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1.
J Agric Food Chem ; 67(45): 12538-12546, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31638796

RESUMO

Cyanobacteria harmful algal blooms are of global concern, but all currently available algicides in the market are nonselective and have potential side effects on nontarget species. In the present work, two series of compounds (4 and 6) comprising 16 novel 1,2,3-triazole aminopyrimidines were rationally designed and synthesized as control agent for cyanobacteria. Our design focus was the inhibiting cyanobacteria by inhibition against pyruvate dehydrogenase complex E1 (PDHc-E1). Compounds 4 and 6 showed potent inhibition against Escherichia coli PDHc-E1 (IC50 = 4.13-23.76 µM) and also strong algicidal activities against Synechocystis sp. PCC 6803 (EC50 = 1.7-8.1 µM) and Microcystis sp. FACHB905 (EC50 = 2.1-11.8 µM). In particular, the algicidal activities of 6d against four algal species were not only higher than that of prometryn; they were also comparable to or higher than that of copper sulfate. The analogues 4c, 4d, 6d, and 6e displayed potent algicidal activities and inhibition of E. coli PDHc-E1 but exhibited negligible inhibition of porcine PDHc-E1. As revealed by molecular docking, site-directed mutagenesis, enzymatic assays, and an inhibition kinetic analysis, 4c and 6d inhibited PDHc-E1 in a competitive manner. Our results suggest that highly selective, effective algicides can be developed by rationally designing competitive PDHc-E1 inhibitors.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Microcystis/efeitos dos fármacos , Pirimidinas/farmacologia , Piruvato Desidrogenase (Lipoamida)/antagonistas & inibidores , Synechocystis/efeitos dos fármacos , Triazóis/farmacologia , Proteínas de Bactérias/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Herbicidas/síntese química , Herbicidas/química , Cinética , Microcystis/química , Microcystis/enzimologia , Simulação de Acoplamento Molecular , Pirimidinas/química , Piruvato Desidrogenase (Lipoamida)/química , Relação Estrutura-Atividade , Synechocystis/química , Synechocystis/enzimologia , Triazóis/química
2.
J Agric Food Chem ; 67(40): 11018-11024, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31512873

RESUMO

In this study, nine pyrimethanil ionic liquids (PILs) were synthesized through an acid-base reaction with nine naturally derived organic acid anions to improve the physicochemical properties and reduce the environmental adverse impacts. The PILs presented lower volatilization, higher photostability, better soil adsorption capacity, and improved fungicidal activity relative to pyrimethanil. When the length of the carbon chains in the anions was increased, the PILs showed better properties in terms of melting point, water solubility, volatility, and surface tension. The photostabilities and fungicidal activities of the PILs were significantly improved when cyclic compounds were used as the paired anion ions. With enhanced physicochemical properties and better fungicidal activity, PIL7 was selected as the best alternative to pyrimethanil. The intrinsic disadvantages of pyrimethanil could be surmounted using the system developed in the study; thus, ILs could have immense potential in the development of eco-friendly and efficient fungicides in the future.


Assuntos
Fungicidas Industriais/química , Líquidos Iônicos/química , Compostos Orgânicos/química , Pirimidinas/química , Adsorção , Ânions/química , Ânions/farmacologia , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Líquidos Iônicos/farmacologia , Cinética , Compostos Orgânicos/farmacologia , Pirimidinas/farmacologia , Solo/química , Solubilidade , Volatilização
3.
Ultrason Sonochem ; 59: 104737, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473427

