RESUMO
The lack of selective inhibitors toward the long, short, or supershort phosphodiesterases (PDE4s) prevented researchers from carefully defining the connection between different enzyme isoforms, their brain localization, and their role in neurodegenerative diseases such as Alzheimer's disease (AD). In the search for new therapeutic agents for treating memory and learning disorders, we synthesized new rolipram related PDE4 inhibitors, which had some selectivity toward the long form PDE4D3. The first series was synthesized as racemate and then resolved by semipreparative HPLC on chiral supports. Herein we report the synthetic pathways to obtain compounds 1a-c, 2a-c, 3a-c, 4a-f, 5a,b, 6a,b, 7a,b, the chiral analytical study to resolve compounds 1a-c, 2a-c, 3a-c, the molecular docking study for compound 1c, and the biological results and some SAR considerations that provide some insights and hints for the structural requirements for PDE4D subtype selectivity and enzyme inhibition.
Assuntos
Benzaldeídos/síntese química , Ciclopentanos/síntese química , Inibidores da Fosfodiesterase 4 , Rolipram/análogos & derivados , Rolipram/síntese química , Benzaldeídos/química , Sítios de Ligação , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Ciclopentanos/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Modelos Moleculares , Conformação Molecular , Morfolinas/síntese química , Morfolinas/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Rolipram/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In this paper we report the synthesis and the chemotaxis inhibitory activity of a number of 1H-pyrazole-4-carboxylic acid ethyl esters 2 functionalized in N1 with a methyl group or different hydroxyalkyl chains and in position 5 with a series of 3-substituted urea groups. These compounds were designed as development of previous pyrazole-urea derivatives that resulted potent IL8-induced neutrophil chemotaxis inhibitors in vitro. Most of the new compounds revealed a potent inhibition of both IL8- and fMLP-OMe-stimulated neutrophil chemotaxis. The most active compounds in the fMLP-OMe induced chemotaxis test showed IC(50) in the range 0.19 nM-2 microM; but we observed a very strong inhibition in the IL8-induced chemotaxis test, having the most active compounds IC(50) at pM concentrations. In vivo compounds 2e and 2f, although to a lesser extent, at 50mg/kg os decreased granulocyte infiltration in zymosan-induced peritonitis in mice.
Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Animais , Desenho de Fármacos , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Humanos , Concentração Inibidora 50 , Interleucina-8/antagonistas & inibidores , Interleucina-8/farmacologia , Masculino , Camundongos , Estrutura Molecular , N-Formilmetionina Leucil-Fenilalanina/análogos & derivados , N-Formilmetionina Leucil-Fenilalanina/antagonistas & inibidores , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/citologia , Ligação Proteica , Pirazóis/síntese química , Relação Estrutura-AtividadeRESUMO
The synthesis of new 4-amino substituted pyrazolo[3,4-d]pyrimidines along with their activity in cell-free enzymatic assays on Src and Abl tyrosine kinases is reported. Some compounds emerged as good dual inhibitors of the two enzymes, showed antiproliferative effects on two Bcr-Abl positive leukemia cell lines K-562 and KU-812, and induced apoptosis, as demonstrated by the PARP assay. Docking studies have been also performed to analyze the binding mode of compounds under study and to identify the structural determinants of their interaction with both Src and Abl.
Assuntos
Simulação por Computador , Modelos Químicos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Proteína Tirosina Quinase CSK , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/química , Proteínas Recombinantes/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Quinases da Família srcRESUMO
Sixty-eight new substituted pyrazolo[3,4-b]pyridine derivatives were synthesized and tested for enriching a library of active A(1) adenosine receptor (AR) antagonists belonging to the same class. These compounds were also used as an external test set to check the reliability of a 3D QSAR model recently reported by us. To investigate the binding mode of pyrazolopyridine derivatives, a model of the bovine A(1)AR (bA(1)AR) was developed by a novel homology modeling approach and used to evaluate the main interactions of the ligands with the receptor through docking studies. Results suggest important interactions of the ligands mainly with L3.33(88), T3.36(91), Q3.37(92) and H6.52(251), in agreement with mutagenesis data. The racemic mixture of the most active compound was separated into the corresponding enantiomers which showed a bA(1)AR affinity in the nanomolar range, with the R enantiomer sevenfold more active than the S enantiomer, according to results derived from calculations on the receptor model. Analysis of the bovine/human A(1)AR affinity profile of ligands supported the hypothesis that such receptors should be characterized by a different size of their binding site, responsible for the different affinity of the antagonists.
