RESUMO
A series of new pyrrole derivatives have been synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. N-Methyl,N-(benzyl),N-(pyrrol-2-ylmethyl)amine (7) and N-(2-benzyl),N-(1-methylpyrrol-2-ylmethyl)amine (18) were the most selective MAO-B (7, SI = 0.0057) and MAO-A (18, SI = 12500) inhibitors, respectively. Docking and molecular dynamics simulations gave structural insights into the MAO-A and MAO-B selectivity. Compound 18 forms an H-bond with Gln215 through its protonated amino group into the MAO-A binding site. This H-bond is absent in the 7/MAO-A complex. In contrast, compound 7 places its phenyl ring into an aromatic cage of the MAO-B binding pocket, where it forms charge-transfer interactions. The slightly different binding pose of 18 into the MAO-B active site seems to be forced by a bulkier Tyr residue, which replaces a smaller Ile residue present in MAO-A.
Assuntos
Benzilaminas/síntese química , Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/química , Pirróis/síntese química , Animais , Benzilaminas/química , Benzilaminas/farmacologia , Sítios de Ligação , Encéfalo/enzimologia , Encéfalo/ultraestrutura , Bovinos , Técnicas In Vitro , Isoenzimas/química , Isoenzimas/metabolismo , Mitocôndrias/enzimologia , Modelos Moleculares , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Pirróis/química , Pirróis/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Cinnamoly compounds 1a-c and 2a-d were designed, synthesized, and in vitro tested as p300 inhibitors. At different degrees, all tested compounds were proven to inactivate p300, particularly, derivative 2c was the most active inhibitor, also showing high specificity for p300 as compared to other histone acetyltransferases. Most notably, 2c showed anti-acetylase activity in mammalian cells. These compounds represent a new class of synthetic inhibitors of p300, characterized by simple chemical structures.
Assuntos
Compostos de Benzilideno/síntese química , Proteínas de Ciclo Celular/antagonistas & inibidores , Cinamatos/síntese química , Cicloexanonas/síntese química , Histona Acetiltransferases/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Acetilação , Compostos de Benzilideno/farmacologia , Permeabilidade da Membrana Celular , Cinamatos/farmacologia , Curcumina/análogos & derivados , Curcumina/síntese química , Curcumina/farmacologia , Cicloexanonas/farmacologia , Células HeLa , Histonas/metabolismo , Humanos , Proteínas Recombinantes/antagonistas & inibidores , Fatores de Transcrição de p300-CBPRESUMO
Indolyl aryl sulfones bearing the 4,5-difluoro (10) or 5-chloro-4-fluoro (16) substitution pattern at the indole ring were potent inhibitors of HIV-1 WT and the NNRTI-resistant strains Y181C and K103N-Y181C. These compounds were highly effective against the 112 and the AB1 strains in lymphocytes and inhibited at nanomolar concentration the multiplication of the IIIBBa-L strain in macrophages. Compound 16 was exceptionally potent against RT WT and RTs carrying the K103N, Y181I, and L100I mutations.
Assuntos
Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Indóis/síntese química , Inibidores da Transcriptase Reversa/síntese química , Sulfonas/síntese química , Linhagem Celular , Farmacorresistência Viral , Transcriptase Reversa do HIV/genética , HIV-1/enzimologia , Humanos , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/virologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
Following the disclosure of dihydro-alkoxy-, dihydro-alkylthio-, and dihydro-alkylamino-benzyl-oxopyrimidines (DABOs, S-DABOs, and NH-DABOs) as potent and selective anti-HIV-1 agents belonging to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, we report here the synthesis and biological evaluation of a novel series of DABOs bearing a N,N-disubstituted amino group or a cyclic amine at the pyrimidine-C2 position, a hydrogen atom or a small alkyl group at C5 and/or at the benzylic position, and the favorable 2,6-difluorobenzyl moiety at the C6 position (F2-N,N-DABOs). The new compounds were highly active up to the subnanomolar level against both wt HIV-1 and the Y181C mutant and at the submicromolar to nanomolar range against the K103N and Y188L mutant strains. Such derivatives were more potent than S-DABOs, NH-DABOs, and nevirapine and efavirenz were chosen as reference drugs. The higher inhibitor adaptability to the HIV-1 RT non-nucleoside binding site (NNBS) may account for the higher inhibitory effect exerted by the new molecules against the mutated RTs.