RESUMO

A convenient strategy for synthesis of the various derivatives of 1,4-dihydropyridine (1,4-DHP), as one of the most important pharmaceutical compounds, is presented in this study. For this purpose, firstly, magnetic iron oxide nanoparticles (Fe3O4 NPs) were fabricated and suitably coated by silica network (SiO2) and trimethoxy vinylsilane (TMVS). Then, their surfaces were well functionalized with pyrimidine-2,4-diamine (PDA) as the main active sites for catalyzing the synthesis reactions. In this regard, the performance of three different methods including reflux, microwave (MW) and ultrasound wave (USW) irradiations have been comparatively monitored via studying various analyses on the fabricated nanocatalyst (Fe3O4/SiO2-PDA). Concisely, high efficiency of the USW irradiation (in an ultrasound cleaning bath with a frequency of 50 kHz and power of 250 W/L) has been well proven through the investigation of the main factors such as excellent surface-functionalization, core/shell structure conservation, particle uniformity, close size distribution of the particles, and great inhibition of the particle aggregation. Then, the effectiveness of the USW irradiation as a promising co-catalyst agent has been clearly demonstrated in the 1,4-DHP synthesis reactions. It has been concluded that the USW could provide more appropriate conditions for activation of the catalytic sites of Fe3O4/SiO2-PDA NPs. However, high reaction yields (89%) have been obtained in the short reaction times (10 min) due to the substantial synergistic effect between the presented nanocatalyst and USW.


Assuntos
Di-Hidropiridinas/química , Di-Hidropiridinas/síntese química , Nanopartículas de Magnetita/química , Pirimidinas/química , Ondas Ultrassônicas , Catálise , Técnicas de Química Sintética , Dióxido de Silício/química
4.
Phys Chem Chem Phys ; 21(38): 21305-21316, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31549692

RESUMO

4-Thiopyrimidine (e.g., 4-thiouracil (4-TU) and 4-thiothymine (4-TT)) is a typical kind of thiobase. With the sulfur substitution at the C4 position of the canonical pyrimidine nucleobase, 4-thiopyrimidine displays unique photophysical and photochemical properties such as red-shifted maximum absorption peaks and efficient triplet state populations. One of the properties is the photocrosslinking reaction between 4-thiopyrimidine and pyrimidine base, which plays important roles in photochemotherapy and photolabeling applications. By using density functional theory (M06-2X), we have explored the potential energy profiles of the photocrosslinking reaction between 4-thiopyrimidine (4-TU and 4-TT) and thymine in the S0 and T1 states as well as the interaction between the two states. For both (6-4) and (5-4) photocrosslinking reactions, multiple nonadiabatic pathways via minimum energy crossing points (MECPs) between potential surfaces (PESs) of the T1 and S0 states greatly facilitate the proceeding of photocrosslinking reactions and lead to the relatively stable thietane intermediate in the S0 state. The subsequent H migration in the thietane intermediate takes place solely in the S0 state with surmountable energy barriers in bulk solution, resulting in the formation of the photocrosslinked product. This research provides not only a new mechanistic insight into the photocrosslinking reaction for 4-thiopyrimidines but also a rational explanation for the experiments of UVA irradiated Tp4ST dinucleotide and 4-thiothymidine-containing oligonucleotides, facilitating the deep understanding of the synergistic cytotoxicity of 4-thiopyrimidines and UVA as well as the development of alternative phototherapeutic agents and photolabeling probes.


Assuntos
Reagentes para Ligações Cruzadas/química , Pirimidinas/química , Timina/química , Simulação por Computador , Teoria da Densidade Funcional , Luz , Estrutura Molecular , Processos Fotoquímicos , Termodinâmica
5.
Bull Environ Contam Toxicol ; 103(3): 484-489, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31399772

RESUMO

Burning of wheat and rice straw on field, after crop harvest, is a quick, cheap and an easy way for land clearing. The ashes generated after burning are mixed with soils and due to their alkaline nature, they may affect the degradation of applied herbicides. Therefore, present paper reports degradation of sulfosulfuron in aqueous suspension of the wheat (WSA) and rice (RSA) straw ashes. The results suggested that both ashes significantly enhanced sulfosulfuron dissipation in water and effect was more with the RSA. The solution pH affected sulfosulfuron dissipation and in control buffers (no ash) herbicide degradation followed the order: acidic > alkaline > neutral. Addition of the RSA significantly increased sulfosulfuron degradation in buffers, but effect was more evident at neutral and alkaline pH. The study has relevance in assessing degradation of sulfosulfuron in soils where crop residues are burned for land clearing.


Assuntos
Recuperação e Remediação Ambiental/métodos , Oryza/química , Pirimidinas/química , Poluentes do Solo/química , Sulfonamidas/química , Triticum/química , Herbicidas/química , Concentração de Íons de Hidrogênio , Suspensões
6.
Eur J Med Chem ; 181: 111590, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408808

RESUMO

Hybridization strategy is an effective strategy to obtain multi-target inhibitors in drug design. In this study, we assembled the pharmacophores of momelotinib and tandutinib to get a series of 4-piperazinyl-2-aminopyrimidine derivatives. All compounds were tested for the inhibition of JAK2 and FLT3 enzymes, of which, compounds with potent enzyme activities were assayed for antiproliferative activities against three cancer cell lines (HEL, MV4-11, and HL60). The structure-activity relationship studies were conducted through variations in two regions, the "A" phenyl ring and "B" phenyl ring. Compound 14j showed the most balanced in vitro inhibitory activity against JAK2 and FLT3 (JAK2 IC50 = 27 nM, FLT3 IC50 = 30 nM), and it also showed potent inhibition against the above tested cell lines. In the cellular context, 14j strongly induced apoptosis by arresting cell cycle in the G1/S phase, and was selected as a promising JAK2/FLT3 dual inhibitor.


Assuntos
Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Humanos , Janus Quinase 2/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Piperazinas/química , Piperazinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/metabolismo
7.
Eur J Med Chem ; 182: 111603, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421633

RESUMO

Conformational restriction is a promising strategy in the development of DAPY-type non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, eighteen thiophene-biphenyl-DAPY derivatives were designed and synthesized as potent HIV-1 NNRTIs in which halogen and methyl groups were introduced to explore the conformationally constrained effects. Molecular docking and dynamic simulation analysis indicated that substituents on different positions of the biphenyl ring induced different dihedral angles and binding conformations, further explaining their anti-viral activities. The 2'-fluoro and 3'-chloro substitutions could form electrostatic or halogen-bonding interactions with adjacent residues of the RT enzyme. The 2'-methyl group contributed to enlarge the dihedral angle of biphenyl ring and was positioned to a space-filling hydrophobic pocket. Notably, compounds 22 and 23 with two methyl groups exhibited potent biological activity against WT HIV-1-infected MT-4 cells (EC50 = 14 and 17 nM, respectively) and RT enzyme (EC50 = 27 and 42 nM, respectively). In particular, 23 exhibited much lower cytotoxicity (CC50 = 264.19 µM) and higher selectivity index (SI = 18,564) than etravirine. Taken together, a rational conformational model for further design of DAPYs is proposed, providing a new guidance for the development of NNRTIs.


Assuntos
Fármacos Anti-HIV/farmacologia , Compostos de Bifenilo/farmacologia , Desenho de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Compostos de Bifenilo/química , Linhagem Celular , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Tiofenos/química
8.
Eur J Med Chem ; 182: 111571, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425908

RESUMO

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/síntese química , Crizotinibe/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Radioisótopos de Flúor , Humanos , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Cintilografia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Distribuição Tecidual
9.
Eur J Med Chem ; 182: 111610, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31434040

RESUMO

Drug therapy for Chagas disease remains a major challenge as potential candidate drugs have failed clinical trials. Currently available drugs have limited efficacy and induce serious side effects. Thus, the discovery of new drugs is urgently needed in the fight against Chagas' disease. Here, we synthesized and evaluated the biological effect of pyrazole-imidazoline (1a-i) and pyrazole-tetrahydropyrimidine (2a-i) derivatives against relevant clinical forms of Trypanosoma cruzi. The structure-activity relationship (SAR), drug-target search, physicochemical and ADMET properties of the major active compounds in vitro were also assessed in silico. Pyrazole derivatives showed no toxicity in Vero cells and also no cardiotoxicity. Phenotypic screening revealed two dichlorinated pyrazole-imidazoline derivatives (1c and 1d) with trypanocidal activity higher than that of benznidazole (Bz) against trypomastigotes; these were also the most potent compounds against intracellular amastigotes. Replacement of imidazoline with tetrahydropyrimidine in the pyrazole compounds completely abolished the trypanocidal activity of series 2(a-i) derivatives. The physicochemical and ADMET properties of the compounds predicted good permeability, good oral bioavailability, no toxicity and mutagenicity of 1c and 1d. Pyrazole nucleus had high frequency hits for cruzipain in drug-target search and structure activity relationship (SAR) analysis of pyrazole-imidazoline derivatives revealed enhanced activity when chlorine atom was inserted in meta-positions of the benzene ring. Additionally, we found evidence that both compounds (1c and 1d) have the potential to interact non-covalently with the active site of cruzipain and also inhibit the cysteine proteinase activity of T. cruzi. Collectively, the data presented here reveal pyrazole derivatives with promise for further optimization in the therapy of Chagas disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Imidazolinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Células Cultivadas , Cercopithecus aethiops , Relação Dose-Resposta a Droga , Humanos , Imidazolinas/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Pirazóis/química , Pirimidinas/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Células Vero
10.
Eur J Med Chem ; 179: 707-722, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284081