Assuntos
Antagonistas do Receptor A1 de Adenosina , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Receptor A1 de Adenosina/química , Antagonistas do Receptor A3 de Adenosina , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Bovinos , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação de Hidrogênio , Ligantes , Modelos Biológicos , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Piridinas/química , Receptor A3 de Adenosina/química , Reprodutibilidade dos Testes , Estereoisomerismo , Fatores de TempoRESUMO
Results from molecular docking calculations and Grid mapping laid the foundations for a structure-based optimization approach to improve the biological properties of pyrazolo-pyrimidine derivatives in terms of inhibition of Abl enzymatic activity and antiproliferative properties toward human leukemia cells. Insertion of halogen substituents with various substitution patterns, suggested by simulations, led to a significant improvement of leukemia cell growth inhibition and to an increase up to 1 order of magnitude of the affinity toward Abl.
Assuntos
Antineoplásicos/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/síntese química , Pirimidinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Fusão bcr-abl , Humanos , Leucemia , Modelos Moleculares , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
New pyrazolo[3,4-d]pyrimidines were synthesized and found to inhibit Src phosphorylation in a cell-free assay. Some of them significantly reduced the growth of human osteogenic sarcoma (SaOS-2) cells. The best compound, in terms of inhibitory properties toward both Src and SaOS-2 cells, was further investigated and found to reduce bone resorption when used to treat mouse osteoclasts, without interfering with normal osteoblast growth. Moreover, its metabolic stability prompted its study on a human SaOS-2 xenograft tumor model in nude mice, where the compound reduced significantly both the volume and weight of the tumor. These experimental findings make the new compound an interesting hit in the field of bone-related diseases.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Pirazóis/síntese química , Pirimidinas/síntese química , Animais , Neoplasias Ósseas/patologia , Reabsorção Óssea/prevenção & controle , Linhagem Celular Tumoral , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteossarcoma/patologia , Fosforilação , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Transplante Heterólogo , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismoRESUMO
Neutrophils chemotaxis is a complex multistep process that, if upregulated, causes acute inflammation and a number of autoimmune diseases. We report here the synthesis of a new N-(4-substituted)pyrazolyl-N'-alkyl/benzyl/phenylureas that are potent inhibitors of interleukin-8 (IL8)-induced neutrophil chemotaxis. The first series of compounds, obtained by functionalization with a urea moiety of the 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3, blocked the IL8-induced neutrophil chemotaxis, while they did not block N-formylmethionylleucylphenylalanine-mediated chemotaxis. The most active compounds, 3-benzyl- (4d), 3-(4-benzylpiperazinyl)- (4i), 3-phenyl- (4k) and 3-isopropylureido (4a) derivatives, showed an IC50 of 10, 14, 45, and 55 nM, respectively. Several different molecules were then synthesized to obtain more information for SAR study. Compounds 4a, 4d, and 4k were inactive in the binding assays on CXCR1 and CXCR2 (IL8 receptors), whereas they inhibited the phosphorylation of PTKs (protein tyrosine kinases) in the 50-70 kDa region. Moreover, in the presence of the same derivatives, we observed a complete block of F-actin rise and pseudopod formation.
Assuntos
Anti-Inflamatórios/síntese química , Quimiotaxia de Leucócito , Interleucina-8/farmacologia , Neutrófilos/efeitos dos fármacos , Compostos de Fenilureia/síntese química , Pirazóis/síntese química , Actinas/antagonistas & inibidores , Adulto , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Humanos , Masculino , Camundongos , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/fisiologia , Cavidade Peritoneal/citologia , Peritonite/patologia , Peritonite/prevenção & controle , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pseudópodes/efeitos dos fármacos , Pseudópodes/fisiologia , Pirazóis/química , Pirazóis/farmacologia , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismo , Relação Estrutura-AtividadeRESUMO
It is well known that both acute and chronic autoimmune inflammatory disorders arise following a breakdown in control of neutrophil activation and recruitment. In the search for new anti-inflammatory agents, we synthesized some new 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives and tested them in vitro in order to evaluate their ability to interfere with human neutrophil functions. All tested compounds showed strong inhibition of fMLP-OMe-induced chemotaxis, although they appeared unable to block degranulation and the fMLP-OMe-induced respiratory burst, and were inactive in binding experiments.