Assuntos
Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Pirimidinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Farmacorresistência Viral , Transcriptase Reversa do HIV/genética , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Modelos Moleculares , Mutação , Ligação Proteica , Pirimidinas/química , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
The new arylthioindole (ATI) derivatives 10, 14-18, and 21-24, which bear a halogen atom or a small size ether group at position 5 of the indole moiety, were compared with the reference compounds colchicine and combretastatin A-4 for biological activity. Derivatives 10, 11, 16, and 21-24 inhibited MCF-7 cell growth with IC50 values <50 nM. A halogen atom (14-17) at position 5 caused a significant reduction in the free energy of binding of compound to tubulin, with a concomitant reduction in cytotoxicity. In contrast, methyl (21) and methoxy (22) substituents at position 5 caused an increase in cytotoxicity. Compound 16, the most potent antitubulin agent, led to a large increase (56%) in HeLa cells in the G2/M phase at 24 h, and at 48 h, 26% of the cells were hyperploid. Molecular modeling studies showed that, despite the absence of the ester moiety present in the previously examined analogues, most of the compounds bind in the colchicine site in the same orientation as the previously studied ATIs. Binding to beta-tubulin involved formation of a hydrogen bond between the indole and Thr179 and positioning of the trimethoxy phenyl group in a hydrophobic pocket near Cys241.
Assuntos
Indóis/síntese química , Modelos Moleculares , Moduladores de Tubulina/síntese química , Apoptose , Biopolímeros/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligação de Hidrogênio , Indóis/química , Indóis/farmacologia , Ligação Proteica , Ensaio Radioligante , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the beta-diketo acids (DKAs) represent a major lead for anti-HIV-1 drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized, and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3'-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-cross-linking experiments.
Assuntos
Inibidores de Integrase de HIV/síntese química , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Hidroxibutiratos/síntese química , Cetoácidos/síntese química , Quinolonas/síntese química , Domínio Catalítico , Linhagem Celular , DNA Viral/química , Desenho de Fármacos , Integrase de HIV/química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Hidroxibutiratos/química , Hidroxibutiratos/farmacologia , Cetoácidos/química , Cetoácidos/farmacologia , Modelos Moleculares , Ligação Proteica , Estrutura Terciária de Proteína , Quinolonas/química , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
Molecular modeling studies and an updated highly predictive 3-D QSAR model led to the discovery of exceptionally potent indolyl aryl sulfones (IASs) characterized by the presence of either a pyrrolidyn-2-one nucleus at the indole-2-carboxamide or some substituents at the indole-2-carbohydrazide. Compounds 7 and 9 were found active in the sub-nanomolar range of concentration in both MT-4 and C8166 cell-based anti-HIV assays. These compounds, and in particular compound 9, also showed excellent inhibitory activity against both HIV-112 and HIV-AB1 primary isolates in lymphocytes and against HIV WT in macrophages.
Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Indóis/síntese química , Modelos Moleculares , Sulfonas/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Células Cultivadas , Desenho de Fármacos , Farmacorresistência Viral , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Indóis/química , Indóis/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/virologia , Pirrolidinonas/química , Relação Quantitativa Estrutura-Atividade , Solubilidade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
Arylthioindoles (ATIs) that possess a 3-methoxyphenylthio or a 3,5-dimethoxyphenylthio moiety at position 2 of the indole ring were effective tubulin assembly inhibitors, but weak inhibitors of MCF-7 cell growth. ATIs bearing a 3-(3,4,5-trimethoxyphenyl)thio moiety were potent tubulin polymerization inhibitors, with IC(50)s in the 2.0 (35) to 4.5 (37) microM range. They also inhibited MCF-7 cell growth at nanomolar concentrations. The 3,4,5-trimethoxy substituted ATIs showed potencies comparable to those of the reference compounds colchicine and combretastatin A-4 in both tubulin assembly and cell growth inhibition assays. Dynamics simulation studies correlate well with the observed experimental data. Furthermore, from careful analysis of the biological and in silico data, we can now hypothesize a basic pharmacophore for this class of compounds.