RESUMO

In the present study, we report the discovery of a novel class of substituted 4-amino-2-thiopyrimidines as antiangiogenic and antiproliferative agents. Structural hybridization between 4-substituted aminopyrimidines (VEGFR-2 inhibitors) and 2-thioxopyrimidines (BRAF inhibitors) was carried out to afford substituted 4-amino-2-thiopyrimidines as type II dual VEGFR-2/BRAF inhibitors. Our design strategy was tailored such that the 4-amino-2-thiopyrimidine scaffold is to be accommodated in the central gate area of the inactive DFG-out conformation of both enzymes. On one side, the hydrophobic substituent on the 4-amino group would occupy the hydrophobic back pocket and on the other side the substituent on the sulfide moiety should extend to fit in the hinge region (front pocket). Molecular docking simulations confirmed the ability of the designed compounds to accomplish the key interactions in VEGFR-2 and BRAF active sites. Most of the synthesized substituted 4-amino-2-thiopyrimidines demonstrated potent VEGFR-2 inhibitory activity at submicromolar concentrations. Compounds 8a, 8d, 9c and 9e showed IC50 = 0.17, 0.12, 0.17 and 0.19 µM, respectively against VEGFR-2 in comparison to sorafenib (I) IC50 = 0.10 µM and regorafenib (II) IC50 = 0.005 µM. While compounds 9c, 9d and 10a showed IC50 = 0.15, 0.22 and 0.11 µM, respectively against BRAF-WT. At 10 µM concentration 9c revealed promising in vitro broad-spectrum antiproliferative activity against cancer cell lines with growth inhibition percent ranging from 10 to 90%. Moreover, compounds 7b, 8d, 9a, 9b, 9c and 9d showed potent activity against MCF7 cell line (IC50 = 17.18, 17.20, 19.98, 19.61, 13.02 and 16.54 µM, respectively). On the other hand, compounds 9c, 9d and 10d were found to be the most potent compounds against T-47D cell line (IC50 = 2.18, 8.09 and 4.36 µM, respectively). Studying the effect of the most potent compounds on VEGFR-2 level in MCF7 cell line revealed that 9c and 9d showed inhibition percent of 84 and 80%, respectively, in comparison to sorafenib (I) (% inhibition = 90%).


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirimidinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
Eur J Med Chem ; 179: 744-752, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284084

RESUMO

The endosomal Toll-like receptor 8 (TLR8) recognizes single-stranded RNA and initiates early inflammatory responses. Despite the importance of endosomal TLRs for human host defense against microbial pathogens, extensive activation may contribute to autoimmune and inflammatory diseases. In contrast to the recent progress made in the development of modulators of plasma membrane-bound TLRs, little is known about endosomal TLR modulation and very few TLR8 inhibitors have been reported. In this study, we discovered and validated novel small-molecule TLR8 inhibitors. Fourteen potential TLR8 modulators were experimentally validated in HEK293T cells stably overexpressing human TLR8 and THP-1 macrophages. Five compounds inhibited TLR8-mediated signaling, representing a hit rate of 36%. The three most potent compounds neither cause cellular toxicity nor inhibition of TLR signaling induced by other receptor subtypes. Conclusively, we experimentally confirm novel and selective, pyrimidine-based TLR8 inhibitors with low cytotoxicity that are relevant candidates for lead optimization and further mechanistic studies.