Assuntos
Química Farmacêutica/métodos , Quimiotaxia/efeitos dos fármacos , N-Formilmetionina Leucil-Fenilalanina/antagonistas & inibidores , N-Formilmetionina Leucil-Fenilalanina/química , Neutrófilos/efeitos dos fármacos , Pirazóis/química , Anti-Inflamatórios/farmacologia , Ligação Competitiva , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Neutrófilos/metabolismo , Ligação Proteica , Transdução de SinaisRESUMO
We report here the synthesis of new pyrazolo[3,4-d]pyrimidine derivatives along with their biological properties as inhibitors of isolated Src and cell line proliferation (A431 and 8701-BC cells). Such compounds block the growth of cancer cells by interfering with the phosphorylation of Src, and they act as proapoptotic agents through the inhibition of the anti apoptotic gene BCL2. Several of them were found to be more active than the reference compound (1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d]pyrimidine, PP2) in inhibiting cell proliferation and in inducing apoptosis, and as active as PP2 in the inhibition of the phosphorylation of isolated Src. Moreover, molecular modeling simulations have been performed to hypothesize the way, at the molecular level, by which the inhibitors were able to act as antiproliferative agents.
Assuntos
Antineoplásicos/síntese química , Apoptose , Pirazóis/síntese química , Pirimidinas/síntese química , Quinases da Família src/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ciclinas/antagonistas & inibidores , Ciclinas/biossíntese , Ciclinas/genética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , RNA Mensageiro/biossínteseRESUMO
Atherothrombotic coronary artery disease, associated with deep vein thrombosis, is one of the most common causes of death worldwide. Recently, antiplatelet combination therapy using agents with different mechanisms of action, such as aspirin, dipyridamole, and thienopyridines, seems to be an attractive preventive approach. Moreover, several large, randomized clinical trials support combination therapy with aspirin plus warfarin in high-risk patients with atherosclerotic heart disease. Our research on the benzopyrano[4,3-d]pyrimidine system gave rise to the synthesis of a large number of compounds endowed with in vitro anti-aggregating activity. Several SAR considerations suggest that the benzopyranopyrimidine system is an appropriate scaffold to obtain molecules that are able to act simultaneously in different pathways of aggregation. Now, we report the synthesis of new 2-substituted benzopyrano[4,3-d]pyrimidin-4-cycloamines and 4-amino/cycloamino-benzopyrano[4,3-d]pyrimidin-5-ones and the results of the pharmacological study on haemostasis. Some tested compounds showed a large-spectrum antiplatelet activity in vitro, and are more potent than aspirin as antithrombotics in vivo but, at variance with aspirin, they do not increase bleeding. This paper describes novel antithrombotic compounds with an interesting pharmacological profile and a potentially attractive benefit/risk ratio, with their mechanism of action generally, but not exclusively, dependent on antiplatelet activity, deserving further investigations.
Assuntos
Antitrombinas/síntese química , Antitrombinas/farmacologia , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Antitrombinas/química , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Estrutura Molecular , Inibidores da Agregação Plaquetária/química , Pirimidinas/química , Coelhos , Ratos , Espectrofotometria InfravermelhoRESUMO
In this paper, we are presenting a quantitative-structure-activity relationship (QSAR) study performed on 21 selective A(1) adenosine receptor agonists plus the endogenous substrate, adenosine, so as to identify those predictors which play a key role in describing the binding of the ligand with the A(1) receptor. A large number of molecular descriptors plus a calculated receptor-agonist binding energy and atomic charges were taken into account to derive different QSAR models, using different regression techniques. The results obtained both with linear and nonlinear approaches converge to the selection of the same informative parameters, highlighting the correlation of these descriptors with the biological Response. The evaluation 'a priori' of these predictors could therefore represent a useful tool in the screening of large libraries of compounds and in the rational design of new selective agonists.
Assuntos
Agonistas do Receptor A1 de Adenosina , Adenosina/farmacologia , Relação Quantitativa Estrutura-Atividade , Adenosina/análogos & derivados , Ligantes , Modelos Estatísticos , Análise de Componente Principal , Ligação ProteicaRESUMO
Two series of N-[5-oxo-4-(arylsulfonyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl]-amides were synthesized and tested in vivo for their analgesic and anti-inflammatory activities. All the new compounds possess good antalgic action in the acetic acid writhing test and some terms of the series showed also fair anti-inflammatory activity in the carrageenan rat paw edema test. Ulcerogenic and irritative action on the gastrointestinal mucose, in comparison with indomethacin is low.