Assuntos
Derivados de Benzeno/síntese química , Indóis/síntese química , Modelos Moleculares , Sulfetos/síntese química , Moduladores de Tubulina/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/química , Indóis/farmacologia , Relação Estrutura-Atividade , Sulfetos/química , Sulfetos/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
Pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxides (PBTDs) induced apoptosis in human BCR-ABL-expressing leukemia cells. The apoptotic activity was also observed in primary leukemic blasts, obtained from chronic myelogenous leukemia (CML) patients at onset or from patients in blast crisis and who were imatinib-resistant. Compounds 5 and 14 induced apoptosis before BCR-ABL protein expression and tyrosin phosphorylation were affected and activated different caspases in the apoptotic pathway. PBTDs are a new class of valid candidates for the treatment of CML.
Assuntos
Antineoplásicos/síntese química , Apoptose , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Pirróis/síntese química , Tiazepinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzamidas , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Caspase 3 , Caspase 8 , Caspase 9 , Caspases/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/química , Pirróis/farmacologia , Tiazepinas/química , Tiazepinas/farmacologia , Células Tumorais CultivadasRESUMO
New non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are active against the commonly occurring mutations of HIV are urgently needed for the treatment of AIDS. We synthesized new NNRTIs of the indolyl aryl sulphone (IAS) family, which are endowed with high antiviral potency against HIV-1 wt (wild-type), and the Y181C and K103N-Y181C drug resistant mutant strains. Several new compounds were highly active in lymphocytes infected with primary isolates carrying the K103N-V1081-M184V and L1001-V1081 mutations. The design of new IASs was based on three-dimensional quantitative structure-activity relationship (3D QSAR) studies and docking simulations. A cross-docking study was also undertaken to gain some insights in to the binding mode of the newly synthesized IASs in the wt and mutated isoforms of reverse transcriptase.
Assuntos
Indóis/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Sulfonas/farmacologia , Linhagem Celular , Humanos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Espectrofotometria Infravermelho , Sulfonas/síntese química , Sulfonas/metabolismoRESUMO
Indolyl aryl sulfones (IASs) are a potent class of NNRTIs developed from L-737,126, a lead agent discovered by Merck AG. IAS derivatives are endowed with inhibitory activities against wt HIV-1 in the low nanomolar concentration range. Introduction of two methyl groups at positions 3 and 5 of the phenyl ring of the aryl sulfonyl moiety furnished IAS derivatives such as 5-chloro- or 5-bromo-3-[(3,5-dimethylphenyl)sulfonyl]indole-2-carboxyamide, which showed very potent and selective anti-HIV-1 activity against some mutants carrying NNRTI resistant mutations at positions 103 and 181 of the reverse transcriptase. IAS derivatives bearing 2-hydroxyethylcarboxyamide or 2-hydroxyethylcarboxyhydrazide groups at position 2 of the indole nucleus were more active than L-737,126 against the K103N-Y181C double mutant. A great improvement of antiviral activity against wt HIV-1 and resistant mutants was obtained by coupling 1-3 simple amino acids, such as glycine and alanine, in sequence, with the 3-[(3,5-dimethylphenyl)sulfonyl]-1H-indole-2-carbonyl moiety. The transformation of the chain terminus into amide or hydrazide, produced short peptides with high selectivity and potent activity against wt HIV-1, and the viral mutants Y181C, K103N-Y181C and EFV(R). IAS having two halogen atoms at the indole showed potent inhibitory activity against the Y181C and the EFV(R) resistant mutant strains. In particular, the introduction of a fluorine atom at position 4 of the indole ring notably contributed to improve the antiviral activities against both wt and the related resistant mutants. 5-Nitro-IASs were highly active against wt HIV-1 and exhibited low cytotoxicity. Experimental data highlighted the class IAS derivatives as promising candidates for clinical trials.
