RESUMO
A series of N2,N2'-bis[4-hydroxycoumarin-3-yl)ethylidene]-2,3-dihydroxysuccino-hydrazides, containing 4-hydroxycoumarin, hydrazine and tartaric acid moieties, have been prepared and examined for possible biological activity. Several of these compounds exhibit promising HIV-1 integrase inhibition (IC50 = 3.5 µM), and anti-T. brucei (32% viability) and anti-mycobacterial (Visual MIC90 = 15.63 µM) activity.
Assuntos
Antifúngicos/farmacologia , Antituberculosos/farmacologia , Cumarínicos/farmacologia , Inibidores de Integrase de HIV/farmacologia , Hidrazinas/farmacologia , Tripanossomicidas/farmacologia , Antifúngicos/síntese química , Antifúngicos/metabolismo , Antituberculosos/síntese química , Antituberculosos/metabolismo , Domínio Catalítico , Cumarínicos/síntese química , Cumarínicos/metabolismo , Integrase de HIV/química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/metabolismo , HIV-1/enzimologia , Células HeLa , Humanos , Hidrazinas/síntese química , Hidrazinas/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Ligação Proteica , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
A series of N-benzylated phosphoramidate esters, containing a 3,4-dihydroxyphenyl Mg2+-chelating group, has been synthesised in five steps as analogues of fosmidomycin, a Plasmodium falciparum 1-deoxy-1-d-xylulose-5-phosphate reductoisomerase (PfDXR) inhibitor. The 3,4-dihydroxyphenyl group effectively replaces the Mg2+-chelating hydroxamic acid group in fosmidomycin. The compounds showed very encouraging anti-parasitic activity with IC50 values of 5.6-16.4 µM against Plasmodium falciparum parasites and IC50 values of 5.2 - 10.2 µM against Trypanosoma brucei brucei (T.b.brucei). Data obtained from in silico docking of the ligands in the PfDXR receptor cavity (3AU9)5 support their potential as PfDXR inhibitors.
Assuntos
Amidas/síntese química , Antimaláricos/síntese química , Complexos de Coordenação/síntese química , Magnésio/química , Ácidos Fosfóricos/síntese química , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/farmacologia , Complexos de Coordenação/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Fosfomicina/análogos & derivados , Fosfomicina/farmacologia , Células HeLa , Humanos , Ligantes , Simulação de Acoplamento Molecular , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
Synthetic pathways have been developed to access a series of N-benzylated phosphoramidic acid derivatives as novel, achiral analogues of the established Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductase (PfDXR) enzyme inhibitor, FR900098. Bioassays of the targeted compounds and their synthetic precursors have revealed minimal antimalarial activity but encouraging anti-trypanosomal activity - in one case with an IC50 value of 5.4 µM against Trypanosoma brucei, the parasite responsible for Nagana (African cattle sleeping sickness). The results of relevant in silico modelling and docking studies undertaken in the design and evaluation of these compounds are discussed.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antimaláricos/síntese química , Antimaláricos/farmacologia , Ácidos Fosfóricos/síntese química , Ácidos Fosfóricos/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Amidas/química , Animais , Antimaláricos/química , Bovinos , Ácidos Fosfóricos/química , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of novel, substituted 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones have been prepared and shown to exhibit promising concentration-dependent activity against human SH-SY5Y cells, Plasmodium falciparum, Mycobacterium tuberculosis and P. aeruginosa. Substituent effects on observed bioactivity have been explored; the para-fluorophenyl derivative 3d exhibited activity across the range of the bioassays employed, indicating the potential of the 2-chloro-3-[(4-arylthiazol-2-yl)amino]-1,4-naphthoquinone scaffold in the development of novel, broad spectrum therapeutics.
Assuntos
Naftoquinonas/síntese química , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of readily accessible 4-arylimino-3-hydroxybutanoic acids have been prepared and evaluated as potential HIV-1 Integrase inhibitors. None of the ligands exhibited significant toxicity against human embryonic kidney (HEK 293) cells, while five of them showed activity against HIV-1 integrase - the most active (6c) with an IC50 value of 3.5⯵M. In silico docking studies indicate the capacity of ligand 6c to interact with several amino acid residues and the two Mg2+ cations in the HIV-1 integrase receptor cavity.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Hidroxibutiratos/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Hidroxibutiratos/síntese química , Hidroxibutiratos/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A practicable six-step synthetic pathway has been developed to access a library of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones using Morita-Baylis-Hillman methodology. These compounds and their 3-[(N-cycloalkylamino)methyl]-2-quinolone precursors have been screened as potential HIV-1 integrase (IN) inhibitors. A concomitant survey of their activity against HIV-1 protease and reverse-transcriptase reveals selective inhibition of HIV-1 IN.
