RESUMO
In this manuscript, the authors compare the chemical composition and the biological effects of extracts of some Sardinian plant species: Glebionis coronaria (L.) Spach [=Chrysanthemum coronarium L.], locally known as 'caragantzu', Glebionis segetum (L.) Fourr. [=Chrysanthemum segetum L.], known as 'caragantzu masedu', and Sardinian endemic species Plagius flosculosus (L.) Alavi and Heywood [=Chrysanthemum flosculosus L.], known as 'caragantzu burdu'. In addition, the authors compare the pyrethrins contained in these species with an extract of Tanacetum cinerariifolium (Trevir.) Sch. Bip. [=Chrysanthemum cinerariifolium (Trevir.) Vis.], a commercial species rich in pyrethrins. The volatile fractions from chrysanthemum flowers were obtained by supercritical fluid extraction (SFE) with CO(2) at 90 bar and 50 degrees C and by hydrodistillation. Pyrethrins were extracted, together with other high molecular mass compounds, by SFE at high pressure, 300 bar and 40 degrees C. The composition of the volatile oils is determined by GC-MS analysis and the amount of pyrethrins by HPLC analysis. Moreover, the antibacterial and antimycotic activities of volatile fractions were investigated in order to compare to their traditional uses.
Assuntos
Chrysanthemum cinerariifolium/química , Extratos Vegetais/farmacologia , Terpenos/isolamento & purificação , Terpenos/farmacologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cromatografia com Fluido Supercrítico , Cromatografia Gasosa-Espectrometria de Massas , Células HeLa , Humanos , Itália , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Terpenos/química , Células VeroRESUMO
In an attempt to identify new inhibitors of the growth of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis, a procedure for the generation, design, and screening of a ligand-based virtual library was applied. This used both an in silico protocol centered on a recursive partitioning (RP) model described herein, and a pharmacophoric model for antitubercular agents previously generated by our research group. Two candidates emerged from databases of commercially available compounds, both characterized by a minimum inhibitory concentration (MIC) of 25 microg mL(-1). Based on these compounds, two series of derivatives were synthesized by both parallel solution-phase and microwave-assisted synthesis, leading to enhanced antimycobacterial activity. During both the design and synthesis, attention was focused on the efficient allocation of available resources with the aim of reducing the overall costs associated with calculation and synthesis.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/farmacocinética , Inteligência Artificial , Biologia Computacional , Simulação por Computador , Bases de Dados Factuais , Avaliação Pré-Clínica de Medicamentos , Ligantes , Testes de Sensibilidade Microbiana , Micro-Ondas , Complexo Mycobacterium avium/efeitos dos fármacos , SoluçõesRESUMO
On the basis of suggestions derived either from a pharmacophoric model for antitubercular agents or from a structure-activity relationship analysis of many pyrroles previously described by us, we report here the design and synthesis of new analogues of 1,5-(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212). Various substituents with different substitution patterns were added to both positions 1 and 5 of the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. Biological data showed that, although some nontuberculosis mycobacterial strains were found to be sensitive, MIC values were higher than those found toward MTB. The best compound (1-(4-fluorophenyl)-2-methyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole, 5) possessed a MIC of 0.4 microg/mL (better than BM212 and streptomycin) and a very high protection index (160), better than BM212, isoniazid, and streptomycin (6, 128, and 128, respectively). Finally, molecular modeling studies were performed to rationalize the activity of the new compounds in terms of both superposition onto a pharmacophoric model for antitubercular compounds and their hydrophobic character.
Assuntos
Antituberculosos/síntese química , Morfolinas/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Piperazinas/síntese química , Pirróis/síntese química , Animais , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Chlorocebus aethiops , Testes de Sensibilidade Microbiana , Modelos Moleculares , Morfolinas/farmacologia , Morfolinas/toxicidade , Piperazinas/farmacologia , Piperazinas/toxicidade , Pirróis/farmacologia , Pirróis/toxicidade , Relação Quantitativa Estrutura-Atividade , Células VeroRESUMO
Two new phenolic glycosides, 4-hydroxy-3-(3-methyl-2-butenyl)phenyl beta-D-glucopyranoside (nebrodenside A) and O-coumaric acid beta-D-allopyranoside (nebrodenside B), were isolated from the aerial parts of Ephedra nebrodensis. In addition, O-coumaric acid glucoside, (-)-epicatechin, and (-)-ephedrine were also isolated. The structures were deduced from extensive 1D and 2DNMR spectroscopy (1H, 13C, DQF-COSY, TOCSY, GHSQC, GHMQC, ROESY) as well as mass spectrometry (EI and HR-MALDI). (-)-Epicatechin showed weak antiviral activity against Influenza A virus and very weak cytotoxicity against MDCK cells.
Assuntos
Cumarínicos/isolamento & purificação , Ephedra/química , Glicosídeos/isolamento & purificação , Catequina/química , Catequina/isolamento & purificação , Catequina/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Efedrina/química , Efedrina/isolamento & purificação , Efedrina/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Vírus da Influenza A/efeitos dos fármacosRESUMO
Our work on antitubercular agents led to the identification of BM 212 as a lead compound among a series of pyrrole derivatives with good in vitro activity against mycobacteria and candidae. Further studies led us to synthesize additional pyrroles bearing the thiomorpholinomethyl moiety and different aryl substituents at N1 and C5. Some of them revealed very active, prompting us to design the new pyrrole derivatives 5-20 in the hope of increasing the activity and better understanding the influence of ortho halogens on the antimycobacterial activity. Microbiological data showed interesting in vitro activity toward Mycobacterium tuberculosis and atypical mycobacteria.
Assuntos
Antituberculosos/farmacologia , Piperazinas/farmacologia , Pirróis/farmacologia , Antituberculosos/química , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Piperazinas/química , Pirróis/químicaRESUMO
We have identified BM212 as a lead compound among a series of pyrrole derivatives with good in vitro activity against mycobacteria and candidae. First studies led us to synthesize some pyrrole compounds in which the thiomorpholine fragment was present. Some compounds revealed very active and these findings prompted us to prepare new pyrrole derivatives 2-15 in the hope of increasing the activity. The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria.
Assuntos
Antituberculosos/farmacologia , Piperazinas/farmacologia , Pirróis/farmacologia , Antituberculosos/química , Farmacorresistência Bacteriana Múltipla , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Mycobacterium/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/química , Pirróis/síntese química , Pirróis/químicaRESUMO
During the course of our investigations in the field of azole antimicrobial agents, we have identified BM 212, a pyrrole derivative with good in vitro activity against mycobacteria and candidae. These findings prompted us to prepare new pyrrole derivatives 1-10 in the hope of increasing the activity. The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria.