Computer assisted synthesis and in-vitro cytotoxic evaluation of new pyrazole-fused isoquinolinoquinones derivatives as PI3K receptor antagonist with promising antitumoral activity

The importance of pyrazole and isoquinoline-5,8-dione scaffolds in medical chemistry is underlined by the high number of drugs currently on trading that contains these active ingredients. Due to their cytotoxic capability, the interest of medicinal chemists in these heterocyclic rings has grown exponentially especially, for cancer therapy. In this project, the first synthesis of pyrazole-fused isoquinoline-5,8-diones has been developed. 1,3-Dipolar cycloaddition followed by oxidative aromatization, established by our research group, has been employed. Screening of reaction conditions and characterization studies about the regioselectivity have been successfully performed. A remote control of regioselectivity, to achieve the two possible regioisomers has been accomplished. Through Molecular Docking studies, Structure-Activity relationship of differently substituted scaffolds containing our central core proved that a family of PI3K inhibitors have been discovered. Finally, in order to verify the promising antitumor activity, a first test of cell viability in vitro on T98G cell line of a solid brain tumor, the Glioblastoma Multiforme, showed cytotoxic inhibition comparable to currently trade anticancer drugs.

Gut hormone GPCRs: structure, function, drug discovery

Crystallization and determination of the high resolution three-dimensional structure of the β2-adrenergic receptor in 2007 was followed by structure elucidation of a number of other receptors, including those for neurotensin and glucagon. These major advances foster the understanding of structure-activity relationship of these receptors and structure-based rational design of new ligands having more predictable activity. At present, structure determination of gut hormone receptors in complex with their ligands (natural, synthetic) and interacting signalling proteins, for example, G-proteins, arrestins, represents a challenge which promises to revolutionize gut hormone endocrinonology.

Morphology and structure of particles produced by femtosecond laser ablation of fused silica

The aim of the present work was to study the morphology and structure of the nanoparticles produced by femtosecond laser ablation of fused silica. Ultrashort laser pulses of 1030 nm wavelength and 550 fs duration were tightly focused by a high numerical aperture microscope objective at the surface of fused silica samples while scanning the sample in relation to the stationary laser beam. Laser tracks were created with pulse energies in the range 5-100 mu J, resulting in ablation debris of different morphologies. The debris were examined by scanning and transmission electron microscopy for their morphology and crystal structure in relation to the incident laser pulse energy. Ejected particles with sizes ranging from a few nanometers to a few microns were found. Their morphologies can be broadly classified into three categories: very fine round nanoparticles with diameters lower than 20 nm, nanoparticles with intermediate sizes between 50 and 200 nm, and big irregular particles with typical size between 0.5 and 1.5 mu m. The fine nanoparticles of the first category are predominantly observed at higher pulse energies and tend to aggregate to form web-like and arborescent-like structures. The nanoparticles with intermediate sizes are observed for all pulse energies used and may appear isolated or aggregated in clusters. Finally, the larger irregular particles of the third category are observed for all energies and appear normally isolated.

Synthesis and antimicrobial activity of some 2- Piperidinomethylamino-4-(7-H/substituted coumarin-3-yl)- 6-chlorosubstitutedphenyl pyrimidines

Purpose: To prepare and evaluate some 2-piperidinomethylamino-4-(7-H/substitutedcoumarin-3-yl)-6- chlorosubstitutedphenyl pyrimidines as antimicrobial agents. Methods: Some 2-piperidinomethylamino-4-(7-H/substitutedcoumarin-3-yl)-6-chlorosubstitutedphenyl pyrimidines were prepared by reacting 2-amino-4-(7-H/substitutedcoumarin-3-yl)-6- (chlorosubstitutedphenyl) pyrimidines with piperidine and formaldehyde. The chemical structures of the synthesized compounds were elucidated by Fourier transform infrared (FTIR), 1H-nuclear magnetic resonance (1H-NMR), mass spectrometry and elemental analysis. These compounds were investigated for their antimicrobial activity against ten bacteria and five fungi by serial plate dilution method using standard drugs, namely, ofloxacin and ketoconazole, respectively, and their minimum inhibitory concentrations (MICs) were also determined. Results: A total of eighteen new compounds (1a-18a) were synthesized. Compound 6a (MIC = 50 μg/mL; p < 0.05 or less) displayed the highest activity against S. aureus , E. faecalis , Staphylococcus epidermidis , B. subtilis , and B. cereus . Compound 6a further showed good activity (MIC = 25 μg/mL; p < 0.05 or less) against E. coli ; P. aeruginosa K. pneumonia , B. bronchiseptica , and P. vulgaris . Compounds 6a (MIC = 25 μg/mL; p < 0.0001) and 17a (MIC = 25 μg/mL; p < 0.0001) displayed very good activity against C. albicans , A. niger , A. flavus , M. purpureous , and P. citrinum , respectively. Analysis of structure-activity relationship revealed that the presence of bromo group at 7-postion of the coumarin moiety along with the 4-chlorophenyl group at position-6 of the pyrimidine ring is critical for antimicrobial activity against Gram-positive bacteria, Gram negative bacteria and fungi. Conclusion: The synthesized 2-piperidino derivatives are better antifungal and antibacterial agents than the earlier reported 2-morpholino derivatives, but require further investigations against other microbial strains to ascertain their broad spectrum antimicrobial activity.