Assuntos
Inibidores de Integrase de HIV/síntese química , Integrase de HIV/química , HIV-1/enzimologia , Quinolonas/química , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , Humanos , Quinolonas/metabolismo , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
(1)H NMR-based kinetic studies have revealed the latent mechanistic complexity of deceptively simple hydrochloric acid-catalyzed reactions of salicylaldehyde-derived Baylis-Hillman adducts. Reactions conducted at 0 °C afforded 2-(chloromethyl)cinnamic acid derivatives as the major products and the corresponding 3-(chloromethyl)coumarin derivatives as the minor products. In reactions conducted in refluxing acetic acid, however, the 3-(chloromethyl)coumarin derivatives are the sole products. Variable-temperature (1)H NMR analysis permitted the determination of the rate constants and kinetic parameters involved in the pseudo-first-order formation of (Z)-2-(chloromethyl)-3-(2-hydroxyphenyl)-2-propenoic acid. The kinetic data clearly preclude the operation of classical kinetic versus thermodynamic control and indicate the operation of three independent reaction pathways. Theoretical studies of these pathways undertaken at the B3LYP/6-31G(d) level permitted rationalization of the experimental data and provided insights into the possible mechanism of the enzymic E-Z isomerization and cyclization of (E)-cinnamic acid analogues to afford coumarins.
RESUMO
Encouraging selectivity and low micromolar activity against HeLa cervical carcinoma (IC50⩾3.0µM) and the aggressive MDA-MB-231 triple negative breast carcinoma (IC50⩾9.6µM) cell lines has been exhibited by a number of readily accessible 4-(N-benzylamino)cinnamate esters. The potential of the ligands as HIV-1 integrase inhibitors has also been examined.
Assuntos
Antineoplásicos/farmacologia , Cinamatos/farmacologia , Ésteres/farmacologia , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/síntese química , Cinamatos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/química , Células HEK293 , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Células HeLa , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of novel and readily accessible N-benzylated (N-arylcarbamoyl)alkylphosphonate esters and related compounds have been prepared as potential antimalarial agents. Bioassays reveal that some of these compounds exhibit promising activity against Plasmodium falciparum, and exhibit no significant growth inhibition of HeLa cells.
Assuntos
Amidas/farmacologia , Antimaláricos/farmacologia , Organofosfonatos/farmacologia , Aldose-Cetose Isomerases/antagonistas & inibidores , Amidas/síntese química , Amidas/toxicidade , Antimaláricos/síntese química , Antimaláricos/toxicidade , Fosfomicina/análogos & derivados , Fosfomicina/farmacologia , Células HeLa , Humanos , Organofosfonatos/síntese química , Organofosfonatos/toxicidade , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Novel 3-hydroxy-3-phenylpropanoate ester-azidothymidine (AZT) conjugates have been prepared using Baylis-Hillman methodology, and their potential as dual-action HIV-1 Integrase and Reverse Transcriptase inhibitors has been explored using enzyme inhibition and computer modelling techniques; their activity and HeLa cell toxicity have been compared with those of their cinnamate ester analogues.
Assuntos
Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Zidovudina/química , Zidovudina/farmacologia , Fármacos Anti-HIV , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa/síntese química , Relação Estrutura-Atividade , Zidovudina/síntese químicaRESUMO
A series of seven novel, rationally designed N-substituted 3-{3,5-dimethylfuro[3,2-g]coumarin-6-yl}propanamides have been prepared as potential HIV-1 integrase (IN) inhibitors via a five-step pathway commencing with resorcinol and diethyl 2-acetylglutarate, and the HIV-1 IN inhibition potential of these compounds has been examined relative to raltegravir, a known HIV-1 IN inhibitor.
