Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability.

While N-acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N-acetyl moiety for a N-carbamoyl group led to analogues with sub- and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug-susceptible and drug-resistant M. tuberculosis isolates. The new N-carbamoyl azaaurones exhibited improved microsomal stability, compared to their N-acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10-8 , a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.

Facile Access to Structurally Diverse Antimalarial Indoles Using a One-Pot A3 Coupling and Domino Cyclization Approach.

A multistep and diversity-oriented synthetic route aiming at the A3 coupling/domino cyclization of o-ethynyl anilines, aldehydes and s-amines is described. The preparation of the corresponding precursors included a series of transformations, such as haloperoxidation and Sonogashira cross-coupling reactions, amine protection, desilylation and amine reduction. Some products of the multicomponent reaction underwent further detosylation and Suzuki coupling. The resulting library of structurally diverse compounds was evaluated against blood and liver stage malaria parasites, which revealed a promising lead with sub-micromolar activity against intra-erythrocytic forms of Plasmodium falciparum. The results from this hit-to-lead optimization are hereby reported for the first time.

Functionalized Cyclopentenones with Low Electrophilic Character as Anticancer Agents.

In this study were synthesized non-Michael acceptor cyclopentenones (CP) from biomass derivative furfural as anticancer agents. Cyclic enones, both from natural sources and synthetic analogues, have been described as cytotoxic agents. Most of these agents were unsuccessful in becoming valuable therapeutic agents due to toxicity problems derived from unselective critical biomacromolecule alkylation. This may be caused by Michael addition to the enone system. Ab initio studies revealed that 2,4-substituted CPs are less prone to Michael additions, and as such were tested three families of those derivatives. We prepare the new CPs from furfural through a tandem furan ring opening/Nazarov electrocyclization and further functionalization. Experimentally the 2,4-substituted CPs exhibited no reactivity towards sulphur nucleophiles, while maintaining cytotoxicity against HT-29, MCF-7, NCI-H460, HCT-116 and MDA-MB 231 cells lines. Moreover, the selected CP are non-toxic against healthy HEK 293T cell lines and present proper calculated drug-like properties.

Colon adenocarcinoma multidrug resistance reverted by Euphorbia diterpenes: structure-activity relationships and pharmacophore modeling.

Multidrug resistance (MDR) is a limiting step on the success of cancer chemotherapy. The drug efflux mediated by P-gp (Pglycoprotein) is one of the best studied mechanisms of MDR. This paper focuses on the inhibitory P-gp efflux activity, pharmacophore modeling and structure-activity relationships studies of sixteen macrocyclic diterpenes and polycyclic derivatives obtained from Euphorbia species. The MDR human colon adenocarcinoma cells (COLO 320 MDR) overexpressing P-gp were used as the biological model to screen for P-gp dependent efflux inhibitors. Most of the compounds showed potential as MDR reversal agents. Combined analysis of two different statistic algorithms, K-means clustering and Principal Component Analysis discriminated two clusters and showed a strong correlation between log P and MDR reversal activity for compounds 1-5. The most effective compounds (1-4 and 11-12) were tested in combination with doxorubicin and all potentiated its activity lowering the ID50. Pharmacophore modeling allowed the definition of an aromatic moiety as an additional feature to a previous published P-gp pharmacophore, creating a new five-point pharmacophore with enhanced selectivity for the most active compounds of the present study. Docking results also show the importance of an aromatic moiety, positively identifying the most relevant residues that can be linked to an inhibitory activity increase.

Antibacterial activity of some African medicinal plants used traditionally against infectious diseases.

CONTEXT: Plants are known to play a crucial role in African traditional medicine for the treatment of infection diseases. OBJECTIVES: To investigate the claimed antimicrobial properties of plants traditionally used in African countries, providing scientific validation for their use. MATERIALS AND METHODS: Eighty-three polar and non-polar extracts from 22 medicinal plants were screened for their antibacterial activity against Gram-positive (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and Mycobacterium smegmatis using the broth microdilution method. RESULTS AND DISCUSSION: In vitro antibacterial activity against one or more tested bacteria was shown by 83% of the extracts. The highest activity was obtained with the methanol extracts of the aerial parts of Acacia karroo Hayne (Fabaceae) and Anacardium occidentale L. (Anacardiaceae) and the roots of Bridelia cathartica G. Bertol (Euphorbiaceae), against S. aureus (minimum inhibitory concentration (MIC) = 7.5 µg/mL). The same MIC values were exhibited against E. faecalis by the methanol extract of A. occidentale, the dichloromethane and methanol extracts of B. cathartica and the ethyl acetate extract of Momordica balsamina l. (Curcubitaceae) leaves. Gram-negative bacteria were less sensitive; the growth of P. aeruginosa was significantly inhibited (MIC = 31 µg/mL) by the n-hexane and methanol extracts of Gomphocarpus fruticosus (l.) Ait. (Asclepiadaceae) fruits and by the dichloromethane extract of Trichilia emetica Vahl (Meliaceae) seeds. Most of the active extracts were rich in fenols/flavonoids. CONCLUSION: This study supports the use of most of the studied plants in traditional medicine, for the treatment of infectious diseases. Some of them are worthy of further investigation.

