Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Viruses ; 12(1)2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31968537

RESUMO

Orthohantaviruses, previously known as hantaviruses (family Hantaviridae, order Bunyavirales), are emerging zoonoses hosted by different rodent and insectivore species. Orthohantaviruses are transmitted by aerosolized excreta (urine, saliva and feces) of their reservoir hosts. When transmitted to humans, they cause hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe and hantavirus (cardio) pulmonary syndrome (HPS) in the Americas. Clinical studies have shown that early treatments of HFRS patients with ribavirin (RBV) improve prognosis. Nevertheless, there is the need for urgent development of specific antiviral drugs. In the search for new RNA virus inhibitors, we recently identified a series of variously substituted 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazole derivatives active against the human respiratory syncytial virus (HRSV). Interestingly, several 2-phenyl-benzotriazoles resulted in fairly potent inhibitors of the Hantaan virus in a chemiluminescence focus reduction assay (C-FRA) showing an EC50 = 4-5 µM, ten-fold more active than ribavirin. Currently, there are no FDA approved drugs for the treatment of orthohantavirus infections. Antiviral activities and cytotoxicity profiles suggest that 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazoles could be promising candidates for further investigation as a potential treatment of hantaviral diseases.


Assuntos
Antivirais/farmacologia , Orthohantavírus/efeitos dos fármacos , Triazóis/química , Triazóis/farmacologia , Animais , Antivirais/química , Chlorocebus aethiops , Descoberta de Drogas , Células Vero
2.
Bioorg Med Chem ; 22(17): 4893-909, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25082514

RESUMO

A library of eighty-six assorted benzimidazole derivatives was screened for antiviral activity against a panel of ten RNA and DNA viruses. Fifty-two of them displayed different levels of activity against one or more viruses, among which CVB-5, RSV, BVDV and Sb-1 were the most frequently affected. In particular, fourteen compounds exhibited an EC50 in the range 9-17µM (SI from 6 to >11) versus CVB-5, and seven compounds showed an EC50 in the range 5-15µM (SI from 6.7 to ⩾20) against RSV, thus resulting comparable to or more potent than the respective reference drugs (NM108 and ribavirin). Most of these compounds derive from 2-benzylbenzimidazole, but also other molecular scaffolds [as 1-phenylbenzimidazole (2), 2-trifluoromethylbenzimidazole (69), dihydropyrido[3',2':4,5]imidazo[1,2-a][1,4]benzodiazepin-5-one (3), dibenzo[c,e]benzimidazo[1,2-a]azepine (22), and 2-(tetrahydropyran-2-yl)benzimidazole (81, 82 and 86)] are related to interesting levels of activity against these or other viruses (BVDV, Sb-1). Thus, these scaffolds (some of which, so far unexplored), represent valid starting points to develop more efficient agents against pathologies caused by CVB-5, RSV, BVDV and Sb-1 viruses.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Enterovirus/efeitos dos fármacos , Poliovirus/efeitos dos fármacos , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/química , Benzimidazóis/síntese química , Benzimidazóis/química , Bovinos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cricetinae , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Células Vero , Replicação Viral/efeitos dos fármacos
3.
Bioorg Med Chem ; 21(21): 6328-36, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24063907

RESUMO

Pyrimidopyrimidine derivatives 1 were prepared as rigid thioanalogues of merbarone (a catalytic topoisomerase II inhibitor) and screened as antiproliferative agents against different tumor cell lines. A number of the synthesized compounds emerged as cytotoxic in cell-based assays (MT-4, HeLa and MCF-7 cells) at low micromolar concentrations. In a National Cancer Institute screening, selected member of the series showed a broad spectrum of antiproliferative activity against various tumours (melanoma, renal, CNS, colon and breast cancers). The acid-base and steric properties of the substituent at position 7 of the pyrimidopyrimidine scaffold deeply affected potency. Enzymatic assays evidenced that a subset of tested derivatives efficiently inhibit topoisomerase IIα accordingly to merbarone mechanism of action. However this property does not fully rationalize the cytotoxicity data of the full ligand panel, suggesting that different target(s) should be additionally involved.


Assuntos
Antineoplásicos/química , Compostos Bicíclicos com Pontes/química , Tiobarbitúricos/química , Inibidores da Topoisomerase II/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células MCF-7 , Pirimidinas/síntese química , Pirimidinas/toxicidade , Relação Estrutura-Atividade , Tiobarbitúricos/síntese química , Tiobarbitúricos/toxicidade , Tionas/síntese química , Tionas/toxicidade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/toxicidade
4.
Eur J Med Chem ; 55: 205-13, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22884523

RESUMO

A series of new thiourea derivatives of 1,2,4-triazole have been synthesized. The difference in structures of obtained compounds are directly connected with the kind of isothiocyanate (aryl/alkyl). The (1)H NMR, (13)C NMR, MS methods were used to confirm structures of obtained thiourea derivatives. The molecular structure of (1, 17) was determined by an X-ray analysis. Two of the new compounds (8 and 14) were tested for their pharmacological activity on animal central nervous system (CNS) in behavioural animal tests. The results presented in this work indicate the possible involvement of the serotonergic system in the activity of 8 and 14. In the case of 14 is also a possible link between its activity and the endogenous opioid system. All obtained compounds were tested for antibacterial activity against gram-positive cocci, gram-negative rods and antifungal activity. Compounds (1, 2, 5, 7, 9) showed significant inhibition against gram-positive cocci. Microbiological evaluation was carried out over 20 standard strains and 30 hospital strains. Selected compounds (1-13) were examined for cytotoxicity, antitumor, and anti-HIV activity.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Tioureia/química , Tioureia/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Linhagem Celular Tumoral , Sistema Nervoso Central/fisiologia , Técnicas de Química Sintética , Desenho de Fármacos , Fungos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Tioureia/síntese química
5.
J Nat Prod ; 75(2): 225-9, 2012 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-22276775

RESUMO

Bioactivity-guided fractionation of a dichloromethane extract of the leaves of Myrtus communis led to the isolation of phloroglucinol derivatives. The structures of the new myrtucommulones J, K, and L (1-3) and the previously known myrtucommulone A (4) were elucidated on the basis of extensive 1D and 2D NMR experiments as well as high-resolutionmass spectrometry. Myrtucommulone J was obtained as a tautomeric pair (1/1a). The compounds were tested in vitro for their cytotoxic and antibacterial activities.


Assuntos
Antibacterianos , Antineoplásicos Fitogênicos , Myrtus/química , Floroglucinol/isolamento & purificação , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Itália , Testes de Sensibilidade Microbiana , Estrutura Molecular , Floroglucinol/análogos & derivados , Floroglucinol/química , Floroglucinol/farmacologia , Folhas de Planta/química , Staphylococcus aureus/efeitos dos fármacos
6.
Bioorg Med Chem ; 19(23): 7070-84, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22047799

RESUMO

In this study three new classes of linear N-tricyclic compounds, derived by condensation of the quinoline nucleus with 1,2,3-triazole, imidazole or pyrazine, were synthesized, obtaining triazolo[4,5-g]quinolines, imidazo[4,5-g]quinolines and pyrido[2,3-g]quinoxalines, respectively. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against RNA viruses representative of the three genera of the Flaviviridae family, that is BVDV (Pestivirus), YFV (Flavivirus) and HCV (Hepacivirus). Quinoline derivatives were also tested against representatives of other RNA virus families containing single-stranded, either positive-sense (ssRNA(+)) or negative-sense (RNA(-)), and double-stranded genomes (dsRNA), as well as against representatives of two DNA virus families. Some quinolines showed moderate, although selective activity against CVB-5, Reo-1 and RSV. However, derivatives belonging to all classes showed activity against BVDV. Among the most potent were the bis-triazoloquinoline 1m, the imidazoquinolines 2e and 2h, and the pyridoquinoxalines 4h, 4j and 5n (EC(50) range 1-5 µM). When tested in a replicon assay, compound 2h was the sole derivative to also display anti-HCV activity (EC(50)=3.1 µM). In enzyme assays, 1m, 2h, 5m and 5n proved to be potent inhibitors of the BVDV RNA-dependent RNA polymerase (RdRp), while only 2h also inhibited the recombinant HCV enzyme.


