Synthesis and anti-Mycobacterium tuberculosis activity of imide-ß-carboline and carbomethoxy-ß-carboline derivatives.

A series of methyl ß-carboline carboxylates (2a-g) and of imide-ß-carboline derivatives containing the phthalimide (4a-g), maleimide (5b, g) and succinimide (6b, e, g) moiety were synthesized, and evaluated for their activity against Mycobacterium tuberculosis H37Rv. The most active ß-carboline derivatives against the reference strain were assayed for their cytotoxicity and the activity against resistant M. tuberculosis clinical isolates. Farther, structure-activity relationship (SAR) studies were carried out using the three and four-dimensional approaches for starting to understand the way of ß-carboline activity in M. tuberculosis. All 19 ß-carboline derivatives were assayed, firstly, by determining the minimum inhibitory concentration (MIC) using resazurin microtiter assay plate (REMA) in M. tuberculosis H37Rv. Then, five derivatives (2c, 4a, 4e, 4g, 6g), which showed MIC ≤ 125 µg/mL, were assayed in nine resistant M. tuberculosis clinical isolates (five MDR, three isoniazid monoresistant and one isoniazid plus streptomycin resistant). The MIC values against the resistant clinical isolates ranged from 31.25 to >250 µg/mL. All five derivatives were non-cytotoxic to the VERO cell line, determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, at the tested concentration (selectivity index ranged from <1.74 to 14.4). Our study demonstrated that (2c) and (6g) derivatives had better anti-M. tuberculosis activity, especially against resistant clinical isolates, what makes them scaffold candidates for further investigations about their anti-tuberculosis activity. The SAR study conducted with the 19 ß-carboline derivatives showed the importance of steric effects for the synthesized ß-carbolines against M tuberculosis, and these models can be used for future proposition of new derivatives, increasing the chances of obtaining potentially anti-tuberculosis compounds.

Hederagenin amide derivatives as potential antiproliferative agents.

In this study, a series of C-28 amides derivatives of hederagenin with or without the presence of an acetyl group at positions 3 and 23 in ring A, were synthetized aiming to develop potent cytotoxic agents. Their structures were confirmed by MS, IR, 1H NMR and 13C NMR spectroscopic analyses and their cytotoxic activities were screened in SRB assays using a panel of six human cancer cell lines. The majority of the amide derivatives were cytotoxic for a variety of human tumor cell lines. In general, the hydroxylated derivatives (1a-1d; EC50 in the range 1.2-22.5 µM) were less active than the acetylated derivatives (2a-2n; EC50 in the range 0.4-9.0 µM). Hydroxylated derivative bearing pyrrolidinyl substituent 1c, was the most active for HT29 human line cells (EC50 = 1.2 µM), however their acetylated derivative 2c was the most potent and selective against A2780, FaDu, SW1736 cells, showing EC50 values between 0.4 and 1.7 µM and SI between 5.6 and 24. Staining experiments combined with fluorescence microscopy indicate that the cell membrane became permeable, and finally a process of secondary necrosis was observed. In addition, the docking results showed that acetylated compounds display more affinity to HER2 than to USP7, indicating that HER2 is a most probable receptor, both proteins found in tumor cell line A2780.

Web-4D-QSAR: A web-based application to generate 4D-QSAR descriptors.

A web-based application is developed to generate 4D-QSAR descriptors using the LQTA-QSAR methodology, based on molecular dynamics (MD) trajectories and topology information retrieved from the GROMACS package. The LQTAGrid module calculates the intermolecular interaction energies at each grid point, considering probes and all aligned conformations resulting from MD simulations. These interaction energies are the independent variables or descriptors employed in a QSAR analysis. A friendly front end web interface, built using the Django framework and Python programming language, integrates all steps of the LQTA-QSAR methodology in a way that is transparent to the user, and in the backend, GROMACS and LQTAGrid are executed to generate 4D-QSAR descriptors to be used later in the process of QSAR model building. © 2018 Wiley Periodicals, Inc.

Multivariate QSAR study on the antimutagenic activity of flavonoids against 3-NFA on Salmonella typhimurium TA98.

A quantitative structure-activity relationship (QSAR) study of twenty flavonoid derivatives with antimutagenic activity against 3-nitrofluoranthene (3-NFA) was performed by Partial Least Squares (PLS), using Ordered Predictors Selection (OPS) algorithm for variable selection. Four descriptors (PJI2, Mor27m, G1e and R4u+) were selected and a good model (n = 19; R(2) = 0.747; SEC = 0.332; PRESS(cal) = 1.768; F((2,27)) = 23.585; Q(LOO)(2) = 0.590; SEV = 0.388; PRESS(val) = 2.858; R(pred)(2) = 0.591; SEP = 0.394; ARE(pred) = 5.230%; k = 1.005; k' = 0.990; |R(02) - R'(02)| = 0.109) was built with two latent variables describing 83.410% of the original information. Leave-N-out cross validation (LNO) and y-randomization were performed in order to confirm the robustness of the model. The topological descriptors selected indicate that the antimutagenic activity against 3-NFA depends on molecular size, shape and Sanderson electronegativity of flavonoids. The proposed model may provide a better understanding of the antimutagenic activity of flavonoids and can be used as a guidance for proposition of new chemopreventive agents.