Assuntos
Pirimidinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Receptor 8 Toll-Like/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Pirimidinas/química , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Células THP-1 , Receptor 8 Toll-Like/metabolismo
12.
J Agric Food Chem ; 67(33): 9220-9231, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31347838

RESUMO

Slow-release fungicide formulations (azoxystrobin, epoxiconazole, and tebuconazole) shaped as pellets and granules in a matrix of biodegradable poly(3-hydroxybutyrate) and natural fillers (clay, wood flour, and peat) were constructed. Infrared spectroscopy showed no formation of chemical bonds between components in the experimental formulations. The formulations of pesticides had antifungal activity against Fusarium verticillioides in vitro. A study of biodegradation of the experimental fungicide formulations in the soil showed that the degradation process was mainly influenced by the type of formulation without significant influence of the type of filler. More active destruction of the granules led to a more rapid accumulation of fungicides in the soil. The content of fungicides present in the soil as a result of degradation of the formulations and fungicide release was determined by their solubility. Thus, all formulations are able to function in the soil for a long time, ensuring gradual and sustained delivery of fungicides.


Assuntos
Argila/química , Preparações de Ação Retardada/química , Composição de Medicamentos/métodos , Fungicidas Industriais/química , Hidroxibutiratos/química , Poliésteres/química , Solo/química , Madeira/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Composição de Medicamentos/instrumentação , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Fungicidas Industriais/farmacologia , Fusarium/efeitos dos fármacos , Cinética , Pirimidinas/química , Pirimidinas/farmacologia , Estrobilurinas/química , Estrobilurinas/farmacologia , Triazóis/química , Triazóis/farmacologia
13.
Chem Biodivers ; 16(8): e1900232, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31287621

RESUMO

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in both vasculogenesis and angiogenesis. Inhibition of VEGFR-2 has been demonstrated as a key method against tumor-associated angiogenesis. Thiazolopyrimidine is an important analog of the purine ring, and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity. In HUVEC inhibition assay, compounds 3l (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(3,4-dimethylphenyl)urea) and 3m (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(4-methoxyphenyl)urea) exhibited the most potent inhibitory effect (IC50 =1.65 and 3.52 µm, respectively). Compound 3l also showed the best potency against VEGFR-2 at 50 µm (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors.


Assuntos
Inibidores da Angiogênese/síntese química , Desenho de Drogas , Pirimidinas/química , Tiazóis/química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Eur J Med Chem ; 177: 221-234, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151057

RESUMO

Alzheimer's disease (AD) is a multifactorial neurological disorder involving complex pathogenesis. Single target directed drugs proved ineffective and since last few years' different pharmacological strategies including multi-targeting agents are being explored for the effective drug development for AD. A total of 19 dipropargyl substituted diphenylpyrimidines have been synthesized and evaluated for the monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibition potential. All the compounds were found to be selective and reversible inhibitors of MAO-B isoform. These compounds also displayed good AChE inhibition potential with IC50 values in low micromolar range. AVB4 was found to be the most potent MAO-B inhibitor with IC50 value of 1.49 ±â€¯0.09 µM and AVB1 was found to be the most potent AChE inhibitor with IC50 value of 1.35 ±â€¯0.03 µM. In the ROS protection inhibition studies, AVB1 and AVB4 displayed weak but interesting activity in SH-SY5Y cells. In the cytotoxicity studies involving SH-SY5Y cells, both AVB1 and AVB4 were found to be non-toxic to the tissue cells. In the molecular dynamic simulation studies of 30 ns, the potent compounds were found to be quite stable in the active site of MAO-B and AChE. The results suggested that AVB1 and AVB4 are promising dual inhibitors and have the potential to be developed as anti-Alzheimer's drug.


Assuntos
Alquinos/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Pirimidinas/farmacologia , Acetilcolinesterase/química , Alquinos/síntese química , Alquinos/química , Alquinos/toxicidade , Doença de Alzheimer/tratamento farmacológico , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Desenho de Drogas , Humanos , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/toxicidade , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/toxicidade , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 178: 329-340, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200235

RESUMO

A novel series of 6-substituted pyrrolo[2,3-d]pyrimidines with reversed amide moieties from the lead compound 1a were designed and synthesized as nonclassical antifolates and as potential antitumor agents. Target compounds 1-9 were successfully obtained through two sequential condensation reactions from the key intermediate 2-amino-6-(2-aminoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one. In preliminary antiproliferation assay, all compounds demonstrated submicromolar to nanomolar inhibitory effects against KB tumor cells, whereas compounds 1-3 also exhibited nanomolar antiproliferative activities toward SW620 and A549 cells. In particular, compounds 1-3 were significantly more potent than the positive control methotrexate (MTX) and pemetrexed (PMX) to A549 cells. The growth inhibition induced cell cycle arrest at G1-phase with S-phase suppression. Along with the results of nucleoside protection assays, inhibition assays of dihydrofolate reductase (DHFR) clearly elucidated that the intracellular target of the designed compounds was DHFR. Molecular modeling studies suggested two binding modes of the target compounds with DHFR.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Antagonistas do Ácido Fólico/farmacologia , Ácido Fólico/metabolismo , Pirimidinas/farmacologia , Pirróis/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Humanos , Células KB , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
16.
Molecules ; 24(12)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234400

RESUMO

A new series of thiazolo[3,2-a]pyrimidine bromide salt derivatives 7a-d were synthesized from 3,4-dihydropyrimidinethione precursors. The target compounds were fully characterized by 1D- and 2D-NMR, high resolution ESI-MS/MS and single crystal X-ray diffraction analysis, which confirmed a regioselective 5H cyclization of the dihydropyrimidinethiones. All target compounds were evaluated in vitro as human acetylcholinesterase (hAChE) inhibitors via an Ellman-based colorimetric assay and showed good inhibition activities (better than 70% at 10 µM and IC50 values in the 1 µM range). Molecular docking simulations for all target products into hAChE were performed and confirmed strong binding to the enzyme. These results provide a promising and new starting point to improve acetylcholinesterase inhibitors and explore novel treatment options against Alzheimer's disease.


Assuntos
Acetilcolinesterase/química , Inibidores da Colinesterase/síntese química , Pirimidinas/síntese química , Acetilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/química , Cristalografia por Raios X , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/química , Espectrometria de Massas em Tandem
17.
AAPS PharmSciTech ; 20(6): 239, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243640

RESUMO

Polymeric films are safe and effective and can be used for vaginal administration of microbicide drug candidates. Dapivirine (DPV), an investigational and clinically advanced antiretroviral drug, was selected as a model compound for this study. We have previously developed and clinically tested a quick-dissolving DPV film using solvent cast (SC) manufacturing technique. As an alternative to current pharmaceutical film manufacturing techniques, we investigated hot melt extrusion (HME) process in this study because it has several benefits, including its capacity as a continuous manufacturing process, lack of solvents, smaller footprint, and ease of scalability. The goal of this work was to evaluate the feasibility of using HME for DPV vaginal film manufacturing and to develop a robust manufacturing process using HME by evaluating the effect of process parameters on film quality and performance. DPV was successfully incorporated into a vaginal film using HME and maintained acceptable characteristics. Three process parameters (zone temperature, screw speed, and feed rate) had an impact on film quality and performance. Of these, the zone temperature was found to most significantly affect weight, thickness, puncture strength, and dissolution of films. Additionally, film manufacturing using HME was highly reproducible. Finally, the DPV HME film was comparable to films manufactured using SC in terms of physicochemical, biological, and safety characteristics including in vitro drug release, mechanical strength, tissue permeability, compatibility with commensal vaginal Lactobacilli, and in vitro bioactivity. These results demonstrate that HME is an effective, robust, and viable manufacturing method to produce vaginal films.