Assuntos
Furocumarinas/química , Furocumarinas/farmacologia , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Cristalografia por Raios X , Infecções por HIV/tratamento farmacológico , Infecções por HIV/enzimologia , Infecções por HIV/virologia , Integrase de HIV/química , Integrase de HIV/metabolismo , HIV-1/enzimologia , Humanos , Relação Estrutura-AtividadeRESUMO
Baylis-Hillman-derived 3-(benzylaminomethyl)coumarins have been treated, sequentially, with chloroacetyl chloride and propargylamine to afford alkynylated coumarins as substrates for Click Chemistry reactions with azidothymidine (AZT) in the presence of a Cu(I) catalyst. The dual-action HIV-1 protease (PR) and reverse transcriptase (RT) inhibition potential of the resulting N-benzylated cycloaddition products, and a series of non-benzylated analogues, has been explored using saturation transfer difference (STD) NMR, computer modelling and enzyme inhibition techniques.
Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Cumarínicos/síntese química , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Protease de HIV/metabolismo , Inibidores da Protease de HIV/síntese química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Modelos Moleculares , Inibidores da Transcriptase Reversa/síntese química , Zidovudina/síntese química , Zidovudina/química , Zidovudina/farmacologiaRESUMO
DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand-receptor interactions.
Assuntos
Aldose-Cetose Isomerases/antagonistas & inibidores , Aldose-Cetose Isomerases/química , Amidas/síntese química , Carbamatos/síntese química , Desenho de Fármacos , Aldose-Cetose Isomerases/metabolismo , Amidas/química , Amidas/farmacologia , Sítios de Ligação , Carbamatos/química , Carbamatos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacosRESUMO
The diethyl esters and disodium salts of a range of heteroarylcarbamoylphosphonic acids have been prepared and evaluated as analogues of the highly active DOXP-reductoisomerase (DXR) inhibitor, fosmidomycin. Computer-simulated docking studies, Saturation Transfer Difference (STD) NMR analysis and enzyme inhibition assays have been used to explore enzyme-binding and -inhibition potential, while in silico analysis of the DXR active site has highlighted the importance of including a well-parameterised metal co-factor in docking studies and has revealed the availability of an additional binding pocket to guide future drug design.
Assuntos
Aldose-Cetose Isomerases/antagonistas & inibidores , Antimaláricos/síntese química , Antimaláricos/farmacologia , Fosfomicina/análogos & derivados , Furanos/síntese química , Complexos Multienzimáticos/antagonistas & inibidores , Organofosfonatos/síntese química , Oxirredutases/antagonistas & inibidores , Aldose-Cetose Isomerases/metabolismo , Antimaláricos/química , Simulação por Computador , Desenho de Fármacos , Fosfomicina/química , Fosfomicina/farmacologia , Furanos/química , Furanos/farmacologia , Estrutura Molecular , Complexos Multienzimáticos/metabolismo , Organofosfonatos/química , Organofosfonatos/farmacologia , Oxirredutases/metabolismo , Ligação ProteicaRESUMO
Baylis-Hillman reactions of 2-nitrobenzaldehydes with various activated alkenes afford adducts that undergo reductive cyclisation to quinoline derivatives. The chemo- and regioselectivity of cyclisation appears to be influenced by the choice of both the substrate and the reagent system, and competing reactions have been observed.
Assuntos
Modelos Químicos , Quinolinas/química , Quinolinas/síntese químicaRESUMO
The influence of substituents and structure on the 13C NMR spectra of four series of benzoxathiepine derivatives has been investigated. Signal assignments in the 13C NMR spectra have been facilitated by the use of several predictive methods, permitting comparison of their relative efficacy.
Assuntos
Benzodiazepinas/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Espectroscopia de Ressonância Magnética/métodos , Isótopos de Carbono , Espectroscopia de Ressonância Magnética/normas , Estrutura Molecular , Padrões de ReferênciaRESUMO
5-Hydroxy-2-isopropyl-7-methoxychromone (1d), a chromone constituent isolated from the aerial parts of Baeckea frutescens, and four analogues (1a-c and 1e), all of which exhibit toxicity to the brine shrimp Artemia salina, have been prepared from 2',4',6'-trihydroxyacetophenone. High-resolution mass spectrometric analysis has permitted elucidation of the fragmentation patterns exhibited by these systems following electron-impact ionization.
Assuntos
Artemia/efeitos dos fármacos , Cromonas , Plantas Medicinais/química , Animais , Cromonas/síntese química , Cromonas/química , Cromonas/isolamento & purificação , Cromonas/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear BiomolecularRESUMO
Evidence is presented which supports the intermediacy of dipolar Baylis-Hillman-type adducts in the synthesis of coumarin and chromene derivatives from the reaction of 2-hydroxybenzaldehydes with methyl acrylate in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO).