síntese química , Pirróis/química , Quinoxalinas/síntese química , Tiazinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologia
7.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919762

RESUMO

The hemibiotrophic ascomycete fungus Colletotrichum gloeosporioides is the causal agent of anthracnose on numerous plants, and it causes considerable economic losses worldwide. Endocytosis is an essential cellular process in eukaryotic cells, but its roles in C. gloeosporioides remain unknown. In our study, we identified an endocytosis-related protein, CgEnd3, and knocked it out via polyethylene glycol (PEG)-mediated protoplast transformation. The lack of CgEnd3 resulted in severe defects in endocytosis. C. gloeosporioides infects its host through a specialized structure called appressorium, and ΔCgEnd3 showed deficient appressorium formation, melanization, turgor pressure accumulation, penetration ability of appressorium, cellophane membrane penetration, and pathogenicity. CgEnd3 also affected oxidant adaptation and the expression of core effectors during the early stage of infection. CgEnd3 contains one EF hand domain and four calcium ion-binding sites, and it is involved in calcium signaling. A lack of CgEnd3 changed the responses to cell-wall integrity agents and fungicide fludioxonil. However, CgEnd3 regulated appressorium formation and endocytosis in a calcium signaling-independent manner. Taken together, these results demonstrate that CgEnd3 plays pleiotropic roles in endocytosis, calcium signaling, cell-wall integrity, appressorium formation, penetration, and pathogenicity in C. gloeosporioides, and it suggests that CgEnd3 or endocytosis-related genes function as promising antifungal targets.


Assuntos
Colletotrichum/patogenicidade , Endocitose , Proteínas Fúngicas/metabolismo , Doenças das Plantas/microbiologia , Populus/microbiologia , Adaptação Fisiológica/efeitos dos fármacos , Antifúngicos/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Celofane , Colletotrichum/efeitos dos fármacos , Colletotrichum/crescimento & desenvolvimento , Colletotrichum/metabolismo , Dioxóis/farmacologia , Endocitose/efeitos dos fármacos , Deleção de Genes , Hifas/efeitos dos fármacos , Melaninas/metabolismo , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/microbiologia , Pressão , Pirróis/farmacologia , Virulência/efeitos dos fármacos
8.
J Med Chem ; 64(9): 6085-6136, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33876936

RESUMO

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.


Assuntos
Antimaláricos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Pirróis/farmacologia , Animais , Antimaláricos/química , Inibidores Enzimáticos/química , Camundongos , Plasmodium falciparum/efeitos dos fármacos , Pirróis/química , Relação Estrutura-Atividade
9.
J Med Virol ; 93(7): 4454-4460, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: covidwho-1263094

RESUMO

Although vaccination campaigns are currently being rolled out to prevent coronavirus disease (COVID-19), antivirals will remain an important adjunct to vaccination. Antivirals against coronaviruses do not exist, hence global drug repurposing efforts have been carried out to identify agents that may provide clinical benefit to patients with COVID-19. Itraconazole, an antifungal agent, has been reported to have activity against animal coronaviruses. Using cell-based phenotypic assays, the in vitro antiviral activity of itraconazole and 17-OH itraconazole was assessed against clinical isolates from a German and Belgian patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Itraconazole demonstrated antiviral activity in human Caco-2 cells (EC50 = 2.3 µM; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). Similarly, its primary metabolite, 17-OH itraconazole, showed inhibition of SARS-CoV-2 activity (EC50 = 3.6 µM). Remdesivir inhibited viral replication with an EC50 = 0.4 µM. Itraconazole and 17-OH itraconazole resulted in a viral yield reduction in vitro of approximately 2-log10 and approximately 1-log10 , as measured in both Caco-2 cells and VeroE6-eGFP cells, respectively. The viral yield reduction brought about by remdesivir or GS-441524 (parent nucleoside of the antiviral prodrug remdesivir; positive control) was more pronounced, with an approximately 3-log10 drop and >4-log10 drop in Caco-2 cells and VeroE6-eGFP cells, respectively. Itraconazole and 17-OH itraconazole exert in vitro low micromolar activity against SARS-CoV-2. Despite the in vitro antiviral activity, itraconazole did not result in a beneficial effect in hospitalized COVID-19 patients in a clinical study (EudraCT Number: 2020-001243-15).


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Furanos/farmacologia , Itraconazol/farmacologia , Pirróis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Triazinas/farmacologia , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Chlorocebus aethiops , Reposicionamento de Medicamentos , Humanos , Células Vero , Replicação Viral/efeitos dos fármacos
10.
Viruses ; 13(2)2021 02 11.
Artigo em Inglês | MEDLINE | ID: covidwho-1079725

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a new human pathogen in late 2019 and it has infected over 100 million people in less than a year. There is a clear need for effective antiviral drugs to complement current preventive measures, including vaccines. In this study, we demonstrate that berberine and obatoclax, two broad-spectrum antiviral compounds, are effective against multiple isolates of SARS-CoV-2. Berberine, a plant-derived alkaloid, inhibited SARS-CoV-2 at low micromolar concentrations and obatoclax, which was originally developed as an anti-apoptotic protein antagonist, was effective at sub-micromolar concentrations. Time-of-addition studies indicated that berberine acts on the late stage of the viral life cycle. In agreement, berberine mildly affected viral RNA synthesis, but it strongly reduced infectious viral titers, leading to an increase in the particle-to-pfu ratio. In contrast, obatoclax acted at the early stage of the infection, which is in line with its activity to neutralize the acidic environment in endosomes. We assessed infection of primary human nasal epithelial cells that were cultured on an air-liquid interface and found that SARS-CoV-2 infection induced and repressed expression of specific sets of cytokines and chemokines. Moreover, both obatoclax and berberine inhibited SARS-CoV-2 replication in these primary target cells. We propose berberine and obatoclax as potential antiviral drugs against SARS-CoV-2 that could be considered for further efficacy testing.


Assuntos
Antivirais/farmacologia , Berberina/farmacologia , Indóis/farmacologia , Pirróis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Adolescente , Animais , COVID-19/virologia , Células Cultivadas , Chlorocebus aethiops , Células Epiteliais/virologia , Humanos , Masculino , RNA Viral/genética , SARS-CoV-2/fisiologia , Células Vero
11.
J Med Virol ; 93(7): 4454-4460, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33666253

RESUMO

Although vaccination campaigns are currently being rolled out to prevent coronavirus disease (COVID-19), antivirals will remain an important adjunct to vaccination. Antivirals against coronaviruses do not exist, hence global drug repurposing efforts have been carried out to identify agents that may provide clinical benefit to patients with COVID-19. Itraconazole, an antifungal agent, has been reported to have activity against animal coronaviruses. Using cell-based phenotypic assays, the in vitro antiviral activity of itraconazole and 17-OH itraconazole was assessed against clinical isolates from a German and Belgian patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Itraconazole demonstrated antiviral activity in human Caco-2 cells (EC50 = 2.3 µM; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). Similarly, its primary metabolite, 17-OH itraconazole, showed inhibition of SARS-CoV-2 activity (EC50 = 3.6 µM). Remdesivir inhibited viral replication with an EC50 = 0.4 µM. Itraconazole and 17-OH itraconazole resulted in a viral yield reduction in vitro of approximately 2-log10 and approximately 1-log10 , as measured in both Caco-2 cells and VeroE6-eGFP cells, respectively. The viral yield reduction brought about by remdesivir or GS-441524 (parent nucleoside of the antiviral prodrug remdesivir; positive control) was more pronounced, with an approximately 3-log10 drop and >4-log10 drop in Caco-2 cells and VeroE6-eGFP cells, respectively. Itraconazole and 17-OH itraconazole exert in vitro low micromolar activity against SARS-CoV-2. Despite the in vitro antiviral activity, itraconazole did not result in a beneficial effect in hospitalized COVID-19 patients in a clinical study (EudraCT Number: 2020-001243-15).