Carotenoids Are Effective Inhibitors Of In Vitro Hemolysis Of Human Erythrocytes, As Determined By A Practical And Optimized Cellular Antioxidant Assay.

β-Carotene, zeaxanthin, lutein, β-cryptoxanthin, and lycopene are liposoluble pigments widely distributed in vegetables and fruits and, after ingestion, these compounds are usually detected in human blood plasma. In this study, we evaluated their potential to inhibit hemolysis of human erythrocytes, as mediated by the toxicity of peroxyl radicals (ROO•). Thus, 2,2'-azobis (2-methylpropionamidine) dihydrochloride (AAPH) was used as ROO• generator and the hemolysis assay was carried out in experimental conditions optimized by response surface methodology, and successfully adapted to microplate assay. The optimized conditions were verified at 30 × 10(6) cells/mL, 17 mM of AAPH for 3 h, at which 48 ± 5% of hemolysis was achieved in freshly isolated erythrocytes. Among the tested carotenoids, lycopene (IC(50) = 0.24 ± 0.05 μM) was the most efficient to prevent the hemolysis, followed by β-carotene (0.32 ± 0.02 μM), lutein (0.38 ± 0.02 μM), and zeaxanthin (0.43 ± 0.02 μM). These carotenoids were at least 5 times more effective than quercetin, trolox, and ascorbic acid (positive controls). β-Cryptoxanthin did not present any erythroprotective effect, but rather induced a hemolytic effect at the highest tested concentration (3 μM). These results suggest that selected carotenoids may have potential to act as important erythroprotective agents by preventing ROO•-induced toxicity in human erythrocytes.

Glicoproteína-P, resistência a múltiplas drogas (MDR) e relação estrutura-atividade de moduladores

Multidrug resistance, MDR is a major obstacle for cancer chemotherapy. MDR can be reversed by drugs that vary in their chemical structure and main biological activity. Many efforts have been done to overcome MDR based on studies of structure-activity relationships and in this review we summarize some aspects of MDR mediated by P-glycoprotein (P-gp), as the most experimentally and clinically tested form of drug resistance. The most significant MDR mechanisms revealed until now are shortly discussed. Physicochemical and structural properties of MDR modulators, measures of the MDR reversal, and QSAR studies are included.

Enzyme kinetics, structural analysis and molecular modeling studies on a series of Schistosoma mansoni PNP inhibitors

The enzyme purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive molecular target for the development of novel drugs against schistosomiasis, a neglected tropical disease that affects about 200 million people worldwide. In the present work, enzyme kinetic studies were carried out in order to determine the potency and mechanism of inhibition of a series of SmPNP inhibitors. In addition to the biochemical investigations, crystallographic and molecular modeling studies revealed important molecular features for binding affinity towards the target enzyme, leading to the development of structure-activity relationships (SAR).

Métodos utilizados na avaliação psicofísica da visão de cores humana

A cor é um atributo perceptual que nos permite identificar e localizar padrões ambientais de mesmo brilho e constitui uma dimensão adicional na identificação de objetos, além da detecção de inúmeros outros atributos dos objetos em sua relação com a cena visual, como luminância, contraste, forma, movimento, textura, profundidade. Decorre daí a sua importância fundamental nas atividades desempenhadas pelos animais e pelos seres humanos em sua interação com o ambiente. A psicofísica visual preocupa-se com o estudo quantitativo da relação entre eventos físicos de estimulação sensorial e a resposta comportamental resultante desta estimulação, fornecendo dessa maneira meios de avaliar aspectos da visão humana, como a visão de cores. Este artigo tem o objetivo de mostrar diversas técnicas eficientes na avaliação da visão cromática humana através de métodos psicofísicos adaptativos.

Hemoglobina extracelular gigante de Glossoscolex paulistus: um extraordinário sistema supramolecular hemoproteico

Giant extracellular hemoglobins are considered the summit of complexity in systems that carry oxygen, constituting an extraordinary model system to the study of hemoproteins. This class includes the hemoglobin of the annelid Glossoscolex paulistus that presents high cooperativity, great oligomeric and redox stabilities and ability of oligomeric reassociation. These properties have motivated evaluations about its utilization as prototype of artificial blood and biosensor. Kinetic studies involving autoxidation and detailed spectroscopic characterizations of its ferrous and ferric species have propitiated information about the structure-activity relationship of this macromolecule. The present review analyzes several biochemical issues, evaluating the state-of-art of this subject.

