RESUMO
The cytotoxic activity of several serotonin transporter (SERT) inhibitors and subtype of serotonin receptor 1A (5-HT1A receptor) ligands have been examined in androgen-insensitive human PC-3 prostate and neuroblastoma SH-SY5Y cancer cells. Almost all of the studied compounds (except 5-HT1A receptor agonist (2R)-(+)-8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT)) exhibited absolute cytotoxic activity against the examined cancer cells. The compound 4-Fluoro-N-[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S14506) that showed highest activity against neuroblastoma tumors was the 5-HT1A receptor agonist (although not alike other 5-HT1A receptor agonists). On the other hand, the compound 6-nitro-2-(4-undecylpiperazin-1-yl)quinoline hydrochloride (AZ07) that had the highest activity against PC-3 prostate cancer cells was a compound exhibiting antagonistic activity against the 5-HT1A receptor. Thus, compounds of oncotoxic properties S14506 and AZ07 should be evaluated further for their potential use in the prevention and treatment of cancer. Most of the 15 compounds tested exhibited either agonistic or antagonistic activity for both the cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathways in human embryonic kidney 293 (HEK293) cells that overexpress the 5HT1AR gene. However, compounds paroxetine, N-Ac-paroxetine and 2-[4-(cyclobutylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride (AB22) simultaneously exhibited antagonistic activity on the cAMP pathway and agonistic activity on the ERK1/2 pathway. Fluoxetine relative to compound AZ07 had almost three times lower cytotoxic activity against PC-3 prostate cancer cells. However, the proapoptotic activity of fluoxetine compared to compound AZ07 is almost two times higher which would suggest that the cytotoxic activity of both compounds may be dependent on different cell death mechanisms. Compound S14506 was found to be an antagonist of the serine-threonine protein kinase B (Akt) pathway. Prosurvival Akt activity may be reversed by Akt antagonists. Therefore, the antagonistic activity of S14506 on the Akt pathway may evoke caspase-3 expression and cytotoxicity. It appears that one should not expect a straightforward relationship between the activation of particular serotonergic pathways by selective serotonin reuptake inhibitors (SSRIs) and 5-HT1A receptor ligands and their cytotoxic or cytoprotective activity. Additionally, nuclear transcription factor κB (NF-κB), which may be involved in 5-HT-dependent biochemical pathways by coordinating different subunits in the formation of a dimer, may regulate the transcription of different transduction pathways. Therefore, it can be suggested that the mechanism of the cytotoxic activity of certain compounds (serotonergic against nonserotonergic) may depend on the compound and cancer type being examined. Docking studies showed that S14506, buspirone and spiperone bind in similar ways in the 5-HT1A receptor model and interacted with similar 5-HT1A receptor residues. S14506 and spiperone were found to be located closer to both phenylalanines in TM6 than buspirone, thus exhibiting more antagonist binding modes.
Assuntos
Carcinogênese/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Células 3T3 , Animais , Linhagem Celular Tumoral , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Ligação Proteica , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/química , Antagonistas do Receptor 5-HT1 de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
In the present paper, we describe proapoptotic activity of several heterocyclic compounds 9, 12, 18, 19 and 20 possessing succinimide (as well as succinimide related) moieties. The compounds properties were examined with the aid of flow cytometry on the promyelocytic leukemia cell line HL-60. The highest proapoptotic activity exhibited compound 12 (4-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}-1,7-diethyl-8,9-diphenyl-4-azatricyklo[5.2.1.0(2,6)]-dec-8-ene-3,5,10-trione). The synthesis of compounds 1-17 is also described. The structures of obtained compounds were characterized by 1H NMR, 13C NMR, ESI MS and/or elemental analyses.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Succinimidas/farmacologia , Citometria de Fluxo , Células HL-60 , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The synthesis and pharmacological activity of N-substituted derivatives of 1,8,11,11-tetramethyl-4-azatricyclo[5.2.2.0(2,6)]undec-8-ene-3,5-dione (1) are described. The molecular structure of starting compound (1) was confirmed by elemental analysis, 13C NMR and X-ray crystallography. The structures of derivatives were confirmed by 1H NMR and mass spectra. The compounds were investigated for antibacterial activity, including Gram-positive cocci, Gram-negative rods, and antifungal activity. Studied compounds were evaluated also for their cytotoxicity and anti-HIV-1 activity in MT-4 cells.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Cristalografia por Raios X , HIV-1/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