Assuntos
Analgésicos/química , Analgésicos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Tiadiazóis/química , Tiadiazóis/farmacologia , Amidas/síntese química , Amidas/química , Analgésicos/síntese química , Animais , Anti-Inflamatórios/síntese química , Avaliação Pré-Clínica de Medicamentos , Feminino , Indometacina/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Masculino , Camundongos , Ratos , Úlcera Gástrica/complicações , Tiadiazóis/síntese químicaRESUMO
A number of 4-aminopyrazolo[3,4-b]pyridines 5-carboxylic acid esters (2-8) were synthesized and evaluated for their binding affinity at the A1, A2A, and A3 adenosine receptors (AR), in bovine cortical membranes, as well as for their affinity toward human A1AR (hA1AR). Some of the new compounds were characterized by a high affinity and selectivity toward the A1 receptor subtype, showing a significant improvement in comparison with other pyrazolo-pyridines previously reported in the literature. In particular the methyl ester 2h as well as the isopropyl ester 5h, both of them bearing a p-methoxyphenylethylamino side chain at the position 4, presented Ki values of 6 and 7 nM, respectively. To rationalize the relationships between structure and affinity of the novel compounds, a 3D QSAR model was also generated starting from compounds belonging to different classes of known A1AR antagonists.
Assuntos
Antagonistas do Receptor A1 de Adenosina , Pirazóis/síntese química , Piridinas/síntese química , Relação Quantitativa Estrutura-Atividade , Receptor A1 de Adenosina/química , Animais , Bovinos , Córtex Cerebral/metabolismo , Humanos , Técnicas In Vitro , Modelos Moleculares , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Ensaio Radioligante , Receptor A1 de Adenosina/metabolismo , Receptor A3 de Adenosina/metabolismo , Receptores A2 de Adenosina/metabolismoRESUMO
A series of ethyl 4-amino-1-(2-chloro-2-phenylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylates () has been synthesized as potential A(1) adenosine receptor (A(1) AR) ligands. Binding affinities of the new compounds were determined for adenosine A(1), A(2A) and A(3) receptors. Compounds and showed good affinity (K(i)= 299 nM and 517 nM, respectively) and selectivity towards A(1) AR, whereas showed good affinity for A(2A) AR (K(i)= 290 nM), higher than towards A(1) AR (K(i)= 1000 nM). The only arylamino derivative of the series displayed high affinity (K(i)= 4.6 nM) and selectivity for A(3) AR. Molecular modelling and 3D-QSAR (CoMFA) studies carried out on the most active compounds gave further support to the pharmacological results.
Assuntos
Antagonistas de Receptores Purinérgicos P1 , Pirazóis/farmacologia , Piridinas/farmacologia , Modelos Moleculares , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Relação Quantitativa Estrutura-AtividadeRESUMO
In this paper we describe our structure-based ligand design, synthetic strategy, and structure-activity relationship (SAR) studies that led to the identification of thiocarbamates (TCs), a novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), isosteres of phenethylthiazolylthiourea (PETT) derivatives. Assuming as a lead compound O-[2-(phthalimido)ethyl]phenylthiocarbamate 12, one of the precursors of the previously described acylthiocarbamates (Ranise, A.; et al. J. Med. Chem. 2003, 46, 768-781), two targeted solution-phase TC libraries were prepared by parallel synthesis. The lead optimization strategy led to para-substituted TCs 31, 33, 34, 39, 40, 41, 44, 45, and 50, which were active against wild-type HIV-1 in MT-4-based assays at nanomolar concentrations (EC50 range: 0.04-0.01 microM). The most potent congener 50 (EC50 = 0.01 microM) bears a methyl group at position 4 of the phthalimide moiety and a nitro group at the para position of the N-phenyl ring. Most of the TCs showed good selectivity indices, since no cytotoxic effect was detected at concentrations as high as 100 microM. TCs 31, 37, 39, 40, and 44 significantly reduced the multiplication of the Y181C mutant, but they were inactive against K103R and K103N + Y181C mutants. Nevertheless, the fold increase in resistance of 41 was not greater than that of efavirenz against the K103R mutant in enzyme assays. The docking model predictions were consistent with in vitro biological assays of the anti-HIV-1 activity of the TCs and related compounds synthesized.
Assuntos
Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/metabolismo , Feniltiazoliltioureia/análogos & derivados , Feniltiazoliltioureia/síntese química , Inibidores da Transcriptase Reversa/síntese química , Tiocarbamatos/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Técnicas de Química Combinatória , Farmacorresistência Viral , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Modelos Moleculares , Mutação , Feniltiazoliltioureia/química , Feniltiazoliltioureia/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Tiocarbamatos/química , Tiocarbamatos/farmacologiaRESUMO
Synthesis and biological evaluation of a new class of 1-aryl-4-amino-1H-pyrazolo[3,4-d]pyrimidine derivatives are reported. A preliminary cellular assay system using the tumor cell line A431 responding to epidermal growth factor (EGF) for its growth, shows that the new compounds are potent inhibitors of cell growth. The inhibition of tumor cell proliferation is not associated with blockage of EGF receptor (EGFR), but substantially due to the interference with the signalling pathway at the level of Src tyrosine kinase and at the level of the downstream effector signal mitogen activated protein kinases (MAPKs), ERK1-2.