Assuntos
HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Indóis/síntese química , Indóis/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Sulfonas/síntese química , Sulfonas/farmacologia , Desenho de Fármacos , Farmacorresistência Viral , HIV-1/genética , Humanos , Mutação , Relação Estrutura-AtividadeRESUMO
Three-dimensional quantitative structure-activity relationship (3-D QSAR) studies and docking simulations were developed on indolyl aryl sulfones (IASs), a class of novel HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (Silvestri, et al. J. Med. Chem. 2003, 46, 2482-2493) highly active against wild type and some clinically relevant resistant strains (Y181C, the double mutant K103N-Y181C, and the K103R-V179D-P225H strain, highly resistant to efavirenz). Predictive 3-D QSAR models using the combination of GRID and GOLPE programs were obtained using a receptor-based alignment by means of docking IASs into the non-nucleoside binding site (NNBS) of RT. The derived 3-D QSAR models showed conventional correlation (r(2)) and cross-validated (q(2)) coefficients values ranging from 0.79 to 0.93 and from 0.59 to 0.84, respectively. All described models were validated by an external test set compiled from previously reported pyrryl aryl sulfones (Artico, et al. J. Med. Chem. 1996, 39, 522-530). The most predictive 3-D QSAR model was then used to predict the activity of novel untested IASs. The synthesis of six designed derivatives (prediction set) allowed disclosure of new IASs endowed with high anti-HIV-1 activities.
Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Sítios de Ligação , Células Cultivadas , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Transcriptase Reversa do HIV/química , Humanos , Hidrazinas/química , Testes de Sensibilidade Microbiana , Nucleosídeos/química , Nucleosídeos/metabolismo , Nucleosídeos/farmacologia , Conformação Proteica , Inibidores da Transcriptase Reversa/química , Software , Sulfonas/químicaRESUMO
Two 2,6-difluoro-DABO derivatives (MC 1047, 1, and MC 1220, 2, respectively) were tested against endogenous, nontelomeric reverse transcriptase (endo-RT) in human differentiating cell systems to investigate their antiproliferative and cytodifferentiating activity. The two compounds significantly reduced cell proliferation and facilitated the morphological differentiation of cells. These results propose F(2)-DABOs as useful tools in preventive and/or curative therapy to counteract the loss of differentiation in dedifferentiating pathologies and as antiproliferative drugs in tumor therapy.
Assuntos
Antineoplásicos/síntese química , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Pirimidinonas/síntese química , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fluorbenzenos , Humanos , Pirimidinonas/química , Pirimidinonas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
1-[2-(Diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs) is a novel family of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) active at submicromolar concentration. Replacement of one phenyl ring of 1-[2-(diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole (4) with heterocyclic rings, such as 2-thienyl or 3-pyridinyl, led to novel DAMNIs with increased activity. In HIV-1 WT cell-based assay the racemic 1-{2-[alpha-(thiophen-2-yl)phenylmethoxy]ethyl}-2-methyl-5-nitroimidazole (7) (EC(50) = 0.03 microM) proved 5 times more active than compound 4. Docking experiments showed that the introduction of a chiral center would not affect the binding of both (R)-7 and (S)-7. The internal scoring function of the Autodock program calculated the same inhibition constant (K(i) = 7.9 nM) for the two enantiomers. Compounds 7 (ID(50) = 8.25 microM) were found more active than efavirenz (ID(50) = 25 microM) against the viral RT carrying the K103N mutation, suggesting for these compounds a potential use in efavirenz based anti-AIDS regimens.
Assuntos
HIV-1/efeitos dos fármacos , Nitroimidazóis/síntese química , Nitroimidazóis/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Animais , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Farmacorresistência Viral , Transcriptase Reversa do HIV , HIV-1/fisiologia , Modelos Moleculares , Conformação Molecular , Nevirapina/química , Nitroimidazóis/química , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC(90) = 0.032 microg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted.