Chemometric Studies on Natural Products as Potential Inhibitors of the NADH Oxidase from Trypanosoma cruzi Using the VolSurf Approach

Natural products have widespread biological activities, including inhibition of mitochondrial enzyme systems. Some of these activities, for example cytotoxicity, may be the result of alteration of cellular bioenergetics. Based on previous computer-aided drug design (CADD) studies and considering reported data on structure-activity relationships (SAR), an assumption regarding the mechanism of action of natural products against parasitic infections involves the NADH-oxidase inhibition. In this study, chemometric tools, such as: Principal Component Analysis (PCA), Consensus PCA (CPCA), and partial least squares regression (PLS), were applied to a set of forty natural compounds, acting as NADH-oxidase inhibitors. The calculations were performed using the VolSurf+ program. The formalisms employed generated good exploratory and predictive results. The independent variables or descriptors having a hydrophobic profile were strongly correlated to the biological data.

Phylogeography and historical demography of the neotropical stingless bee Melipona quadrifasciata (Hymenoptera, Apidae): incongruence between morphology and mitochondrial DNA

The stingless bees are among the most abundant and ecologically important social invertebrates in tropical communities. The Neotropical stingless bee Melipona quadrifasciata has two subspecies: M. quadrifasciata quadrifasciata and M. quadrifasciata anthidioides. The main difference between subspecies are the yellow metassomal stripes, which are continuous in M. q. quadrifasciata and discontinuous in M. q. anthidioides. Recently, two populations were described with continuous stripes and inhabiting clearly disjunct areas in relation to M. q. quadrifasciata. We sequenced 852 bp of the mtDNA COI gene from 145 colonies from 56 localities, and for the first time performed a detailed phylogeographic study of a neotropical stingless bee. Phylogenetic analyses revealed the existence of two clades exhibiting a south to north distribution: southern populations comprise the subspecies M. q. quadrifasciata, and northern populations are composed of M. q. anthidioides and two disjunct populations with continuous stripes. The divergence time of these two phylogroups was estimated between 0.233 and 0.840 million years ago in the Pleistocene, a period of climatic changes and geomorphological alterations in the Neotropical region. No evidence of genetic structure in relation to the tergal stripes was found, indicating that the morphological trait regarding the pattern of stripes on tergites is not an accurate diagnostic for the subspecies of M. quadrifasciata.

QSAR Modeling of a Set of Pyrazinoate Esters as Antituberculosis Prodrugs

Tuberculosis is an infection caused mainly by Mycobacterium tuberculosis. A first-line antimycobacterial drug is pyrazinamide (PZA), which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid (POA). As pyrazinoic acid presents some difficulty to cross the mycobacterial cell wall, and also the pyrazinamide-resistant strains do not express the pyrazinamidase, a set of pyrazinoic acid esters have been evaluated as antimycobacterial agents. In this work, a QSAR approach was applied to a set of forty-three pyrazinoates against M. tuberculosis ATCC 27294, using genetic algorithm function and partial least squares regression (WOLF 5.5 program). The independent variables selected were the Balaban index (I), calculated n-octanol/water partition coefficient (ClogP), van-der-Waals surface area, dipole moment, and stretching-energy contribution. The final QSAR model (N = 32, r(2) = 0.68, q(2) = 0.59, LOF = 0.25, and LSE = 0.19) was fully validated employing leave-N-out cross-validation and y-scrambling techniques. The test set (N = 11) presented an external prediction power of 73%. In conclusion, the QSAR model generated can be used as a valuable tool to optimize the activity of future pyrazinoic acid esters in the designing of new antituberculosis agents.

Molecular modeling and QSAR studies of a set of indole and benzimidazole derivatives as H(4) receptor antagonists

Histamine is an important biogenic amine, which acts with a group of four G-protein coupled receptors (GPCRs), namely H(1) to H(4) (H(1)R - H(4)R) receptors. The actions of histamine at H(4)R are related to immunological and inflammatory processes, particularly in pathophysiology of asthma, and H(4)R ligands having antagonistic properties could be helpful as antiinflammatory agents. In this work, molecular modeling and QSAR studies of a set of 30 compounds, indole and benzimidazole derivatives, as H(4)R antagonists were performed. The QSAR models were built and optimized using a genetic algorithm function and partial least squares regression (WOLF 5.5 program). The best QSAR model constructed with training set (N = 25) presented the following statistical measures: r (2) = 0.76, q (2) = 0.62, LOF = 0.15, and LSE = 0.07, and was validated using the LNO and y-randomization techniques. Four of five compounds of test set were well predicted by the selected QSAR model, which presented an external prediction power of 80%. These findings can be quite useful to aid the designing of new anti-H(4) compounds with improved biological response.

Generation and Analysis of Interaction Energy Maps of p-Substituted Benzoic Acid [(5-Nitro-thiophen-2-yl)-methylene]-Hydrazides Active against MRSA

In this preliminary study eighteen p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides with antimicrobial activity were evaluated against multidrug-resistant Staphylococcus aureus, correlating the three-dimensional characteristics of the ligands with their respective bioactivities. The computer programs Sybyl and CORINA were used, respectively, for the design and three-dimensional conversion of the ligands. Molecular interaction fields were calculated using GRID program. Calculations using Volsurf resulted in a statistically consistent model with 48 structural descriptors showing that hydrophobicity is a fundamental property in the analyzed biological response.