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1.
Eur J Med Chem ; 84: 8-16, 2014 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-25014745

RESUMO

Continuing our program of research concerning the antiviral activity of a wide series of new angular and linear azolo bicyclic and tricyclic derivatives, now we have simplified and modified the 4-chloro-2-(4-nitrophenyl)-3H-imidazo[4,5-g]quinoline 1, which previously resulted the most active derivative, through either the elimination of the central ring or the opening of the imidazole ring, obtaining various imidazopyridines and N-benzylidenequinolinamines respectively. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against representatives of two DNA virus families as wells as against representatives of RNA virus families containing single-stranded, either positive-sense (ssRNA(+)) or negative-sense (ssRNA(-)), and double-stranded genomes (dsRNA). Some imidazo[4,5-b]pyridines emerged as new derivatives endowed with antiviral activity against Vaccinia Virus (VV) at concentrations ranging from 2 to 16 µM. In particular, compound 2b demonstrate to be about 10 times more potent than Cidofovir, used as reference drug. Similarly, the imidazo[4,5-c]pyridines and N-benzylidenequinolinamines derivatives resulted active against Bovine Viral Diarrhoea virus (BVDV), at concentrations ranging from 1.2 to 28 µM. Above all compounds 1, 3a and 3f showed an EC50 of the same order of magnitude of the reference drug, the 2'-C-methyl-guanosine. Moreover, several N-benzylidenequinolinamines showed an interesting activity against Respiratory Syncytial Virus (RSV) at concentrations between 12 and 26 µM.


Assuntos
Aminoquinolinas/farmacologia , Antivirais/farmacologia , Vírus de DNA/efeitos dos fármacos , Imidazóis/farmacologia , Piridinas/farmacologia , Vírus de RNA/efeitos dos fármacos , Aminoquinolinas/síntese química , Aminoquinolinas/química , Animais , Antivirais/síntese química , Antivirais/química , Bovinos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 75: 169-83, 2014 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-24531230

RESUMO

Based on our previous results on the ascertained potent growth inhibition effect against a panel of 60 human tumors cell lines at National Cancer Institute of Bethesda (NCI), we have synthesized a novel series of thirty-one 2-[N-methyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines (1-31). The lead compound 1 was previously reported to be endowed with significant inhibition against hDHFR enzyme, with a Ki of 0.2 µM. Docking studies were performed on compound 1 and here reported to predict its binding conformation to human dihydrofolate reductase (hDHFR). All compounds (1-31) were assayed versus hDHFR and human thymidylate synthase (hTS). From the screening emerged that all compounds inhibited hDHFR with Ki values included between 0.2 and 11 µM, while only a few (6, 21, 24, 27, 29) showed great activity and selectivity towards hTS. Evaluation of the anticancer activity was performed by NCI, first against the three cell line panel, and only the most active compounds (17, 21, 24, 26, 27) were evaluated on a panel of 60 human tumor cell lines. Compound 21 was the most active against all cell lines with log GI50 equal to -5.49 and log LC50 equal to -4.19 and maintained significant percent of growth inhibition on seven cancer cell lines at the concentration of 1 µM. Compound 17 was the second most active and moreover showed interesting selectivity against some cell lines (Lung cancer: A549/ATCC, Melanoma: UACC-257, Ovarian Cancer: ovcar-8 and Renal cancer: RXF 393) at all concentration examined (100-0.01 µM).


Assuntos
Antineoplásicos/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Quinoxalinas/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Timidilato Sintase/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Fólico/metabolismo , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Halogenação , Humanos , Metilação , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade , Timidilato Sintase/metabolismo
3.
Biochemistry ; 52(21): 3752-64, 2013 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-23627712

RESUMO

The virus-encoded RNA-dependent RNA polymerase (RdRp) has emerged as a primary target in the search for selective inhibitors of Flaviviridae. Recently, we reported on the selective inhibition, in cell-based assays, of both BVDV (EC50 = 0.80 ± 0.06 µM) and HCV (EC50 = 1.11 ± 0.15 µM) by 2-{1-[2-(2,4-dimethoxyphenyl)-1H-benzimidazol-5-yl]ethylidene}hydrazinecarbothioamide (227G). Here we show that, in enzyme assays with recombinant enzymes, 227G inhibits, in a dose-dependent manner, the RdRp of both BVDV (IC50 = 0.0020 ± 0.0004 µM) and HCV (IC50 = 0.40 ± 0.04 µM). Furthermore, we report on the selection and molecular analysis of a BVDV-resistant mutant, characterized by the presence of the I261M mutation. By applying a multilevel computational approach, we identified different 227G binding sites on the two RdRps. They were further validated by the good agreement between the calculated affinities and those extrapolated from IC50 values. Our findings suggest different molecular mechanisms of inhibition of the HCV and BVDV RdRps by 227G and indicate the importance of understanding ligand-enzyme interactions at the molecular level for the rational design of new and more potent leads.


Assuntos
Benzimidazóis/farmacologia , Vírus da Diarreia Viral Bovina/enzimologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Animais , Bovinos , Linhagem Celular , Simulação de Acoplamento Molecular
4.
Mol Divers ; 17(3): 409-19, 2013 08.
Artigo em Inglês | MEDLINE | ID: mdl-23585057

RESUMO

Twenty benzimidazole derivatives bearing in position 1 a ([Formula: see text]-tert-amino)alkyl chain (mainly quinolizidin-1-ylmethyl) and in position 2 an aromatic moiety (phenyl, benzyl or benzotriazol-1/2-ylmethyl) were evaluated at the National Cancer Institute (NCI) for anti-proliferative activity against a panel of 60 human cancer cell lines. Four compounds (6, 7, 9 and 10) displayed a large spectrum of activity with [Formula: see text] 10 [Formula: see text] on 24-57 cell lines, while thirteen compounds exhibited sub-micromolar or even nanomolar activity against single cell lines, such as leukemia CCRF-CEM, HL-60 and MOLT-4, CNS cancer SF-268 and, particularly, renal cancer UO-31, sometimes with outstanding selectivity (compounds 5-7, 11, 13 and 18).


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Quinolizidinas/farmacologia , Antineoplásicos/química , Benzimidazóis/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/tratamento farmacológico , Quinolizidinas/química , Relação Estrutura-Atividade
5.
J Med Chem ; 55(19): 8318-29, 2012 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-22946585

RESUMO

The upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides a salvage pathway that bypasses dihydrofolate reductase (DHFR) inhibition. The structure-based optimization of the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]piperidine-4-carboxylate (1) led to the synthesis of a focused compound library which showed significantly improved selectivity for the parasite's folate-dependent enzyme. When used in combination with pyrimethamine, a DHFR inhibitor, a synergistic effect was observed for compound 5b. This work represents a step forward in the identification of effective antileishmania agents.


Assuntos
Leishmania/enzimologia , Oxirredutases/antagonistas & inibidores , Tripanossomicidas/síntese química , Linhagem Celular , Sinergismo Farmacológico , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Ácido Fólico/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Leishmania/efeitos dos fármacos , Leishmania major/efeitos dos fármacos , Leishmania major/enzimologia , Leishmania mexicana/efeitos dos fármacos , Leishmania mexicana/enzimologia , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Pirimetamina/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia
6.
Eur J Med Chem ; 53: 83-97, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22513121

RESUMO

Within a project aimed at discovering new Flaviviridae inhibitors, new variously substituted 2-phenylbenzimidazoles were synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representatives of the three genera of the Flaviviridae family, i.e.: Pestivirus (BVDV), Flavivirus (YFV) and Hepacivirus (HCV). Title compounds were also tested against RNA viruses representative of other single-stranded, positive-sense (ssRNA(+)) negative-sense (RNA(-)), or double-stranded (dsRNA) genomes, as well as against representatives of two DNA virus families. Nine compounds showed activity against BVDV (EC(50) = 0.8-8.0 µM), compound 31 being the most potent (EC(50) = 0.80 µM) and selective (SI = CC(50)/EC(50) = >100). When tested in an HCV replicon assay, compound 31 resulted again the most potent, displaying an EC(50) value of 1.11 µM and an SI of 100. Besides inhibiting BVDV, two compounds (35 and 38) showed a moderate activity also against YFV (EC(50) = 13 µM). Interestingly, 35 was moderately active also against RSV (EC(50) = 25 µM).


