Solution phase synthesis of a combinatorial library of chalcones and flavones as potent cathepsin V inhibitors.

Cathepsin V is a papain-like cysteine protease. It is involved in the control of human T cells (responsible for cell immunity), and presents the largest elastolytic activity among the proteolytic enzymes. Therefore, cathepsin V is a potential molecular target for the treatment of atherosclerosis. In the present work, natural flavonoids were screened against cathepsin V, and two flavones were identified as potent inhibitors of cathepsin V. On the basis of this result, a combinatorial library of chalcones and flavones was prepared, in solution phase employing a scavenger reagent, and fully evaluated.

Simultaneous enantioselective quantification of fluoxetine and norfluoxetine in human milk by direct sample injection using 2-dimensional liquid chromatography-tandem mass spectrometry.

A two-dimensional liquid chromatography system coupled to triple quadrupole tandem mass spectrometer (2D LC-MS/MS) was employed for the simultaneously quantification of fluoxetine (FLX) and norfluoxetine (NFLX) enantiomers in human milk by direct injection of samples. A restricted access media of bovine serum albumin octadecyl column (RAM-BSAC18) was used in the first dimension for the milk proteins depletion, while an antibiotic-based chiral column was used in the second dimension. The results herein described show good selectivity, extraction efficiency, accuracy, and precision with limits of quantification in the order of 7.5ngmL(-1)for the FLX enantiomers and 10.0ngmL(-1) for NFLX enantiomers. Furthermore, it represents a practical tool in terms of sustainability for the sample preparation of such a difficult matrix.

Structure-activity relationship of (-) mammea A/BB derivatives against Leishmania amazonensis.

To study the structure-activity relationship of coumarin (-) mammea A/BB isolated from the CH(2)Cl(2) extract of Calophyllum brasiliense leaves, we evaluated the antileishmanial activity of natural, synthetic and derivatives of this coumarin, against promastigote and intracellular amastigote forms of Leishmania amazonensis, and their cytotoxicity to J774G8 murine macrophages. The derivatives were obtained by hydrogenation and methoxylation reactions. The compound structures were elucidated on the basis of spectroscopic data. The compounds 5,7-dihydroxy-8-(2-methylbutanoyl)-6-(3-methylbutyl)-4-phenyl-chroman-2-one (3), 7-hydroxy-5-methoxy-8-(2-methylbutanoyl)-6-(3-methylbut-2-en-1-yl)-4-phenylcoumarin (4) and 5,7-dimethoxy-8-(1-methoxy-2-methylbutyl)-6-(3-methylbut-2-en-1-yl)-4 phenylcoumarin (6) were more biologically active than the compound (-) mammea A/BB (1) (7.4 microM), with IC(50) values from 0.9, 2.4 and 1.9 microM respectively; compound (3) displayed the highest activity. The compounds mammea B/BB (2), 5,7-dimethoxy-8-(2-methylbutanoyl)-6-(3-methylbut-2-en-1-yl)-4-phenylcoumarin (5) and 5,7-dihydroxy-4-phenylcoumarin (7) were less active than (-) mammea A/BB (1), with IC(50) of 30.1, 15.1 and 60.2 microM respectively; compound (7) showed the lowest antileishmanial activity of all. Compounds (1), (3), (4) and (6) were active not only against promastigote forms of L. amazonensis, but also against intracellular amastigote forms with IC(50) of 14.3, 0.6, 34.0 and 22.2 microM, respectively. Interestingly, compound (3) showed the most antileishmanial activity of all. This study demonstrated that several aspects of the structure were important for antileishmanial activity.