Chemical and biological comparisons on supercritical extracts of Tanacetum cinerariifolium (Trevir) Sch. Bip. with three related species of chrysanthemums of Sardinia (Italy).

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.

Antimycobacterial agents. Novel diarylpyrrole derivatives of BM212 endowed with high activity toward Mycobacterium tuberculosis and low cytotoxicity.

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.

Ligand-based virtual screening, parallel solution-phase and microwave-assisted synthesis as tools to identify and synthesize new inhibitors of mycobacterium tuberculosis.

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.

Phenolic constituents from Ephedra nebrodensis.

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.

Antimycobacterial compounds. Optimization of the BM 212 structure, the lead compound for a new pyrrole derivative class.

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.

Antimycobacterial compounds. New pyrrole derivatives of BM212.

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.

Importance of the thiomorpholine introduction in new pyrrole derivatives as antimycobacterial agents analogues of BM 212.

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.