Search

Bioactivity-guided fractionation of the methanolic root bark extract of Leucophyllum frutescens led to the identification of leubethanol (1), a new serrulatane-type diterpene with activity against both multi-drug-resistant and drug-sensitive strains of virulent Mycobacterium tuberculosis. Leubethanol (1) was identified by 1D/2D NMR data, as a serrulatane closely related to erogorgiane (2), and exhibited anti-TB activity with minimum inhibitory concentrations in the range 6.25-12.50 μg/mL. Stereochemical evidence for 1 was gleaned from 1D and 2D NOE experiments, from 1H NMR full spin analysis, and by comparison of the experimental vibrational circular dichroism (VCD) spectrum to density functional theory calculated VCD spectra of two diastereomers.

Abstract Ethnopharmacological relevance In Mexico, plants are an important element of traditional medicine, and many are considered part of Mexican cultural heritage from prehispanic and colonial times. Nevertheless, relatively few systematic scientific studies have been conducted to fully characterize the chemical composition and pharmacological activities of Mexican medicinal plants. Acacia farnesiana is used in Mexican traditional medicine to treat dysentery and tuberculosis and therefore could have bioactive compounds that may explain its traditional use. Aims of the study i) To isolate and characterize the compounds from the hexanic, chloroformic and methanolic extracts; ii) to identify the volatile compounds from methylated hexanic and chloroformic extracts using GC-FID and GC-MS methods; iii) to identify the compounds from methanolic and aqueous extracts using HPLC-Q-TOF-MS; iv) to test the activity of extracts and isolated compounds against Mycobacterium tuberculosis and dysentery bacteria. Material and methods A. farnesiana fruits were collected in Acatlán de Osorio, Puebla, Mexico. Hexanic, chloroformic, methanolic and aqueous extracts were prepared and analyzed by different chromatographic techniques including column chromatography, flash chromatography, GC-FID, GC-MS and HPLC-Q-TOF-MS. Structural elucidation was carried out by NMR spectroscopic analysis. The activity of extracts, phytochemicals and semi-synthetic derivatives against Mycobacterium tuberculosis H37Rv and G122 as well as dysentery bacteria (Campylobacter jejuni , Shigella flexneri , Salmonella enteritidis , Yersinia enterocolitica and enterohemorrhagic Escherichia coli) was determined by the broth microdilution method and reported as minimal inhibitory concentration (MIC µg/mL). Results From both hexane and chloroform extracts, tetracosanoic acid (2 S)-2,3-dihydroxypropyl ester (1) and (3β,22 E)-estigmasta-5,22-dien-3-yl β-D-glucopyranoside (2) were isolated and characterized. From the methanolic extract, methyl gallate (3), gallic acid (4), (3β,22 E)-estigmasta-5,22-dien-3-yl β-D-glucopyranoside (2), (2 S) naringenin 7- O -β-glucopyranoside (prunin, 5), pinitol (6) and sucrose (7) were isolated and characterized. Furthermore, hexanic and chloroformic extracts were analyzed by GC-FID and GC-MS and 18 methylated fatty acids were identified for each extract in addition to three sterols. The methanolic and aqueous extracts were analyzed separately by HPLC-Q-TOF-MS, and 15 compounds were identified in each extract. The compounds 1 , 2 , and 7 , in addition to 13 fatty acids and eight phenolic compounds, were identified for the first time in A. farnesiana. The extracts showed antitubercular (MIC 100–200 µg/mL) and antidysentery activity (MIC 100–200 µg/mL). Methyl gallate and its acetylated derivative showed activity against the sensible strain M. tuberculosis H37Rv with MIC values of 50–25 µg/mL, respectively. The flavanone prunin showed activity against multidrug resistant M. tuberculosis G122 (MIC 50 μg/mL). Methyl gallate, gallic acid and prunin showed activity against C. jejuni (MIC 50 μg/mL). Conclusions The activity of tested extracts and isolated compounds against M. tuberculosis and dysentery bacteria justifies the ethnomedical use of A. farnesiana fruits for the treatment of tuberculosis and dysentery. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Thirty-three meso -dihydroguaiaretic acid ( meso -DGA) derivatives bearing esters, ethers, and amino-ethers were synthesized. All derivatives were tested against twelve drug-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including sensitive (H37Rv) and multidrug-resistant Mycobacterium tuberculosis strains. Among the tested compounds, four esters ( 7 , 11 , 13 , and 17 ), one ether ( 23 ), and three amino-ethers ( 30 , 31 , and 33 ) exhibited moderate activity against methicillin-resistant Staphylococcus aureus , whereas 30 and 31 showed better results than levofloxacin against vancomycin-resistant Enterococcus faecium . Additionally, nineteen meso -DGA derivatives displayed moderate to potent activity against M. tuberculosis H37Rv with minimum inhibitory concentration (MIC) values ranging from 3.125 to 50 µg/mL. Seven meso -DGA derivatives bearing amino-ethers ( 26 – 31 and 33 ) exhibited the lowest MICs against M. tuberculosis H37Rv and G122 strains, with 31 being as potent as ethambutol (MICs of 3.125 and 6.25 µg/mL). The presence of positively charged group precursors possessing steric and hydrophobic features (e.g. N -ethylpiperidine moieties in meso - 31 ) resulted essential to significantly increase the antimycobacterial properties of parent meso -DGA as supported by the R-group pharmacophoric and field-based QSAR analyses. To investigate the safety profile of the antimycobacterial compounds, cytotoxicity on Vero cells was determined. The amino-ether 31 exhibited a selectivity index value of 23, which indicate it was more toxic to M. tuberculosis than to mammalian cells. Therefore, 31 can be considered as a promising antitubercular agent for further studies. [ABSTRACT FROM AUTHOR]

The synthesis of 19 compounds derived from l -serine and analogs of p -substituted cinnamic acid is reported. Oxazolines 9 and oxazoles 10 have high antitubercular activity with Minimum Inhibitory Concentration (MIC) of 0.7812–25.0 µg/mL (3.21–100.3 µM), against two strains of Mycobacterium tuberculosis sensitive to first-line drugs Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB), Pyrazinamide (PZE) (H37Rv) and a clinical isolate resistant to INH, RIF and EMB (G122). The cytotoxic evaluation shows that oxazoles have low activity, finding viability>96% against the VERO cell line. The results show these compounds could be considered as future alternatives for antitubercular treatment. [ABSTRACT FROM AUTHOR]