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Furanos/farmacologia , Itraconazol/farmacologia , Pirróis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Triazinas/farmacologia , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Chlorocebus aethiops , Reposicionamento de Medicamentos , Humanos , Células Vero , Replicação Viral/efeitos dos fármacos
12.
Eur J Med Chem ; 217: 113339, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33744686

RESUMO

Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) together with nucleoside triphosphate diphosphohydrolases (NTPDases) and alkaline phosphatases (APs) are nucleotidases located at the surface of the cells. NPP1 and NPP3 are important members of NPP family that are known as druggable targets for a number of disorders such as impaired calcification, type 2 diabetes, and cancer. Sulfonylurea derivatives have been reported as antidiabetic and anticancer agents, therefore, we synthesized and investigated series of sulfonylurea derivatives 1a-m possessing pyrrolo[2,3-b]pyridine core as inhibitors of NPP1 and NPP3 isozymes that are over-expressed in cancer and diabetes. The enzymatic evaluation highlighted compound 1a as selective NPP1 inhibitor, however, 1c was observed as the most potent inhibitor of NPP1 with an IC50 value of 0.80 ± 0.04 µM. Compound 1l was found to be the most potent and moderately selective inhibitor of NPP3 (IC50 = 0.55 ± 0.01 µM). Furthermore, in vitro cytotoxicity assays of compounds 1a-m against MCF-7 and HT-29 cancer cell lines exhibited compound 1c (IC50 = 4.70 ± 0.67 µM), and 1h (IC50 = 1.58 ± 0.20 µM) as the most cytotoxic compounds against MCF-7 and HT-29 cancer cell lines, respectively. Both of the investigated compounds showed high degree of selectivity towards cancer cells than normal cells (WI-38). Molecular docking studies of selective and potent enzyme inhibitors revealed promising mode of interactions with important binding sites residues of both isozymes i.e., Thr256, His380, Lys255, Asn277 residues of NPP1 and His329, Thr205, and Leu239 residues of NPP3. In addition, the most potent antiproliferative agent, compound 1h, doesn't produce hypoglycemia as a side effect when injected to mice. This is an additional merit of the promising compound 1h.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Piridinas/farmacologia , Pirofosfatases/antagonistas & inibidores , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Diester Fosfórico Hidrolases/metabolismo , Piridinas/síntese química , Piridinas/química , Pirofosfatases/metabolismo , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
13.
Int J Mol Sci ; 22(4)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671517

RESUMO

Recently, it has been suggested that progesterone affects the contractile activity of pregnant myometrium via nongenomic pathways; therefore, we aimed to clarify whether progesterone causes and/or inhibits pregnant myometrial contractions via nongenomic pathways. Our in vitro experiments using myometrial strips obtained from rats at 20 days of gestation revealed that progesterone caused myometrial contractions in a concentration- and time-dependent manner at concentrations up to 5 × 10-7 M; however, this effect decreased at concentrations higher than 5 × 10-5 M. Similarly, progesterone enhanced oxytocin-induced contractions up to 5 × 10-7 M and inhibited contractions at concentrations higher than 5 × 10-5 M. Conversely, progesterone did not enhance high-KCl-induced contractions but inhibited contractions in a concentration- and time-dependent manner at concentrations higher than 5 × 10-7 M. We also found that RU486 did not affect progesterone-induced contractions or the progesterone-induced inhibition of high-KCl-induced contractions; however, progesterone-induced contractions were blocked by calcium-free phosphate saline solution, verapamil, and nifedipine. In addition, FPL64176, an activator of L-type voltage-dependent calcium channels, enhanced high-KCl-induced contractions and rescued the decrease in high-KCl-induced contractions caused by progesterone. Together, these results suggest that progesterone exerts conflicting nongenomic effects on the contractions of pregnant myometrium via putative L-type voltage-dependent calcium channels.


