A Quantitative Structure-Activity Relationships (QSAR) Study of Piperine Based Derivatives with Leishmanicidal Activity

Leishmaniasis is a parasitic disease which represents a serious public health problem in developing countries. It is considered a neglected tropical disease, for which there is little initiative in the search for therapeutic alternatives by pharmaceutical industry. Natural products remain a great source of inspiration for obtaining bioactive molecules. In 2010, Singh and co-workers published the synthesis and in vitro biological activity of piperoyl-aminoacid conjugates, as well as of piperine, against cellular cultures of Leishmania donovani. The piperine is an alkaloid isolated from Piper nigrum that has many activities described in the literature. In this work, we present a Quantitative Structure-Activity Study of piperine derivatives tested by Singh and co-workers, aiming to highlight important molecular features for leishmanicidal activity, obtaining a mathematical model to predict the activity of new analogs. Compounds were submitted to a geometry optimization computational procedure at semiempirical level of quantum theory. Molecular descriptors for the set of compounds were calculated by E-Dragon online plataform, followed by a variable selection procedure using Ordered Predictors Selection algorithm. Validation parameters obtained showed that a good QSAR model, based on multiple linear regression, was obtained (R2 = 0.85; Q2 = 0.69), and the following conclusions regarding the structure-activity relationship were elucidated: Compounds with electronegative atoms on different substituent groups of analogs, absence of unsaturation on lateral chain, presence of ester instead of carboxyl, and large volumes (due the presence of additional aromatic rings) trends to increase the activity against promastigote forms of leishmania. DOI: http://dx.doi.org/10.17807/orbital.v9i1.89

Reverse and Forward Engineering of Local Voltage Control in Distribution Networks

The increasing penetration of renewable and distributed energy resources in distribution networks calls for real-time and distributed voltage control. In this paper we investigate local Volt/VAR control with a general class of control functions, and show that the power system dynamics with non-incremental local voltage control can be seen as distributed algorithm for solving a well-defined optimization problem (reverse engineering). The reverse engineering further reveals a fundamental limitation of the non-incremental voltage control: the convergence condition is restrictive and prevents better voltage regulation at equilibrium. This motivates us to design two incremental local voltage control schemes based on the subgradient and pseudo-gradient algorithms respectively for solving the same optimization problem (forward engineering). The new control schemes decouple the dynamical property from the equilibrium property, and have much less restrictive convergence conditions. This work presents another step towards developing a new foundation -- network dynamics as optimization algorithms -- for distributed realtime control and optimization of future power networks

Quantitative Structure-Activity Relationship (QSAR) Studies of Morita-Baylis- Hillman Adducts bioactive against Leishmania amazonensis.

The Morita-Baylis-Hillman Adducts (MBHA) is a class of molecules studied by our research group on synthetic, theoretical and bioactivity aspects. In this work, we present Quantitative Structure-Activity Relationship (QSAR) models involving 32 aromatic MBHA. Initially, the most stable conformations of thirty-two MBHA were investigated by theoretical methods, which were used to construct models. For this study, were obtained potential energy curves using AM1 semi-empirical method, considering rotational degrees of freedom (sigma bonds). From these curves, the less energy conformation to each molecule was selected and optimized at B3LYP/6- 31+G(d) level, considering solvent effects through Polarizable Continuum Model (PCM). Proton Nuclear Magnetic Ressonance data are in agreement with the conformational study. Intramolecular Hydrogen Bonds (IHB) are presents in the most of the studied compounds, according to structural characterization and QTAIM calculations. Curiously, compounds that showed hydrogen bonds involving the nitro and hydroxyl groups have the best values of biological activity (IC50). An explanation is based on redox mechanism of action of nitrocompounds. NBO (Natural Bond Orbital) charges and LUKO (Lowest Unoccupied Kohn-Sham Orbitals) analysis at the ortho-nitro group are in agreement with these analyses. Considering quantum calculations and structural observations, four descriptors were selected a priori and submitted to a QSAR study using PLS (Partial Least Squares) and MLR (Multiple Linear Regression) modeling. A second QSAR approach was made from the another set of descriptors obtained through the online platform E-DRAGON, which were submitted to a variable selection method. The quality parameters obtained for models indicate that both are robust and predictive.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESOs Adutos de Morita-Baylis-Hillman (AMBH) compreendem uma classe de moléculas investigadas por nosso grupo de pesquisas nos aspectos sintéticos, teóricos e de bioatividade. Neste trabalho, apresentamos modelos de Relação Quantitativa entre a Estrutura Química e a Atividade Leishmanicida (QSAR) envolvendo 32 AMBH aromáticos. Deste modo, inicialmente foram investigadas as conformações mais estáveis de cada composto através de métodos teóricos, as quais foram utilizadas na construção dos modelos. Foram obtidas curvas de energia potencial utilizando o método semi-empírico AM1, considerando graus de liberdade rotacionais (ligações sigma). A partir destas curvas, a conformação de menor energia para cada molécula foi selecionada e otimizada ao nível B3LYP/6-31+G(d), considerando os efeitos do solvente aquoso usando PCM ( Polarizable Continuum Model ). Dados espectroscópicos de Ressonância Magnética Nuclear de prótons corroboraram o estudo conformacional. Ligações de Hidrogênio Intramoleculares (LHI) se mostraram presentes na maioria das moléculas estudadas, conforme caracterização estrutural e cálculos QTAIM ( Quantum Theory Atoms in Molecules ). Curiosamente, os compostos que apresentaram Ligações de Hidrogênio envolvendo o grupo nitro (NO2) e a hidroxila (OH) possuem melhores valores de atividade biológica (menor IC50). Uma explicação está baseada no mecanismo de ação redox de nitrocompostos. Observação das cargas NBO ( Natural Bond Orbitals ) e análise dos orbitais de fronteira LUKO ( Lowest Unoccupied Kohn-Sham Orbitals ) ao nível do grupo orto-nitro estão de acordo com estas análises. Considerando os cálculos quânticos, bem como observações estruturais, quatro descritores foram selecionados a priori e submetidos a um estudo QSAR ( Quantitative Structure- Activity Relationships ) utilizando modelagem PLS ( Partial Least Squares ) e MLR ( Multiple Linear Regression ). Uma segunda abordagem QSAR foi realizada a partir de outro conjunto de descritores obtidos através da plataforma online E-DRAGON, os quais foram submetidos ao método de seleção de variáveis OPS ( Ordered Predictor Selection ). Os parâmetros de qualidade obtidos para os modelos indicam que ambos são robustos e preditivos

Complexation with β-cyclodextrin enhances apoptosis-mediated cytotoxic effect of harman in chemoresistant BRAF-mutated melanoma cells

International audienc

Bis-nor-diterpene from Cnidoscolus quercifolius (Euphorbiaceae) induces tubulin depolymerization-mediated apoptosis in BRAF-mutated melanoma cells

International audienc

2D comparative representation of the NSAID meloxicam and LASSBio-1586.

<p>2D comparative representation of the NSAID meloxicam and LASSBio-1586.</p

Effect of LASSBio-1586 (40 mg/kg, p.o.) on paw edema induced by histamine in mice.

<p>The sham group was treated only with saline, whereas the control group received saline and histamine. Values are expressed as the mean ± S.E.M. (n = 6, per group), where <i>a</i> indicates <i>p</i><0.05, significantly different from the control group, according to ANOVA, followed by Tukey’s test.</p