Assuntos
Antineoplásicos/síntese química , Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Pirimidinas/síntese química , Antineoplásicos/farmacologia , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/antagonistas & inibidores , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Pirazóis/síntese química , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Quinases da Família src/metabolismoRESUMO
During the course of our studies in the azole antifungals area, we synthesized a number of 1,5-disubstituted 4-[1H-imidazol-1-yl(phenyl)methyl]-1H-pyrazoles, analogues of bifonazole. 1,5-Diphenyl-1H-pyrazole 3 showed weak antimycotic and antibacterial activities in vitro against Candida albicans, Cryptococcus neoformans and Staphylococcus aureus. In order to increase these properties, given that the halo substitution was found to be capable of enhancing antifungal effects, we prepared a series of fluoro and chloro derivatives of 3. The microbiological evaluation carried out on newly synthesized compounds included in vitro assays for antifungal, antibacterial and antimycobacterial activities. Among the tested compounds, some dichloro and trichloro-derivatives showed interesting antimicrobial properties. In particular, compounds 10j,k,l produced inhibitory effects against pathogen representatives of yeast (C. albicans, C. neoformans) and Gram positive bacteria (S. aureus) similar or superior to those of bifonazole. In addition, their activity against Mycobacterium tuberculosis was superior to that of clotrimazole and econazole, which were used as reference drugs. The replacement, in these compounds, of chlorine with fluorine atoms led to inactive derivatives. Docking studies were carried out on the most active compounds, in order to rationalize the pharmacological results.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Imidazóis/química , Pirazóis/síntese química , Pirazóis/farmacologia , Antibacterianos/química , Antifúngicos/química , Sítios de Ligação , Humanos , Hidrocarbonetos Halogenados/química , Imidazóis/síntese química , Imidazóis/farmacologia , Modelos Moleculares , Pirazóis/químicaRESUMO
Novel 1,4,6-trisubstituted pyrazolo[3,4-d]pyrimidines are reported with preliminary in vitro activity data indicating that several of them are potent inhibitors (better than the reference compound) of Src phosphorylation of the breast cancer cells 8701-BC, known to overexpress Src. The ability of such compounds to significantly reduce 8701-BC cell proliferation suggests that this scaffold could be a promising lead for the development of antitumoral agents able to block Src phosphorylation of breast cancer cells.
Assuntos
Antineoplásicos/síntese química , Pirazóis/síntese química , Pirimidinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Immunoblotting , Fosforilação , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Quinases da Família src/metabolismoRESUMO
A new series of 4-amino-6-methylthio-1H-pyrazolo[3,4-d]pyrimidines (2a-m) bearing the 2-chloro-2-phenylethyl chain at the N1 position, has been synthesized. The affinity of these compounds for A1 adenosine receptor (A1AR) was measured. The compounds showed poor affinity. A more interesting result was obtained by 2a, 2d, 2g, which demonstrated inhibitory activity on cell proliferation of the A-431 cell line stimulated by epithelial growth factor (EGF) and on EGF receptor tyrosine kinase (EGFR-TK) phosphorylation.
Assuntos
Pirimidinas/síntese química , Pirimidinas/farmacologia , Antagonistas do Receptor A1 de Adenosina , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Fator de Crescimento Epidérmico/antagonistas & inibidores , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/antagonistas & inibidores , Humanos , Estrutura Molecular , Fosforilação , Receptor A1 de Adenosina/metabolismoRESUMO
In several non-infectious human diseases, such as ulcerous colitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), the extravasal recruitment of neutrophils plays a crucial role in the development of tissue damage, which, when persistent, can lead to the irreversible organ dysfunction. The neutrophil activation is controlled by a number of intracellular pathways, particularly by a cAMP-dependent protein kinase A (PKA) which also acts on phosphodiesterase IV (PDE4) gene stimulating the synthesis of this enzyme, able to transform cAMP to inactive AMP. PDE4 inhibitors enhance intracellular cAMP and decrease inflammatory cell activation. Several 3-cyclopentyloxy-4-methoxybenzaldehyde and 3-cyclopentyloxy-4-methoxybenzoic acid derivatives were synthesized and studied by us to evaluate their ability to inhibit the superoxide anion production in human neutrophils. These compounds were found able to inhibit the neutrophil activation and some of them increased the cAMP level on tumor necrosis factor-alpha-stimulated neutrophils. Moreover, they also inhibited selectively the human PDE4 enzyme, although they are less potent than the reference compound Rolipram. We report here synthesis, biological studies and some SAR considerations concerning the above mentioned compounds.