Assuntos
Miométrio/fisiologia , Progesterona/fisiologia , Contração Uterina/fisiologia , Animais , Agonistas dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Feminino , Antagonistas de Hormônios/farmacologia , Mifepristona/farmacologia , Miométrio/efeitos dos fármacos , Nifedipino/farmacologia , Técnicas de Cultura de Órgãos , Ocitocina/farmacologia , Cloreto de Potássio/farmacologia , Gravidez , Progesterona/farmacologia , Pirróis/farmacologia , Ratos Wistar , Contração Uterina/efeitos dos fármacos , Verapamil/farmacologia
14.
Eur J Pharmacol ; 899: 174032, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33753107

RESUMO

Diabetic retinopathy is a serious complication of diabetes, marked by retinal vascular damage, inflammation, and angiogenesis. This study's objective was to assess the potential benefits of saroglitazar, a peroxisome proliferator-activated receptor-alpha/gamma (PPAR-α/γ) agonist in diabetic retinopathy. Diabetic retinopathy was induced by streptozotocin in Sprague Dawley rats. The effect of saroglitazar was also assessed in the oxygen-induced retinopathy model in newborn rats and VEGF-induced angiogenesis in the chick chorioallantoic membrane (CAM) assay. Treatment of saroglitazar (1 and 4 mg/kg, oral) for 12 weeks significantly ameliorated retinal vascular leakage and leukostasis in the diabetic rats. Saroglitazar decreased oxidative stress, VEGF receptor signalling, NF-κBp65, and ICAM-1 in the retina of diabetic rats. The beneficial effects of saroglitazar (1 and 4 mg/kg, oral) were also observed on the neovascularization in oxygen-induced retinopathy in newborn rats. Saroglitazar also reduced VEGF-induced angiogenesis in CAM assay. This study reveals that saroglitazar has the potential to prevent the progression of retinopathy in diabetic patients.


Assuntos
Inibidores da Angiogênese/farmacologia , Retinopatia Diabética/tratamento farmacológico , PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos/farmacologia , Pirróis/farmacologia , Retina/efeitos dos fármacos , Neovascularização Retiniana/tratamento farmacológico , Vasos Retinianos/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Embrião de Galinha , Diabetes Mellitus Experimental/induzido quimicamente , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Feminino , Hiperóxia/complicações , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Retina/metabolismo , Retina/patologia , Neovascularização Retiniana/etiologia , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Transdução de Sinais , Estreptozocina , Fator de Transcrição RelA/metabolismo
15.
ACS Chem Neurosci ; 12(7): 1228-1240, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33705101

RESUMO

Serotonin type 6 receptor (5-HT6R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1H-pyrrolo[3,2-c]quinoline scaffold to provide the 2-phenyl-1H-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT6R. This modification has changed the compound's activity at 5-HT6R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT6R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1H-pyrrole-3-carboxamide might be used as a template for designing 5-HT6R inverse agonists.


Assuntos
Pirróis , Receptores de Serotonina , Animais , Cognição , Pirróis/farmacologia , Ratos , Relação Estrutura-Atividade
16.
Viruses ; 13(2)2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670363

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a new human pathogen in late 2019 and it has infected over 100 million people in less than a year. There is a clear need for effective antiviral drugs to complement current preventive measures, including vaccines. In this study, we demonstrate that berberine and obatoclax, two broad-spectrum antiviral compounds, are effective against multiple isolates of SARS-CoV-2. Berberine, a plant-derived alkaloid, inhibited SARS-CoV-2 at low micromolar concentrations and obatoclax, which was originally developed as an anti-apoptotic protein antagonist, was effective at sub-micromolar concentrations. Time-of-addition studies indicated that berberine acts on the late stage of the viral life cycle. In agreement, berberine mildly affected viral RNA synthesis, but it strongly reduced infectious viral titers, leading to an increase in the particle-to-pfu ratio. In contrast, obatoclax acted at the early stage of the infection, which is in line with its activity to neutralize the acidic environment in endosomes. We assessed infection of primary human nasal epithelial cells that were cultured on an air-liquid interface and found that SARS-CoV-2 infection induced and repressed expression of specific sets of cytokines and chemokines. Moreover, both obatoclax and berberine inhibited SARS-CoV-2 replication in these primary target cells. We propose berberine and obatoclax as potential antiviral drugs against SARS-CoV-2 that could be considered for further efficacy testing.