In the search for novel biological agents, a series of new derivatives N-substituted 1,3-benzoxazol-2(3H)-one, 5-chloro-1,3-benzoxazol-2(3H)-one, 6-bromo-1,3-benzoxazol-2(3H)-one were prepared. All of the compounds were characterized by 1H NMR, 13C NMR and ESI MS spectra. Moreover, for compound 1 an Xray structure was determined. All derivatives were tested for antimicrobial activity against a selection of Gram-positive, Gram-negative bacteria and yeasts. The selected compounds (2-8, 10) were tested for their cytotoxic properties in K562, HeLa and normal cells.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Células HeLa , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Células K562 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Leveduras/efeitos dos fármacos , Leveduras/crescimento & desenvolvimentoRESUMO
The preparation of 16 derivatives of 3,5,8-trioxo-4-azatricyclo- [5.2.2.0(2.6)]undec-1-yl acetate and 8 derivatives of 1-isobutoxy-4-azatricyclo[5.2.2.0(2.6)]undecane-3,5,8-trione was described. Substituents to the imide N-atom were alkyl-(aryl)piperazine fragments with an alkyl linker being propyl or butyl group. Selected newly obtained compounds were evaluated in vitro against anti-HIV-1 activity. A broad group o fderivatives were tested for their antibacterial and antifungal activity. The pharmacological properties of butyl derivatives of imide 6 were evaluated in three behavioral tests in mice. The molecular structures of starting polycyclic 6-acetyl-imides, 1 and 5, were determined by X-ray crystallography. Presented tests have not revealed any activity of the compounds, however, selected derivatives exerted no neurotoxicity in behavioral tests.
Assuntos
Imidas/síntese química , Imidas/farmacologia , Compostos Policíclicos/síntese química , Compostos Policíclicos/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antifúngicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Indicadores e Reagentes , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Análise de Regressão , Relação Estrutura-AtividadeRESUMO
We found that amiodarone has potent antifungal activity against a broad range of fungi, potentially defining a new class of antimycotics. Investigations into its molecular mechanisms showed amiodarone mobilized intracellular Ca2+, which is thought to be an important antifungal characteristic of its fungicidal activity. Amiodarone is a synthetic drug based on the benzofuran ring system, which is contained in numerous compounds that are both synthetic and isolated from natural sources with antifungal activity. To define the structural components responsible for antifungal activity, we synthesized a series of benzofuran derivatives and tested them for the inhibition of growth of two pathogenic fungi, Cryptococcus neoformans and Aspergillus fumigatus, to find new compounds with antifungal activity. We found several derivatives that inhibited fungal growth, two of which had significant antifungal activity. We were surprised to find that calcium fluxes in cells treated with these derivatives did not correlate directly with their antifungal effects; however, the derivatives did augment the amiodarone-elicited calcium flux into the cytoplasm. We conclude that antifungal activity of these new compounds includes changes in cytoplasmic calcium concentration. Analyses of these benzofuran derivatives suggest that certain structural features are important for antifungal activity. Antifungal activity drastically increased on converting methyl 7-acetyl-6-hydroxy-3-methyl-2-benzofurancarboxylate (2b) into its dibromo derivative, methyl 7-acetyl-5-bromo-6-hydroxy-3-bromomethyl-2-benzofurancarboxylate (4).
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Benzofuranos/síntese química , Benzofuranos/farmacologia , Fungos/efeitos dos fármacos , Equorina , Amiodarona/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Cálcio/metabolismo , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/crescimento & desenvolvimento , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Desenho de Fármacos , Sinergismo Farmacológico , Fungos/crescimento & desenvolvimento , Fungos/metabolismo , Humanos , Indicadores e Reagentes , Células K562 , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-AtividadeRESUMO
Halogen and aminoalkyl derivatives of methyl 5-methoxy-2-methyl-1-benzofuran-3-carboxylate were prepared using 5-hydroxy-2-methyl-3-benzofuranocarboxylic acid as starting material. (1)H-NMR spectra were obtained for all of the synthesized structures, and for compounds 1 and 2 X-ray crystal structures were obtained too. All derivatives were tested for antimicrobial activity against a selection of Gram-positive cocci, Gram-negative rods and yeasts.
