Design and synthesis of new benzophenone derivatives with in vivo anti-inflammatory activity through dual inhibition of edema and neutrophil recruitment.

A series of novel benzophenone derivatives containing a thiazole heterocyclic nucleus were designed by molecular hybridization. Molecular docking studies have demonstrated the inhibitory potential of the designed compounds against cyclooxygenase (COX) isoenzymes. These compounds were synthesized, characterized, and evaluated for their anti-inflammatory properties by the croton oil-induced ear edema assay to examine their effect on both prostaglandin (PG) production and neutrophils recruitment. The thiazole derivatives displayed a potent effect in terms of reducing ear edema. The analysis suggested that the presence of 4-phenyl-2-hydrazinothiazole and the absence of C40 -OCH3 on the benzophenone derivative structure are strongly related to the inhibition of PG production. In addition, the derivatives 2e, 3a and 3c concomitantly inhibit PG production and neutrophil recruitment, which may be a mechanism of action better than of common NSAIDs due to their inability to inhibit the neutrophil recruitment. Thus, these compounds can be considered as potential lead compounds toward the development of new anti-inflammatory drugs with an innovating mechanism of actio

Síntese de análogos da papulacandina D por simplificação molecular e avaliação de sua atividade antifúngica

Exportado OPUSMade available in DSpace on 2019-08-13T17:45:18Z (GMT). No. of bitstreams: 1 disserta__o_final.pdf: 13558410 bytes, checksum: ff0e51dd6b05c6e2e4264d94a5f539e5 (MD5) Previous issue date: 26As papulacandinas são uma família de glicolipídeos isolados, por fermentação, de Papularia spherosperma, e que apresentam potente atividade antifúngica in vitro contra diferentes cepas de Candida sp. Esses compostos inibem a enzima â(1,3)-Dglicana sintase impedindo a síntese de â(1,3)-D-glicana, um constituinte vital da parede celular dos fungos. As papulacandinas A, B e C são espiroglicosídeosderivados do dissacarídeo lactose e ligadas a duas cadeias de ácidos graxos insaturados por ligações éster, nas posições C-3 e C-6. A papulacandina D, o membro mais simples da família, é um espiroglicosídeo derivado da D-glicose e ligado a uma cadeia de ácido graxo insaturado na posição C-3. A estrutura mais simples aliada à menor atividade fungicida da papulacandina D levou ao interesse pelo planejamento e síntese, por meio do método da simplificação molecular, de análogos dessa substância, para avaliação de suaatividade antifúngica, além de se estabelecer um maior conhecimento acerca da relação entre a estrutura química e a atividade biológica desses compostos. Nove análogos inéditos da papulacandina D foram sintetizados. Estes e os intermediários de síntese foram submetidos a ensaios de inibição do crescimento de Candida albicans, Candida krusei, Candida parapsilosis e Candida tropicalis. Dois desses análogos da papulacandina D apresentaram inibição de 50% docrescimento de Candida tropicalis, na concentração de 200 ìg/mL. Doisintermediários de síntese também apresentaram inibição de 50% do crescimento de Candida albicans e Candida tropicalis, também na concentração de 200 ìg/mL.The papulacandins are a family of glycolipids isolated, by fermentation, from Papularia spherosperma, and that have shown potent in vitro antifungal activity against different strains of Candida sp. These compounds inhibit the enzyme â(1,3)-Dglucan synthase preventing the â(1,3)-D-glucan synthesis, a vital constituent of fungal cell wall. The papulacandins A, B e C are spiroglycosides derived from lactose andattached to two unsatured fatty acids by ester-bonds at C-3 and C-6 positions. The papulacandin D, the simplest member of the family, is a spiroglycoside derived from D-glucose and attached to an unsatured fatty acid at C-3 position. The less complex structure of papulacandin D as compared to the others compounds of the class and its lower antifungal activity was the inspiration for the design and synthesis of analogs of this compound, by molecular simplification, aimed at obtaining analogs with interesting antifungal activity, and establishing more knowledge about the chemical structure-biological activity relationship of these compounds.Nine new analogs of the papulacandin D were synthesized. These compounds and some synthetic intermediaries were evaluated against Candida albicans, Candida krusei, Candida parapsilosis and Candida tropicalis. Two papulacandin D analogs showed 50% inhibition growth of Candida tropicalis to 200 ìg/mL. Two intermediaries showed 50% inhibition of Candida albicans and Candida tropicalis growth, also to 200 ìg/mL