Assuntos
Antivirais/farmacologia , Berberina/farmacologia , Indóis/farmacologia , Pirróis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Adolescente , Animais , COVID-19/virologia , Células Cultivadas , Chlorocebus aethiops , Células Epiteliais/virologia , Humanos , Masculino , RNA Viral/genética , SARS-CoV-2/fisiologia , Células Vero
17.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669786

RESUMO

We investigated the effects of esaxerenone, a novel, nonsteroidal, and selective mineralocorticoid receptor blocker, on cardiac function in Dahl salt-sensitive (DSS) rats. We provided 6-week-old DSS rats a high-salt diet (HSD, 8% NaCl). Following six weeks of HSD feeding (establishment of cardiac hypertrophy), we divided the animals into the following two groups: HSD or HSD + esaxerenone (0.001%, w/w). In survival study, all HSD-fed animals died by 24 weeks of age, whereas the esaxerenone-treated HSD-fed animals showed significantly improved survival. We used the same protocol with a separate set of animals to evaluate the cardiac function by echocardiography after four weeks of treatment. The results showed that HSD-fed animals developed cardiac dysfunction as evidenced by reduced stroke volume, ejection fraction, and cardiac output. Importantly, esaxerenone treatment decreased the worsening of cardiac dysfunction concomitant with a significantly reduced level of systolic blood pressure. In addition, treatment with esaxerenone in HSD-fed DSS rats caused a reduced level of cardiac remodeling as well as fibrosis. Furthermore, inflammation and oxidative stress were significantly reduced. These data indicate that esaxerenone has the potential to mitigate cardiac dysfunction in salt-induced myocardial injury in rats.


Assuntos
Cardiotônicos/uso terapêutico , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Pirróis/uso terapêutico , Receptores de Mineralocorticoides/metabolismo , Sulfonas/uso terapêutico , Animais , Cardiotônicos/farmacologia , Eletrocardiografia , Fibrose , Hipertensão/diagnóstico por imagem , Hipertensão/fisiopatologia , Inflamação/complicações , Inflamação/tratamento farmacológico , Masculino , Pirróis/farmacologia , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta , Sulfonas/farmacologia , Análise de Sobrevida , Remodelação Ventricular/efeitos dos fármacos
18.
Molecules ; 26(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33673017

RESUMO

Influenza A virus (IAV) encodes a polymerase composed of three subunits: PA, with endonuclease activity, PB1 with polymerase activity and PB2 with host RNA five-prime cap binding site. Their cooperation and stepwise activation include a process called cap-snatching, which is a crucial step in the IAV life cycle. Reproduction of IAV can be blocked by disrupting the interaction between the PB2 domain and the five-prime cap. An inhibitor of this interaction called pimodivir (VX-787) recently entered the third phase of clinical trial; however, several mutations in PB2 that cause resistance to pimodivir were observed. First major mutation, F404Y, causing resistance was identified during preclinical testing, next the mutation M431I was identified in patients during the second phase of clinical trials. The mutation H357N was identified during testing of IAV strains at Centers for Disease Control and Prevention. We set out to provide a structural and thermodynamic analysis of the interactions between cap-binding domain of PB2 wild-type and PB2 variants bearing these mutations and pimodivir. Here we present four crystal structures of PB2-WT, PB2-F404Y, PB2-M431I and PB2-H357N in complex with pimodivir. We have thermodynamically analysed all PB2 variants and proposed the effect of these mutations on thermodynamic parameters of these interactions and pimodivir resistance development. These data will contribute to understanding the effect of these missense mutations to the resistance development and help to design next generation inhibitors.