Assuntos
Anti-Infecciosos/síntese química , Benzofuranos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Relação Estrutura-Atividade , Difração de Raios XRESUMO
In the search for novel antimicrobial agents, a series of new derivatives - N-substituted imides were prepared. All of the compounds were characterized by 'H NMR and ESI MS spectra. These derivatives were tested for antimicrobial activity. Microorganisms used in this study included aerobic and facultative anaerobic bacteria such as Staphylococcus aureus, Escherichia coli, Stenotrophomonas maltophilia, and obligatory anaerobes such as Bacteroides fragilis, Bacteroides thetaiotaomicron and Propionibacterium acnes. Moreover, Candida albicans yeast was used. For representatives of all species the MICs of the investigated compounds were determined. Most of investigated derivatives had no antimicrobial activity (MIC > 512 mg/L) except the derivative 22 which showed slight activity against Gram-positive aerobes and anaerobes.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Imidas/síntese química , Imidas/farmacologia , Bactérias/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Testes de Sensibilidade MicrobianaRESUMO
Halogen derivatives of selected 3-benzofurancarboxylic acids were prepared using 6-acetyl-5-hydroxy-2-methyl-3-benzofuranocarboxylic acid as starting material. (1)H-NMR spectra were obtained for all of the synthesized structures, and for compound VI, an X-ray crystal structure was also obtained. All derivatives were tested for antimicrobial activity against a selection of Gram-positive cocci, Gram-negative rods and yeasts. Three compounds, III, IV, and VI, showed antimicrobial activity against Gram-positive bacteria (MIC 50 to 200 microg/mL). Compounds VI and III exhibited antifungal activity against the Candida strains C. albicans and C. parapsilosis (MIC-100 microg/mL).
Assuntos
Anti-Infecciosos/síntese química , Benzofuranos/farmacologia , Ácidos Carboxílicos/farmacologia , Anti-Infecciosos/farmacologia , Benzofuranos/química , Ácidos Carboxílicos/química , Fungos/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Halogenação , Testes de Sensibilidade MicrobianaRESUMO
A series of twenty arylpiperazine derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione have been prepared. These derivatives were tested in vitro with the aim of identifying novel lead compounds active against emergent and re-emergent human and cattle infectious diseases (AIDS, hepatitis B and C, tuberculosis, bovine viral diarrhea). In particular, these compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA(+) viruses Yellow fever virus (YFV) and Bovine viral diarrhea virus (BVDV), both belonging to the Flaviridae. Compounds 2c, 2g and 3d showed a modest activity against CVB-2. The molecular structures of the starting imide 1 and one of propyl-piperazine derivatives, 3b, have been determined by an X-ray crystallography study.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Animais , Linhagem Celular , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura MolecularRESUMO
A new quaternary ammonium compound, bis-[2-hydroxy-3-(1,7,8,9,10-pentamethyl-3,5-dioxo-4-aza-tricyclo[5.2.1.0(2,6)]dec-8-en-4-yloxy)-propyl]-dimethyl-ammonium chloride (4), was synthesized. The compound was investigated for antibacterial activity, including Gram-positive cocci and Gram-negative rods, and antifungal activity. Compound 4 showed significant inhibition against Staphylococcus aureus. Research was carried out over 4 standard strains and 40 hospital strains. Elementary analysis and/or MS, (1)H NMR and (13)C NMR spectra confirmed the identity of the products. The molecular structure of 3 was determined by an X-ray analysis.
Assuntos
Cloreto de Amônio/síntese química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Cloreto de Amônio/química , Cloreto de Amônio/farmacologia , Antibacterianos/química , Meios de Cultura , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura MolecularRESUMO
A series of twenty six arylpiperazine and aminoalkanol derivatives of 4-azatricyclo[5.2.2.0(2,6)]undecane-3,5,8-trione have been prepared. The synthesized compounds were evaluated for their cytotoxicity and anti-HIV-1 activity in MT-4 cells.