Assuntos
Antivirais/química , Antivirais/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Vírus/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/toxicidade , Benzimidazóis/síntese química , Benzimidazóis/toxicidade , Bovinos , Linhagem Celular , Cricetinae , Desenho de Fármacos
7.
Med Chem ; 6(2): 70-8, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20470249

RESUMO

As a follow up of an anti-Flaviviridae project, a new series of variously substituted 2-styryl-benzimidazoles were synthesized and tested in vitro for biological activity. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Pestiviruses and Flaviviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae) as well as for cytotoxicity tests, run in parallel with antiviral assays,against MDBK, BHK and Vero 76 cells. In the series examined, new leads emerged against BVDV, CVB-2 and RSV. Compounds 11, 12, 17, 18, 24, 31 exhibited anti-BVDV activity in the concentration range 1.7-16 microM; among them, compound 17 was the most active, with an EC(50) = 1.7 microM. Compounds 18 and 21 were equally active against CVB-2, with EC(50) values of 7 - 8 microM, while the derivative 30 was active against RSV with EC(50)= 1 microM and represents a new lead compound.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Vírus de DNA/efeitos dos fármacos , Flaviviridae/efeitos dos fármacos , Vírus de RNA/efeitos dos fármacos , Estirenos/síntese química , Estirenos/farmacologia , Animais , Antivirais/química , Benzimidazóis/química , Bovinos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cricetinae , Relação Dose-Resposta a Droga , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Estirenos/química , Células Vero
8.
Bioorg Med Chem ; 18(8): 2937-53, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20359898

RESUMO

Seventy-six 2-phenylbenzimidazole derivatives were synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of 10 RNA and DNA viruses. The most commonly affected viruses were, in decreasing order, CVB-2, BVDV, Sb-1, HSV-1, and YFV, while HIV-1 and VSV were not affected, and RSV, VV and Reo-1 were only susceptible to a few compounds. Thirty-nine compounds exhibited high activity (EC(50)=0.1-10microM) against at least one virus, and four of them were outstanding for their high and selective activity against VV (24, EC(50)=0.1microM) and BVDV (50, 51, and 53 with EC(50)=1.5, 0.8, and 1.0microM, respectively). The last compounds inhibited at low micromolar concentrations the NS5B RdRp of BVDV and also of HCV, the latter sharing structural similarity with the former. The considered compounds represent attractive leads for the development of antiviral agents against poxviruses, pestiviruses and even HCV, which are important human and veterinary pathogens.


Assuntos
Antivirais/química , Benzimidazóis/química , Animais , Antivirais/síntese química , Antivirais/toxicidade , Benzimidazóis/síntese química , Benzimidazóis/toxicidade , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Vírus de DNA/efeitos dos fármacos , Humanos , Vírus de RNA/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Células Vero
9.
Gynecol Oncol ; 117(2): 202-10, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20031193

RESUMO

OBJECTIVE: Polyamines have been shown to play a role in the growth and survival of several solid tumors, including ovarian cancer. Intracellular polyamine depletion by the inhibition of biosynthesis enzymes or by the induction of the catabolic pathway leads to antiproliferative effects in many different tumor cell lines. Recent studies showed that the thymidylate synthase inhibitor 5-fluorouracil (5-FU) affects polyamine metabolism in colon carcinoma cells through the induction of the key catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT). METHODS: We therefore examined whether combinations of novel folate cycle inhibitors with quinoxaline structure and drugs that specifically target polyamine metabolism, such as diethylderivatives of norspermine (DENSPM) or spermine (BESpm), have synergistic effect in killing cisplatin-sensitive and drug-resistant daughter human ovarian cell lines. RESULTS: Our results showed that simultaneous drug combination or quinoxaline pre-treatment synergistically increased SSAT expression, depleted polyamines, increased reactive oxygen species production, and produced synergistic tumor cell killing in both cell lines. Of note, this combined therapy increased the chemosensitivity of cisplatin-resistant cells and cross-resistant to the polyamine analogues. On the contrary, some pre-treatment regimens of Spm analogues were antagonistic. CONCLUSIONS: These results show that SSAT plays an important role in novel folate cycle inhibitors effects and suggest that their combination with analogues has potential for development as therapy for ovarian carcinoma based on SSAT modulation.