Assuntos
Antifúngicos/síntese química , Candida albicans/efeitos dos fármacos , Imidazóis/síntese química , Pirróis/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Pirróis/química , Pirróis/farmacologia , Relação Quantitativa Estrutura-AtividadeRESUMO
A molecular modeling strategy using aryl diketo acid (ADK) derivatives recently reported in the literature as hepatitis C virus (HCV) polymerase inhibitors was designed. A 3D chemical-feature-based pharmacophore model was developed using Catalyst software, which produced 10 pharmacophore hypotheses. The top-ranked one (Hypo 1), characterized by a high correlation coefficient (r = 0.965), consisted of two hydrogen bond acceptors, one negative ionizable moiety, and two hydrophobic aromatics. This model was used to predict the anti-RNA-dependent RNA polymerase (anti-RdRp) activity of 6-(1-arylmethylpyrrol-2-yl)-1,4-dioxo-5-hexenoic acids and other ADK derivatives previously synthesized in our laboratories as HIV-1 integrase inhibitors. Furthermore, the experimental IC50 values of 9 compounds, tested in vitro against recombinant HCV polymerase, were compared with the corresponding values predicted using Hypo1. A good agreement between experimental and simulated data was obtained. The results demonstrate that the hypothesis derived in this study can be considered to be a useful tool in designing new leads based on ADK scaffolds as HCV RdRp inhibitors.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Cetoácidos/química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/química , Desenho de Fármacos , Modelos Moleculares , Estrutura Molecular , Relação Quantitativa Estrutura-AtividadeRESUMO
Pyrrolylethanoneamines 1-12, 18-23 and related amino alcohols 13-15, 24-27 were synthesized and tested against monoamine oxidases A and B (MAO-A and MAO-B) enzymes. In general, aminoketones 1-12, 18-23 were found to be potent and selective MAO-A inhibitors. In particular, 18 was more potent and selective against the MAO-A isoenzyme than reference drugs. Interestingly, amino alcohol 25 selectively inhibited MAO-B enzyme and could be a lead compound for designing more potent and selective MAO-B inhibitors.
Assuntos
Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Piperazinas/farmacologia , Pirrolidinas/farmacologia , Desenho de Fármacos , Cinética , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/farmacologia , Oxazolidinonas/química , Piperazinas/síntese química , Piperazinas/química , Piperidinas/química , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-AtividadeRESUMO
The affinities of the enantiomers of 1,3,4,14b-tetrahydro-2,10-dimethyl-2H,10H-pyrazino[2,1-d]pyrrolo[1,2-b] [1,2,5]benzotriazepine (10-methyl-10-azaaptazepine, 5) and 2-methyl-1,3,4,14b-tetrahydro-2H-pyrazino[2,1-d]pyrrolo[1,2-b] [1,2,5]benzothiadiazepine 10,10-dioxide (tiaaptazepine, 6) were evaluated in receptor binding assays. Compound (+)-(S)-5, the most significant tested enantiomer, showed good affinities for 5-HT1A, 5-HT2A 5-HT2C and alpha2NA receptors, moderate affinities for DA1, DA3r and 5-HT3 receptors and it was devoid of affinity for DA2, alpha(1NA) and muscarinic receptors. Compound (+)-(S)-5 showed an interesting pharmacological profile different from those of the reference compounds mirtazepine, mianserin and 6-methoxymianserin.