Assuntos
Álcoois/farmacologia , Fármacos Anti-HIV/química , Piperazinas/farmacologia , Álcoois/química , Alcanos/química , Alcanos/farmacologia , Fármacos Anti-HIV/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Piperazinas/química , Relação Estrutura-AtividadeRESUMO
Antibacterial and antifungal activity of 2,4-dihydro- [1,2,4]triazol-3-one derivatives were examined by the disc-diffusion method (growth inhibition zone diameter in agar medium). The MIC's for the most active agents were determined. Of all the tested compounds, aminomethyl derivatives of 2,4-dihydro-[1,2,4]triazol-3-one exhibit activity against the majority of microorganisms studied.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Triazóis/farmacologia , Leveduras/efeitos dos fármacos , Antibacterianos/química , Antifúngicos/química , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Triazóis/químicaRESUMO
This paper reports the synthesis of a number of aminoalkyl derivatives of 8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.0(2,6)]undec-8-en-1-yl acetate and 1,11 -dimethyl-4-azatricyclo [5.2.2.0(2,6)]undecan-3,5,8-tri-one. Fourteen compounds were prepared and the in vitro cytotoxic activities were evaluated against human cancer cell lines originating from solid tumors in the National Cancer Institute, Bethesda, MD, USA.
Assuntos
Antineoplásicos/síntese química , Compostos Aza/síntese química , Alcanos/síntese química , Alcanos/farmacologia , Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-AtividadeRESUMO
A series of aminoalkanol derivatives of 4-hydroxy-1,7,8,9,10-pentamethyl-4-aza-tricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione have been prepared. The pharmacological profile of selected compounds was evaluated for their affinities at beta-adrenoreceptors.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Amino Álcoois/farmacologia , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/síntese química , Amino Álcoois/síntese química , Animais , Sítios de Ligação , Córtex Cerebral/metabolismo , Técnicas In Vitro , Masculino , Ensaio Radioligante , Ratos , Ratos WistarRESUMO
A series of aminoalkanol derivatives of 8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.0(2,6)] undec-8-en-1-yl acetate and 1,11-dimethyl-4-azatricyclo[5.2.2.0(2,6)]undecane-3,5,8-trione was prepared. The pharmacological profile of selected compounds was evaluated for affinity to beta-adrenoreceptors and serotoninergic receptors (5HT1A and 5HT2A).
Assuntos
Amino Álcoois/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Adrenérgicos beta/metabolismo , Amino Álcoois/síntese química , Animais , Sítios de Ligação , Córtex Cerebral/metabolismo , Técnicas In Vitro , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeAssuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HeLa , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Concentração Inibidora 50 , Células K562 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The preparation of a number of cyclic imide 5-HT(1A) receptor ligand derivatives has been described. Their structures were conformationally constrained by introducing rigid linkers containing unsaturated bonds or aromatic benzene rings. These compounds are expected to possess anxiolytic and antidepressant activity.
Assuntos
Imidas/química , Imidas/síntese química , Piperazinas/química , Piperazinas/síntese química , Receptor 5-HT1A de Serotonina/química , Ligantes , Conformação MolecularRESUMO
A series of aminoalkanol derivatives of 10-(diphenylmethylene)-4-azatricyclo[5.2.1.0(2.6)]dec-8-ene-3,5-dione and 4-hydroxy-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione have been prepared. The pharmacological profile of selected compounds was evaluated for their affinities at beta-adrenoceptors. The investigated compounds exhibit modest affinity for these receptors.
Assuntos
Antagonistas Adrenérgicos beta/síntese química , Compostos Heterocíclicos de Anel em Ponte/síntese química , Antagonistas Adrenérgicos beta/metabolismo , Animais , Desenho de Fármacos , Óxido de Etileno/síntese química , Masculino , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/metabolismoRESUMO
A series of 13 new ether-linked derivatives of 2,2-dimethyl-2.3-dihydro-7-benzofuranol have been designed and synthesized. Seven of them were evaluated for anti-HIV potency. They showed a relatively high cytotoxicity and a low anti-HIV- I activity.