Assuntos
Acetiltransferases/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Espermina/análogos & derivados , Acetiltransferases/biossíntese , Acetiltransferases/deficiência , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/enzimologia , Cistadenocarcinoma Seroso/patologia , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Antagonistas do Ácido Fólico/administração & dosagem , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Quinoxalinas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Espermina/administração & dosagem , Espermina/metabolismo , Espermina/farmacologia
10.
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
11.
Eur J Pharmacol ; 615(1-3): 17-26, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19446547

RESUMO

The cytotoxicity of two novel folate cycle inhibitors with quinoxalinic structure, 3-methyl-7-trifluoromethyl-2(R)-[3,4,5-trimethoxyanilino]-quinoxaline (453R) and 3-piperazinilmethyl-2[4(oxymethyl)-phenoxy]quinoxaline (311S), was tested against a panel of both cisplatin(cDDP)-sensitive and -resistant carcinoma cell lines. Interestingly, the cisplatin-resistant human ovarian line, C13 cells, exhibited collateral sensitivity towards the two compounds when compared to its sensitive parental 2008 cells. In this resistant line, which showed elevated expression of the folate cycle enzymes, thymidylate synthase (TS) and dihydrofolate reductase (DHFR), due to cisplatin-resistance phenotype, collateral sensitivity correlated with the greater reduction of enzyme expression. In addition, TS and DHFR expression of the other resistant lines, the human ovarian carcinoma A2780/CP cells and the human breast cancer MDA/CH cells, were decreased in accordance with the similar sensitivity or the low level of cross-resistance to these compounds in comparison to their respective parental lines. Noteworthy, unlike 5-fluorouracil, both drugs reduced the level of TS without inducing ternary complex formation with the co-substrate and the nucleotide analogue. Median effect analysis of the interactive effects of cisplatin with the two quinoxalines mainly showed additive or synergistic cell killing, depending on schedules of drug combinations. In particular, synergistic effects were more often obtained, even on the resistant cells, when cisplatin was added at the beginning of the treatment. These results indicate that, despite the possibility of other mechanisms being involved, inhibition of TS cycle enzymes plays an important role in the pharmacology of these compounds, which might also represent a useful component in drug treatment protocols against cDDP-resistant cells.


Assuntos
Cisplatino/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Tetra-Hidrofolato Desidrogenase/biossíntese , Timidilato Sintase/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistadenocarcinoma Seroso , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluoruracila/farmacologia , Humanos , Neoplasias Ovarianas , Quinoxalinas/farmacologia , Tetra-Hidrofolato Desidrogenase/genética , Timidilato Sintase/biossíntese
12.
Eur J Med Chem ; 44(4): 1579-91, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18774202

RESUMO

A series of novel 5,7-diamino-3-phenyl-2-benzylamino, 2-phenoxy, and 2-thiophenyl substituted quinoxalines has been designed, synthesized and evaluated for their in vitro antitumor activity towards cell lines of nine different types of human cancers. Some of these compounds exhibited inhibitory effects on the growth of a wide range of cancer cell lines generally at 10(-6) M, in some cases at 10(-7) M and 10(-8) M concentrations. Within this series the benzylamino quinoxaline derivatives 1b-7b were the most active, whereas compound 2c showed the highest MG_MD value (-5.66).


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Quinoxalinas/química
13.
Chem Biodivers ; 5(11): 2386-401, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19035566