Euphoportlandols A and B, tetracylic diterpene polyesters from Euphorbia portlandica and their anti-MDR effects in cancer cells.

Two new tetracyclic diterpene polyesters, euphoportlandols A (1) and B (2), have been isolated along with 12 known tetracyclic triterpenes from an acetone extract of Euphorbia portlandica. Their structures were established as 5alpha,11alpha,14alpha,17-tetraacetoxy-3beta-benzoyloxy-6beta,15beta-dihydroxy-9-oxoseget-8(12)-ene (1) and 5alpha,11alpha,14alpha,17-tetraacetoxy-3beta-benzoyloxy-6beta,15beta-dihydroxy-9-oxosegetane (2), respectively, by spectroscopic data interpretation. Compounds 1 and 2 were evaluated for their ability to inhibit multidrug resistance in cancer cells. Both compounds were found to be inhibitors of P-glycoprotein activity.

Inhibition of P-glycoprotein transport activity in a resistant mouse lymphoma cell line by diterpenic lactones.

Multidrug resistance (MDR) is believed to be a major reason for the failure of cancer treatment. It is in most cases caused by the activity of the various ABC transporters, multidrug resistance (MDR) gene-encoded p-glycoproteins that pump anticancer drugs out of the cells. P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1) are the most important and widely studied members of the ABC superfamily of transporters. The ability of four diterpenic lactones isolated from Euphorbia species to modulate the transport activity of P-gp in mouse lymphoma cells was evaluated by flow cytometry. The reversion of MDR was investigated by using a standard functional assay with rhodamine 123 as a fluorescent substrate analogue of doxorubicin. Verapamil was applied as a positive control. All the compounds were able to reverse the MDR of the tested human MDR1 gene-transfected mouse lymphoma cells, in a concentration-dependent manner from 4 to 40 microg/mL, in a short-term experiment below the cytotoxic doses.

A new sesquiterpene-coumarin ether and a new abietane diterpene and their effects as inhibitors of P-glycoprotein.

A new sesquiterpene-coumarin ether (5'beta,9'alpha,10'alpha)-7-0-(3alpha-methoxy-8'(12')-drimen-11'-yl)-scopoletin, designated driportlandin (1) and a new abietane quinoid diterpene 16-hydroxy-abieta-8,12-diene-11,14-dione, named portlanquinol (2) together with lupeol, nepehinol, wrightial, formonetin and davidigenin were isolated and characterized from the Me2CO extract of whole dried plant of Euphorbia portlandica. The structures of the new compounds were elucidated from spectral data including 2D-NMR experiments of COSY, HMQC, HMBC and NOESY. When examined for their effects on the reversal of multidrug resistance(MDR) on mouse lymphoma cells, compound 1 proved to be more active than the positive control verapamil and compound 2 was found to be toxic. This is the first report on the isolation of a sesquiterpene-coumarin and a quinoid-type diterpenoid from Euphorbia.

Rearranged jatrophane-type diterpenes from euphorbia species. Evaluation of their effects on the reversal of multidrug resistance.

The rearranged jatrophane-type diterpenes ( 1 - 3), isolated from the Me (2)CO extracts of Euphorbia portlandica and Euphorbia segetalis, were examined for their effects on multidrug resistance (MDR) in mouse lymphoma cells. Compounds 2 and 3 revealed to be active with the latter being more active than the positive control verapamil, a known resistance modifier. The new compound 1, named portlandicine, was isolated from Euphorbia portlandica and its structure characterised by high-field NMR spectroscopic methods including 2D NMR techniques: COSY, HMQC, HMBC and NOESY. The known diterpene 2, together with aleuritolic acid ( 4), oleanolic acid ( 5), and betulin diacetate ( 6), were also isolated from the same species.