Assuntos
Antivirais/química , Antivirais/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Antivirais/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Flaviviridae/efeitos dos fármacos , Flaviviridae/enzimologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
7.
Antiviral Res ; 91(2): 133-41, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21619897

RESUMO

Twenty-six 9-aminoacridine derivatives were evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of 10 RNA and DNA viruses. While seven compounds (9, 10, 14, 19, 21, 22, 24) did not affect any virus and two (6, 11) were moderately active against CVB-5 or Reo-1, 17 compounds exhibited a marked specific activity against BVDV, prototype of pestiviruses which are responsible for severe diseases of livestock. Most anti-BVDV agents showed EC(50) values in the range 0.1-8 µM, thus comparing favorably with the reference drugs ribavirine and NM 108. Some compounds, particularly those bearing a quinolizidinylalkyl side chain, displayed pronounced cytotoxicity. Further studies are warranted in order to achieve still better anti-BVDV agents, and to explore the potential antiproliferative activity of this kind of compounds.


Assuntos
Acridinas/farmacologia , Aminoacridinas/farmacologia , Antivirais/farmacologia , Vírus de DNA/efeitos dos fármacos , Vírus da Diarreia Viral Bovina/efeitos dos fármacos , Acridinas/síntese química , Acridinas/química , Aminoacridinas/química , Animais , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Dimetil Sulfóxido/química , Humanos , Modelos Lineares , Testes de Sensibilidade Microbiana , Estrutura Molecular , Vírus de RNA/efeitos dos fármacos
8.
Med Chem ; 5(6): 507-16, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19534676

RESUMO

In prosecution of an anti-Flaviviridae project a new series of variously substituted 2-diphenyl-benzimidazoles were synthesized and tested in vitro for antiviral and antiproliferative activities. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Flaviviruses and Pestiviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae). The 5-Acetyl-2-(4'-nitrobiphenyl-4-yl)-1H-benzimidazole (24) emerged as potent active lead compound against Yellow Fever Virus (a Flavivirus) (EC(50) = 0.5 microM) and CVB-2 at 1 microM and was not cytotoxic, whereas the other title benzimidazoles showed no antiviral activity at concentrations not cytotoxic for the resting cell monolayers. Among the examined series, the most cytotoxic derivatives (11,12,14,16,18,19,20,21,23,25-30) against mock-infected MT-4 cells (CC50 < 8.0 microM) were evaluated against a panel of human cell lines derived from haematological and solid tumours,using 6-mercaptopurine (6-MP) and etoposide as reference drugs. In particular, compounds 26 and 28 showed a similar potency of 6-MP and etoposide.


Assuntos
Antivirais/química , Antivirais/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Animais , Antivirais/toxicidade , Benzimidazóis/toxicidade , Linhagem Celular Tumoral , Flaviviridae/efeitos dos fármacos , Humanos
9.
Eur J Med Chem ; 44(3): 1106-18, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18667259

RESUMO

Fifty-one acylthioureas (ATUs) incorporating imidazolidine-2-thione or its upper cyclohomologue were prepared by parallel synthesis and evaluated against a high number of human cancer cell lines for antiproliferative activity. ATUs 1o (3,5-dichlorobenzoyl), 1s (2-furoyl), 3s (2-furoyl) and 1t (2-thenoyl) displayed activity against leukemia, melanoma LOX IMVI, non-small cell lung NCI-H522, renal 786-0, CAKI-1, SN12C, UO-31 and breast MCF7, MDA-MB-435, T-47D cancer cell lines in the 0.3-9.7 microM concentration range. Compound 14s exhibited selectivity for melanoma SK-MEL-5 (GI(50)<5 nM); 1s for leukemia MOLT-4 (GI(50): 300 nM); 1q, 3b and 3q for renal cancer UO-31 (GI(50): 70-200 nM); 8s, 9s for non-small cell lung cancer EKVX (GI(50): 300, 10 nM) and 3j for HOP-92 (GI(50): 700 nM) cell line.