Assuntos
Preparações Farmacêuticas/química , Pirimidinas/química , Inibidores da Transcriptase Reversa/química , Tecnologia Farmacêutica/métodos , Administração Intravaginal , Liberação Controlada de Fármacos , Feminino , Congelamento , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Temperatura Alta , Humanos , Testes de Sensibilidade Microbiana , Polímeros/química , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacologia
18.
Eur J Med Chem ; 177: 32-46, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129452

RESUMO

A series of 2,4-diarylaminopyrimidine derivatives containing dithiocarbamate moiety were designed by molecular hybridization strategy and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most of these compounds exhibit significant antiproliferative activities on human cancer cell lines expressing high levels of FAK at nanomolar concentrations. The compound 14z was identified as the most potent FAK inhibitor among these candidates. 14z has excellent anti-proliferative effect with IC50 values from 0.001 µM to 0.06 µM on HCT116, PC-3, U87-MG and MCF-7 cell lines and relatively less cytotoxicity to a nonmalignant cell line MCF-10A compared with MCF-7 cells (SI value > 10). 14z also exhibits significant FAK inhibitory activity (IC50 = 0.07 nM). In addition, compound 14z causes cell cycle arrest at G2/M and prompted apoptosis in both HCT116 and MCF-7 cells in a dose-dependent manner. Further studies show that compound 14z inhibits migration of MCF-7 and has anti-angiogenesis effect on HUVEC cells.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tiocarbamatos/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/toxicidade , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/química , Tiocarbamatos/toxicidade
19.
Artigo em Inglês | MEDLINE | ID: mdl-31135268

RESUMO

Cancer diseases are widely recognised as an important medical problem and killing millions of people in a year. Chemotherapeutic drugs are successful against cancer in many cases and different compounds, including the analogues of natural substances, may be used for anticancer agents. Nucleoside analogues also have become a necessity for the treatment of cancer diseases. Nucleoside, nucleotide and base analogues have been utilised for decades for the treatment of viral pathogens, neoplasms and in anticancer chemotherapy. This review focuses on the different types of nucleosides and their potential role as anticancer agents. It also discusses the nucleoside analogues approved by FDA and in process of approval. The effect of the substitution on the nucleoside analogues and their pharmacological role is also discussed in the review. Owing to the advances in computational chemistry, it concludes with the future advancement and possible outcome of the nucleoside analogues. Also, it depicts the development of heterocyclic nucleoside analogues, explores the QSAR of the synthesised compounds and discusses the 3 D QSAR pharmacophore modelling in order to examine their potential anti-cancer activities.


Assuntos
Antineoplásicos/farmacologia , Nucleosídeos/farmacologia , Purinas/química , Pirimidinas/química , Antineoplásicos/química , Dioxolanos/química , Aprovação de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Nucleosídeos/química , Relação Quantitativa Estrutura-Atividade , Estados Unidos , United States Food and Drug Administration
20.
J Environ Sci Health B ; 54(7): 590-597, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31046583

RESUMO

Azoxystrobin (methyl(2E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy] phenyl}-3-methoxyacrylate) is an active ingredient used to protect crops against fungal diseases. The experience of the Polish control laboratory indicates relatively frequent cases of counterfeit plant protection products (PPPs) containing this active substance. The present study aimed to use chemometric methods to model chemical fingerprints obtained by different chromatographic techniques to verify the original formulation of PPPs containing the active substance azoxystrobin. The pesticides used in the study came from different sources (including stores and warehouses), were manufactured at a different time and came from different production batches. The results obtained with the HPLC-DAD and HS-GC-MS techniques were then modeled using principal component analysis (PCA) and soft independent modeling by class analogy (SIMCA) classifier. The proposed approach has been confirmed as useful for verifying the authenticity of PPPs and can be used in the routine control testing of SC pesticides containing azoxystrobin.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fungicidas Industriais/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Pirimidinas/química , Estrobilurinas/química , Cromatografia Líquida de Alta Pressão/estatística & dados numéricos , Fungicidas Industriais/análise , Cromatografia Gasosa-Espectrometria de Massas/estatística & dados numéricos , Análise de Componente Principal , Pirimidinas/análise , Controle de Qualidade , Estrobilurinas/análise
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