RESUMO

Forty-three 2-[(benzotriazol-1/2-yl)methyl]benzimidazoles, bearing either linear (dialkylamino)alkyl- or bulkier (quinolizidin-1-yl)alkyl moieties at position 1, were evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representative of two of the three genera of the Flaviviridae family, i.e. Flaviviruses (Yellow Fever Virus (YFV)) and Pestiviruses (Bovine Viral Diarrhoea Virus (BVDV)), as Hepaciviruses can hardly be used in routine cell-based assays. Compounds were also tested against representatives of other virus families. Among ssRNA+ viruses were a retrovirus (Human Immunodeficiency Virus type 1 (HIV-1)), two picornaviruses (Coxsackie Virus type B2 (CVB2), and Poliovirus type-1, Sabin strain (Sb-1)); among ssRNA- viruses were a Paramyxoviridae (Respiratory Syncytial Virus (RSV)) and a Rhabdoviridae (Vesicular Stomatitis Virus (VSV)) representative. Among double-stranded RNA (dsRNA) viruses was a Reoviridae representative (Reo-1). Two representatives of DNA virus families were also included: Herpes Simplex type 1, (HSV-1; Herpesviridae) and Vaccinia Virus (VV; Poxviridae). Most compounds exhibited potent activity against RSV, with EC(50) values as low as 20 nM. Moreover, some compounds, in particular when bearing a (quinolizidin-1-yl)alkyl residue, were also moderately active against BVDV, YFV, and CVB2.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Animais , Antivirais/química , Antivirais/toxicidade , Benzimidazóis/química , Benzimidazóis/toxicidade , Células Cultivadas , Vírus de DNA/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Flavivirus/efeitos dos fármacos , Haplorrinos , Humanos , Pestivirus/efeitos dos fármacos , Vírus de RNA/efeitos dos fármacos , Relação Estrutura-Atividade
14.
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
15.
Proc Natl Acad Sci U S A ; 105(5): 1448-53, 2008 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-18245389

RESUMO

Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase. Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes. Compound 6a displayed a K(i) of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:6a ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds. A second round of design, synthesis, and assay produced a compound (6b) with a significantly improved K(i) (37 nM) against LmPTR1, and the structure of this complex was also determined. Biological evaluation of selected inhibitors was performed against the extracellular forms of T. cruzi and L. major, both wild-type and overexpressing PTR1 lines, as a model for PTR1-driven antifolate drug resistance and the intracellular form of T. cruzi. An additive profile was observed when PTR1 inhibitors were used in combination with known DHFR inhibitors, and a reduction in toxicity of treatment was observed with respect to administration of a DHFR inhibitor alone. The successful combination of antifolates targeting two enzymes indicates high potential for such an approach in the development of previously undescribed antiparasitic drugs.


Assuntos
Antiprotozoários/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Ácidos Isonipecóticos/farmacologia , Leishmania major/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Pteridinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/química , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Ácido Fólico/química , Ácidos Isonipecóticos/química , Leishmania major/enzimologia , Oxirredutases/química , Testes de Sensibilidade Parasitária , Proteínas de Protozoários/química , Pteridinas/química , Tetra-Hidrofolato Desidrogenase/efeitos dos fármacos , Timidilato Sintase/antagonistas & inibidores , Tripanossomicidas/química , Trypanosoma cruzi/enzimologia
16.
Eur J Med Chem ; 43(1): 189-203, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17532099

RESUMO

Several diamino quinoxalines were designed, synthesized and evaluated as anti-tumor agents. Two compounds showed the most potent cytotoxic activities against the leukemia CCRF-CEM cell line (GI(50)<0.01microM) and the ovarian cancer cell line OVCAR-4 (GI(50)=0.03microM), respectively, with comparable/better activities than Methotrexate (MTX). Docking calculations of the complexes of hDHFR with the most active compounds identified the binding mode of the described molecules with respect to MTX.


Assuntos
Compostos de Anilina/síntese química , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Glutamatos/síntese química , Glutamatos/farmacologia , Quinoxalinas/química , Compostos de Anilina/química , Compostos de Anilina/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/metabolismo , Glutamatos/química , Glutamatos/metabolismo , Humanos , Cinética , Modelos Moleculares , Conformação Molecular
17.
Bioorg Med Chem Lett ; 17(17): 4791-4, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17604166

RESUMO

In this preliminary study we report the activity of 3-methyl-9-substituted-6-oxo-6,9-dihydro-3H-[1,2,3]-triazolo[4,5-h]quinolone-carboxylic acids and their esters as a new class of antiinfective agents against MDR Mycobacterium tuberculosis. In antitubercular screening against H37Rv and 11 clinically isolated strains of M. tuberculosis several derivatives (1o,3a,c,i,j,p) showed MIC(90) in the range 0.5-3.2 microg/mL. 3c showed no cytotoxicity and proved to be the most potent derivative exhibiting MIC(90)=0.5 microg/mL against all M. tuberculosis strains and infected human macrophages (J774-A1) tested.