Assuntos
Antidepressivos/metabolismo , Azepinas/farmacologia , Mianserina/metabolismo , Pirazinas/farmacologia , Pirróis/farmacologia , Animais , Antidepressivos/química , Encéfalo/metabolismo , Cobaias , Técnicas In Vitro , Cinética , Mianserina/análogos & derivados , Mianserina/química , Ratos , Receptores Adrenérgicos alfa/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , EstereoisomerismoRESUMO
Dihydro-alkoxy-benzyl-oxopyrimidines (DABOs) are a family of potent NNRTIs developed in the past decade. Attempts to improve their potency and selectivity led to thio-DABOs (S-DABOs), DATNOs, and difluoro-thio-DABOs (F(2)-S-DABOs). More recently, we reported the synthesis and molecular modeling studies of a novel conformationally constrained subtype of the S-DABO series characterized by the presence of substituents on the methylene linkage connecting the pyrimidine ring to the aryl moiety (Mai, A., et al. J. Med. Chem. 2001, 44, 2544-2554). Now we report the computer-aided design, synthesis, and biological evaluation of four new DABO prototypes (5-alkyl-2-cyclopentylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydropyrimidin-4(3H)-ones, F(2)-NH-DABOs) in which the sulfur atom of the related F(2)-S-DABOs is replaced by an amino group. For these studies, we used as a reference model the cocrystallized MKC-442/RT complex. Docking studies with Autodock of the newly designed F(2)-NH-DABOs on the ligand-derived RT confirmed the findings previously described for the F(2)-S-DABOs. The F(2)-NH-DABO binding mode resembles that reported for F(2)-S-DABOs, with the difference that the NH moiety at the C-2 position represents a new anchor site for ligand/enzyme complexation. The predicted inhibition constant (K(i)) values by the internal scoring function of Autodock, and the predicted IC(50) values by the application of a VALIDATE II/HIV-RT model strongly suggested the synthesis of the designed amino-DABOs. F(2)-NH-DABOs were shown to be highly active in both anti-RT and anti-HIV biological assays with IC(50) and EC(50) comparable with that of the reference compound MKC-442. Interestingly, 2-cyclopentylamino-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methyl pyrimidin-4(3H)-one (9d) was active against the Y181C HIV-1 mutant strain at submicromolar concentration, with a resistance value similar to that of efavirenz, the last FDA-approved NNRTI for AIDS therapy, and 2-fold lower than that of its 2-cyclopentylthio counterpart 8d. The introduction in 9d of a new anchor point (pyrimidine C-2 NH group), with the formation of a new hydrogen bond with Lys101, could compensate for the lack of positive hydrophobic ligand/NNBP interactions due to the Tyr181 to Cys181 mutation.
Assuntos
Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Pirimidinonas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Linhagem Celular , Simulação por Computador , Desenho de Fármacos , Farmacorresistência Viral , HIV-1/genética , HIV-2/efeitos dos fármacos , Humanos , Modelos Moleculares , Mutação , Pirimidinonas/química , Pirimidinonas/farmacologia , Relação Quantitativa Estrutura-Atividade , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
The synthesis, anti-Candida activity, and quantitative structure-activity relationship (QSAR) studies of a series of 2,4-dichlorobenzylimidazole derivatives having a phenylpyrrole moiety (related to the antibiotic pyrrolnitrin) in the alpha-position are reported. A number of substituents on the phenyl ring, ranging from hydrophobic (tert-butyl, phenyl, or 1-pyrrolyl moiety) to basic (NH(2)), polar (CF(3), CN, SCH(3), NO(2)), or hydrogen bond donors and acceptor (OH) groups, were chosen to better understand the interaction of these compounds with cytochrome P450 14-alpha-lanosterol demethylase (P450(14DM)). Finally, the triazole counterpart of one of the imidazole compounds was synthesized and tested to investigate influence of the heterocyclic ring on biological activity. The in vitro antifungal activities of the newly synthesized azoles 10p-v,x-c' were tested against Candida albicans and Candida spp. at pH 7.2 and pH 5.6. A CoMFA model, previously derived for a series of antifungal agents belonging to chemically diverse families related to bifonazole, was applied to the new products. Because the results produced by this approach were not encouraging, Catalyst software was chosen to perform a new 3D-QSAR study. Catalyst was preferred this time because of the possibility of considering each compound as a collection of energetically reasonable conformations and of considering alternative stereoisomers. The pharmacophore model developed by Catalyst, named HYPO1, showed good performances in predicting the biological activity data, although it did not exhibit an unequivocal preference for one enantiomeric series of inhibitors relative to the other. One aromatic nitrogen with a lone pair in the ring plane (mapped by all of the considered compounds) and three aromatic ring features were recognized to have pharmacophoric relevance, whereas neither hydrogen bond acceptor nor hydrophobic features were found. These findings confirmed that the key interaction of azole antifungals with the demethylase enzyme is the coordination bond to the iron ion of the porphyrin system, while interactions with amino acids localized in proximity of heme could modulate the biological activity of diverse antifungal agents. In conclusion, HYPO1 conveys important information in an intuitive manner and can provide predictive capability for evaluating new compounds.