RESUMO
A new series of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was designed and synthesized using readily available starting materials, specifically, ß-enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC50 = 19.4 ± 0.22 and 14.5 ± 0.30 µM, respectively) compared with doxorubicin (IC50 = 40.0 ± 3.9 µM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research.
Assuntos
Antineoplásicos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Linhagem Celular Tumoral , Desenho de FármacosRESUMO
A novel series of pyrido[2,3-d]pyrimidines; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines were synthesized via different chemical transformations starting from pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylcarbamimidic chloride 3b (prepared from the reaction of o-aminonitrile 1b and phosogen iminiumchloride). The structures of the newly synthesized compounds were elucidated based on spectroscopic data and elemental analyses. Designated compounds are subjected for molecular docking by using Auto Dock Vina software in order to evaluate the antiviral potency for the synthesized compounds against SARS-CoV-2 (2019-nCoV) main protease M pro. The antiviral activity against SARS-CoV-2 showed that tested compounds 7c, 7d, and 7e had the most promising antiviral activity with lower IC50 values compared to Lopinavir, "the commonly used protease inhibitor". Both in silico and in vitro results are in agreement.
Assuntos
Antivirais , Pirimidinas , SARS-CoV-2 , Antivirais/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Pirimidinas/química , SARS-CoV-2/efeitos dos fármacosRESUMO
Alzheimer's disease (AD) is a chronic dysfunction of neurons in the brain leading to dementia. It is characterized by gradual mental failure, abnormal cognitive functioning, personality changes, diminished verbal fluency, and speech impairment. It is caused by neuronal injury in the cerebral cortex and hippocampal area of the brain. The number of individuals with AD is growing at a quick rate. The pathology behind AD is the progress of intraneuronal fibrillary tangles, accumulation of amyloid plaque, loss of cholinergic neurons, and decrease in choline acetyltransferase. Unfortunately, AD cannot be cured, but its progression can be delayed. Various FDA-approved inhibitors of cholinesterase enzyme such as rivastigmine, galantamine, donepezil, and NDMA receptor inhibitors (memantine), are available to manage the symptoms of AD. An exhaustive literature survey was carried out using SciFinder's reports from Alzheimer's Association, PubMed, and Clinical Trials.org. The literature was explored thoroughly to obtain information on the various available strategies to prevent AD. In the context of the present scenario, several strategies are being tried including the clinical trials for the treatment of AD. We have discussed pathophysiology, various targets, FDA-approved drugs, and various drugs in clinical trials against AD. The goal of this study is to shed light on current developments and treatment options, utilizing phytopharmaceuticals, nanomedicines, nutraceuticals, and gene therapy.
Assuntos
Doença de Alzheimer , Plantas Medicinais , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Humanos , Indanos/farmacologia , Nanotecnologia , Piperidinas/farmacologia , RivastigminaRESUMO
In the current study, new thienopyrimidine conjugates bearing 1,2,3-triazole core and different sugar moieties have been designed and synthesized by Cu(I)-catalysed click dipolar cycloaddition. The cytotoxic activity of the synthesised conjugates 2, 5, 7, and 13-18 was studied against HCT-116 and MCF-7 cell lines by the MTT assay. The triazole glycosides 16 and 18 provided significant cytotoxic activities against HCT-116 cell lines comparable to that of doxorubicin and other studied compounds. The cytotoxic behaviour against MCF-7 exhibited that all the investigated compounds were more potent than doxorubicin. Moreover, all screened targets were evaluated against mutant EGFR kinase type L858R and the results revealed that the acetylated 1,2,3-triazole glycosides 13-18 exhibited excellent EGFR inhibitory activity in comparison with gefitinib. Furthermore, molecular modelling studies were performed to investigate the binding affinity of the most active compounds to EGFR enzyme.
Assuntos
Antineoplásicos/farmacologia , Glicosídeos/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Química Click , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Glicosídeos/química , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Relação Estrutura-Atividade , Triazóis/química , Células Tumorais CultivadasRESUMO
New thienyl- or chlorophenyl-substituted thiazolopyrimidine derivatives and their derived sugar hydrazones incorporating acyclic d-galactosyl or d-xylosyl sugar moieties in addition to their per-O-acetylated derivatives were synthesized. Heterocyclization of the formed sugar hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the cyclization process. The cytotoxic activity of the synthesized compounds was studied against human breast cancer MCF7 and MDA-MB-231 cell lines as well as human colorectal cancer HCT 116 and Caco-2 cell lines. High activities were revealed by compounds 1, 8, 10, 11, and 13 against Caco-2 and MCF7 cells in addition to moderate activities exhibited by other compounds against HCT116 or MDA-MB-231 cells.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Estrutura Molecular , Nucleosídeos/análogos & derivadosRESUMO
The reaction of compounds 1, 2, 3, 4, or 13 with 2-chloroethyl methyl ether or 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide, afforded some acyclic and cyclic nucleosides of thieno[2,3-d]pyrimidine derivatives. Furthermore, cyclic C-nucleosides 24 and 25 were prepared from the reaction of 20, 21 or from 26, 27 with D-glucose. The antimicrobial evaluation of some prepared products showed promising antimicrobial activity.
Assuntos
Anti-Infecciosos/síntese química , Nucleosídeos/síntese química , Pirimidinas/síntese química , Anti-Infecciosos/farmacologia , Bactérias/crescimento & desenvolvimento , Candida albicans/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Nucleosídeos/farmacologia , Pirimidinas/farmacologiaRESUMO
In this study, 2-N-arylimino-2,3-dihydro-1,3,4-thiadiazoles derivatives (6a-h) were synthetized. The mechanism of the studied reactions was discussed. The chemical structures of the compounds were elucidated by their IR, 1H-NMR, 13C-NMR, and Mass spectral data and elemental analyses. The compounds were tested for antimicrobial activity using diffusion agar technique.