Assuntos
Proliferação de Células/efeitos dos fármacos , Imidazolidinas/síntese química , Imidazolidinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Acilação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectrofotometria Infravermelho
10.
Med Chem ; 4(3): 194-205, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18473911

RESUMO

A series of quinoxalines variously substituted, namely 3-arylthiomethyl-1,6-dimethylquinoxalin-2-ones (6a-f), 3-arylthiomethyl-1-benzyl-7-trifluoromethylquinoxalin-2-ones (8a-g) and 2-arylthiomethyl-3-benzyloxy-6-trifluoro-methylquinoxalines (10a,b,e-h), were synthesized and compared with previous arylphenoxymethylquinoxalines (1a-f, 2a-f and 3a-b). The purpose was to verify whether the replacement of oxygen with sulphur atom and the insertion of different substituents on the phenyl side chain were able to improve the capability to inhibit the Pgp pump and restore the antiproliferative activity of clinically useful drugs, such as doxorubicin (Doxo), vincristine (VCR) and etoposide (VP16), in drug-resistant human nasopharyngeal carcinoma KB cells (KB(wt), KB(MDR), KB(7D) and KB(V20C)). Furthermore, 2,3-bis(aryloxy-methyl)-6-trifluoromethylquinoxalines (13a-c) were designed with the objective to evaluate the capability of the double side chain to potentiate the antiproliferative activity of the drugs tested. Biological assays showed that title compounds were, in general, endowed with good activity as Pgp inhibitors. In particular compound 3a, bearing 2-CONHPh substituent on phenoxymethyl side chain, resulted the most effective, while the double side chain (compound 13c) gives the ability to inhibit a different MRP pump (a membrane glycoprotein named mrp). Furthermore, we can conclude that replacement of oxygen with sulphur atom did not improve the biological activity.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/síntese química , Quinoxalinas/síntese química , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Transfecção
11.
Eur J Med Chem ; 42(3): 293-306, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17254669

RESUMO

A series of novel N(3/8)-disubstituted-3,8-diazabicyclo[3.2.1]octanes in order to improve the in vitro activity of the prototype 3,8-bis[2-(3,4,5-trimethoxyphenyl)pyridyl-4-yl)methylpiperazine (1) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines. Compounds 2a,b,f and m demonstrated not only growth-inhibitory activities against leukemia cancer cells, but also fairly good activities against the growth of certain solid tumors. Among them, 2a is the most potent one with IC(50) values in the low micromolar range. Moreover, compound 2a has been selected for in vitro testing on MCF-7 cell to evaluate the mode of action of this lead compound.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Alquilação , Apoptose/efeitos dos fármacos , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/ultraestrutura , Proliferação de Células/efeitos dos fármacos , Corantes , Diploide , Eletroforese em Gel de Poliacrilamida , Humanos , Indicadores e Reagentes , Micro-Ondas , Propídio , Relação Estrutura-Atividade
12.
J Pharm Pharmacol ; 58(10): 1415-20, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17034667

RESUMO

New alkyl imidazoline derivatives have been synthesized as potential anti-cancer agents. The anti-proliferative activity of these compounds, evaluated against representative human haematological and solid neoplastic cell lines, showed that N, N'-di (4,5-dihydro-1H-imidazol-2-yl)3-aza-1,10-decane-diamine (8) and N, N'-di (4,5-dihydro-1H-imidazol-2-yl)3-aza-1,10-dodecane-diamine (9) were the most active compounds; in fact, they inhibited the cell proliferation at submicromolar concentrations. In enzyme assays, compound 9 turned out to be an inhibitor of topoisomerase II at concentrations comparable with those of the reference topoisomerase II inhibitor, etoposide.


Assuntos
Alcanos/síntese química , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Diaminas/síntese química , Alcanos/química , Alcanos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diaminas/química , Diaminas/farmacologia , Humanos , Ligantes , Relação Estrutura-Atividade
13.
Med Chem ; 2(2): 113-22, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16787360

RESUMO

Two series of 1,6-dimethyl-3-phenoxymethylquinoxalin-2-ones and 1-benzyl-3-phenoxymethyl-7-trifluoromethylquinoxalin-2-ones, and a series of 2-benzyloxy-3-phenoxymethyl-7-trifluoromethylquinoxaline were synthesized. Their capability to restore/potentiate the antiproliferative activity of clinically useful drugs, such as doxorubicin (Doxo), vincristine (VCR) and etoposide (VP16), in drug-resistant human nasopharyngeal carcinoma KB cells (KB(WT), KB(MDR), KB(7D)and KB(V20C)) was evaluated. In vitro data show that many quinoxalin-2-ones and quinoxalines potentiate the antiproliferative activity of Doxo and VCR in tumor-derived MDR cell lines. In this series, 17a turned out to be the most potent quinoxaline derivative in potentiating the antiproliferative activity of doxorubicin and vincristine against KB(MDR) and KB(V20C) resistant cell lines, respectively.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Sinergismo Farmacológico , Etoposídeo/farmacologia , Humanos , Células KB , Neoplasias/patologia , Células Tumorais Cultivadas , Vincristina/farmacologia
14.
J Med Chem ; 48(11): 3858-73, 2005 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-15916438