Assuntos
Antibacterianos/química , Química Farmacêutica/métodos , Farmacorresistência Bacteriana , Resistência a Múltiplos Medicamentos , Mycobacterium tuberculosis/metabolismo , Quinolonas/química , Triazóis/química , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antibacterianos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Modelos Químicos
18.
Bioorg Med Chem ; 15(5): 1914-27, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17251029

RESUMO

Following the antiviral screening of a wide series of new angular and linear N-tricyclic systems both in silico and in vitro, the [4,7]phenantroline nucleus emerged as a new ring system endowed with activity against viruses containing single-stranded, positive-sense RNA genomes (ssRNA+). Here, we report our new pathway to the synthesis of this nucleus and of several related derivatives, as well as the results of both cell-based antiviral assays and molecular dynamics simulations. In the antiviral screening, several compounds (9 and 16-20) showed to be fairly active against BVDV, CVB-2, and Polio 1 (EC50, 6-25 microM). According to molecular dynamics simulations, compounds (15) and (17) emerged for its potency against the HCV NS5B, with a calculated IC50 of 11-12 microM.


Assuntos
Antivirais/química , Antivirais/farmacologia , Fenantrolinas/química , Fenantrolinas/farmacologia , Vírus de RNA/efeitos dos fármacos , Animais , Antivirais/síntese química , Linhagem Celular , Desenho de Fármacos , Humanos , Modelos Moleculares , Fenantrolinas/síntese química , Análise Espectral
19.
Med Chem ; 2(6): 577-89, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17105439

RESUMO

A series N-[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkylcarboxamides (8e-k, 9e-i, k, l) and their parent amines (5a-c and 6a-d) were prepared according to Schemes (1 and 2). Compounds were evaluated in vitro for cytotoxicity and antiviral activity against a wide spectrum of RNA (positive- and negative-sense) viruses, like [Bovine Viral Diarrhea Virus (BVDV), Yellow Fever Virus (YFV), Coxsackie Virus B (CVB-2), Polio Virus (Sb-1), Human Immunodeficiency Virus (HIV-1), Respiratory Syncytial Virus (RSV)] or double-stranded (dsRNA) virus, like Reoviridae (Reo-1). The Entero (CVB-2 and Sb-1) were the only viruses inhibited by title compounds. In particular, two of them emerged for their selective, although not very potent, antiviral activity: 8i, which was the most active against CVB-2 (CC50 >100 microM; EC50 = 10 microM) and 9l, which was the most active against Sb-1 (CC50 90 microM; EC50 = 30 microm). Title compounds were evaluated in silico against the Sb-1 helicase, as the crystal structure of this enzyme was not available, the corresponding 3D model was obtained by homology techniques (see Fig. 2).


Assuntos
Amidas/síntese química , Amidas/farmacologia , Antivirais/síntese química , Vírus de RNA/efeitos dos fármacos , Amidas/química , Animais , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Modelos Moleculares , RNA Helicases/antagonistas & inibidores , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 41(9): 1102-7, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16828932

RESUMO

Fifteen imidazo[1,2-a] and [1,2,4]triazolo[4,3-a]quinoxalines were prepared. These compounds bear at position 4 various substituents related to the moieties present in classical and non-classical antifolic agents. And we evaluated in vitro antimicrobial, antiviral and antiproliferative activities. In particular, title compounds were evaluated in vitro against representative strains of Gram-positive and Gram-negative bacteria (S. aureus, Salmonella spp.), mycobacteria (M. fortuitum, M. smegmatis ATCC 19420 and M. tuberculosis ATCC 27294), yeast and moulds (C. albicans ATCC 10231 and A. fumigatus). Furthermore, their antiretroviral activity against HIV-1 was determined in MT-4 cells together with cytotoxicity. In these assays title compounds were tested for their capability to prevent MT-4 cell growth. Among the examined series, the compounds 5, 7 and 10 showed cytotoxicity against mock-infected MT-4 cells.


Assuntos
Imidazóis/química , Quinoxalinas/química , Quinoxalinas/toxicidade , Triazóis/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Quinoxalinas/síntese química , Relação Estrutura-Atividade
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