Assuntos
Farmacorresistência Viral/efeitos dos fármacos , Vírus da Influenza A/enzimologia , Subunidades Proteicas/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Virais/antagonistas & inibidores , Cristalografia por Raios X , Vírus da Influenza A/efeitos dos fármacos , Modelos Moleculares , Proteínas Mutantes/metabolismo , Mutação/genética , Domínios Proteicos , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Teoria Quântica , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/química , Termodinâmica , Proteínas Virais/química , Proteínas Virais/metabolismo
19.
BMC Cancer ; 21(1): 106, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33530952

RESUMO

BACKGROUND: Inhibition of nuclear import via Karyopherin beta 1 (Kpnß1) shows potential as an anti-cancer approach. This study investigated the use of nuclear import inhibitor, INI-43, in combination with cisplatin. METHODS: Cervical cancer cells were pre-treated with INI-43 before treatment with cisplatin, and MTT cell viability and apoptosis assays performed. Activity and localisation of p53 and NFκB was determined after co-treatment of cells. RESULTS: Pre-treatment of cervical cancer cells with INI-43 at sublethal concentrations enhanced cisplatin sensitivity, evident through decreased cell viability and enhanced apoptosis. Kpnß1 knock-down cells similarly displayed increased sensitivity to cisplatin. Combination index determination using the Chou-Talalay method revealed that INI-43 and cisplatin engaged in synergistic interactions. p53 was found to be involved in the cell death response to combination treatment as its inhibition abolished the enhanced cell death observed. INI-43 pre-treatment resulted in moderately stabilized p53 and induced p53 reporter activity, which translated to increased p21 and decreased Mcl-1 upon cisplatin combination treatment. Furthermore, cisplatin treatment led to nuclear import of NFκB, which was diminished upon pre-treatment with INI-43. NFκB reporter activity and expression of NFκB transcriptional targets, cyclin D1, c-Myc and XIAP, showed decreased levels after combination treatment compared to single cisplatin treatment and this associated with enhanced DNA damage. CONCLUSIONS: Taken together, this study shows that INI-43 pre-treatment significantly enhances cisplatin sensitivity in cervical cancer cells, mediated through stabilization of p53 and decreased nuclear import of NFκB. Hence this study suggests the possible synergistic use of nuclear import inhibition and cisplatin to treat cervical cancer.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Cisplatino/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Pirróis/farmacologia , Quinoxalinas/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , beta Carioferinas/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Cisplatino/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Pirróis/uso terapêutico , Quinoxalinas/uso terapêutico , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
20.
Eur J Med Chem ; 215: 113169, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33588178

RESUMO

The study focuses on the prudent design and synthesis of anilide type class I HDAC inhibitors employing a functionalized pyrrolo[2,3-d]pyrimidine skeleton as the surface recognition part. Utilization of the bicyclic aromatic ring to fabricate the target compounds was envisioned to confer rigidity to the chemical architecture of MS-275 and chidamide. In-vitro enzymatic and cellular assays led to the identification of compound 7 as a potent inhibitor of HDAC1 and 2 isoform that exerted substantial cell growth inhibitory effects against human breast MDA-MB-231, cervical HeLa, breast MDA-MB-468, colorectal DLD1, and colorectal HCT116 cell lines with an IC50 values of 0.05-0.47 µM, better than MS-275 and chidamide. In addition, the anilide 7 was also endowed with a superior antiproliferative profile than MS275 and chidamide towards the human cutaneous T cell lymphoma (HH and HuT78), leukemia (HL60 and KG-1), and HDACi sensitive/resistant gastric cell lines (YCC11 and YCC3/7). Exhaustive exploration of the construct 7 confirmed it to be a microtubule-targeting agent that could trigger the cell-cycle arrest in mitosis. In pursuit of extracting the benefits of evidenced microtubule-destabilizing activity of the anilide 7, it was further evaluated against non-small-cell lung cancer cell lines as well as the multiple-drug resistant uterine cancer cell line (MES-SA/Dx5) and overwhelmingly positive results in context of inhibitory effects were attained. Furthermore, molecular modelling studies were performed and some key interactions of the anilide 7 with the amino acid residues of the active site of HDAC1 isoform and tubulin were figured out.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Moduladores de Tubulina/farmacologia , Aminopiridinas/química , Anilidas/síntese química , Anilidas/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Benzamidas/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirróis/síntese química , Pirróis/metabolismo , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo
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