RESUMO

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/farmacologia
15.
Farmaco ; 60(2): 113-25, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15752470

RESUMO

A series of 11 new 9H-bis-[1,2,4]triazolo[4,3-a:3',4'-d] [1,5]benzodiazepine derivatives 8e-o was synthesized. Ten of these compounds (8e-m,o), along with four analogues (8a-d) (previously synthesized by us) were tested in vitro in order to evaluate their cytotoxic and anti-HIV-1 properties. In this connection other six original compounds, i.e., five 9-substituted compounds prepared starting from the 6,12-diphenylderivative 8c (compounds 10, 11, 12, 13a,b) and the bis-triazolone derivative 14, were synthesized and tested for the same purpose. While none of the 20 compounds tested exhibited any appreciable anti-HIV-1 activity, some of them exhibited interesting cytotoxic properties, the best results being shown by compounds 8c,d,k and 11 (CC(50) range=3-12 microM). Therefore, these four compounds were further evaluated for their antiproliferative activity against a panel of human tumor cell lines; actually, compounds 8d, 8k and 11 showed antiproliferative properties against either or both leukemia- and lymphoma-derived cell lines in the low micromolar range.


Assuntos
Fármacos Anti-HIV/síntese química , Antineoplásicos/síntese química , Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Células Tumorais Cultivadas
16.
Farmaco ; 59(8): 637-44, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15262533

RESUMO

A new series of variously substituted 3-aryl-2-[1H(2H)-benzotriazol-1(2)-yl]acrylonitriles was synthesized and tested for antiproliferative and antitubercular activity as part of our continuing research program in the antimicrobial and antitumor fields. The most cytotoxic derivatives (5a,g,i,j,l and 7b) (CC50 < 3.0 microM against MT-4 cells) were evaluated against a panel of human cell lines derived from hematological and solid tumors, using 6-mercaptopurine (6-MP) and etoposide as reference drugs. In particular, E-2-(5,6-dimethyl-1H-benzotriazol-1-yl)-3-(3-nitrophenyl)acrylonitrile (5g) resulted more potent than 6-MP on all cell lines, even if 2-14-fold less potent than etoposide. In the antitubercular screening, the derivatives 5i,j and 7e showed moderate activity against some resistant strains of Mycobacterium tested.


Assuntos
Acrilonitrila , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Acrilonitrila/análogos & derivados , Acrilonitrila/síntese química , Acrilonitrila/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade
17.
Farmaco ; 58(9): 639-50, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-13679156

RESUMO

Twenty eight pyrrolo[1,2-a]quinoxalines bearing at position 4 various substituents related to the moieties present in classical and non classical antifolic agents were prepared and evaluated in vitro for antiproliferative activity. In an in vitro screening performed at NCI, several compounds emerged as potent antiproliferative agents at concentrations ranging between 10 and 100 microM. Interestingly, some of these compounds proved active also against bovine and murine DHFR (Farmaco 53 (1998) 480). More recently, a compound of classical antifolate type has been reported to be a potent inhibitor of hDHFR in vitro (Farmaco 58 (2003) 51). We then synthesized new derivatives that, in our hands, were endowed with in vitro antiproliferative activities as low as 3.4 microM against a panel of cell lines derived from hematological and solid tumours. In addition, a complete screening of cytotoxicity, antiretroviral HIV-1 and antimicrobial activity has been carried out.


Assuntos
Compostos de Anilina/síntese química , Glutamatos/síntese química , Pirróis/síntese química , Quinoxalinas/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Bovinos , Linhagem Celular , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacologia , Glutamatos/química , Glutamatos/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Camundongos , Pirróis/química , Pirróis/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...