Synthesis of novel papulacandin D analogs and evaluation of their antifungal potential

Systemic fungal infections are a growing problem in contemporary medicine and few drugs are licensed for therapy of invasive fungal infections. Differences between fungi and humans, like the presence of a cell wall in fungal cells, can be explored for designing new drugs. (1,3)-β-D-glucan synthase, an enzyme that catalyzes the synthesis of (1,3)-β-D-glucan, a structural and essential component of the fungal cell wall, is absent in mammals and this makes it an excellent target for the development of new antifungal agents. Papulacandins are a family of natural antifungal agents targeting (1,3)-β-D-glucan synthase. In this study we describe the synthesis and biological evaluation of two new Papulacandin analogs as potential (1,3)-β-D-glucan synthase inhibitors

Synthesis, activity, and molecular modeling studies of 1,2,3? triazole derivatives from natural phenylpropanoids as new trypanocidal agents.

The search for compounds with new structural scaffolds is an important tool to the discovery of new drugs against Chagas disease. We report herein the synthesis of 1,2,3?triazoles obtained from eugenol and di?hydroeugenol and their in vitro and in vivo trypanocidal activity. These derivatives were obtained by a three?step objective route and were suitably characterized by 1H and 13C nuclear magnetic resonance spectroscopy and high?resolution mass spectrometry. Two compounds (9 and 10 ) showed activity against epimastigote forms of Trypanosoma cruzi (Y strain) in the range 42.8?88.4 ?M and were weakly toxic to cardiomyoblast cells (H9c2 cells). The triazole 10 was the most active derivative and could reduce more than 50% of parasitemia after a 100?mg/kg oral treatment of mice infected with T. cruzi . Molecular docking studies suggested this compound could act as a trypanocidal agent by inhibiting cruzain, an essential enzyme for T. cruzi metabolism, usually inhibited by triazole compounds

Synthesis, activity, and molecular modeling studies of 1,2,3‐triazole derivatives from natural phenylpropanoids as new trypanocidal agents

The search for compounds with new structural scaffolds is an important tool to the discovery of new drugs against Chagas disease. We report herein the synthesis of 1,2,3?triazoles obtained from eugenol and di?hydroeugenol and their in vitro and in vivo trypanocidal activity. These derivatives were obtained by a three?step objective route and were suitably characterized by 1H and 13C nuclear magnetic resonance spectroscopy and high?resolution mass spectrometry. Two compounds (9 and 10 ) showed activity against epimastigote forms of Trypanosoma cruzi (Y strain) in the range 42.8?88.4 ?M and were weakly toxic to cardiomyoblast cells (H9c2 cells). The triazole 10 was the most active derivative and could reduce more than 50% of parasitemia after a 100?mg/kg oral treatment of mice infected with T. cruzi . Molecular docking studies suggested this compound could act as a trypanocidal agent by inhibiting cruzain, an essential enzyme for T. cruzi metabolism, usually inhibited by triazole compounds

SYNTHESIS AND ANTIFUNGAL ACTIVITY OF PALMITIC ACID-BASED NEOGLYCOLIPIDS RELATED TO PAPULACANDIN D

A series of six new palmitic acid-based neoglycolipids related to Papulacandin D were synthesized in five steps, resulting in good yields, and they were evaluated against Candida spp. All twelve synthetic intermediates were also evaluated. The synthesis involved the initial glycosylation of two phenols (4-hydroxy-3-methoxybenzaldehyde and 3-hydroxybenzaldehyde) via their reaction with peracetylated glucosyl bromide. This was followed by deacetylation with potassium methoxide/metanol solution and the protection of two hydroxyls (C4 and C6 positions) of the saccharide unit as benzilidene acetals (10-11). The next step involved the acylation of the acetal derivatives with palmitic acid, thereby affording a mixture of two isomers mono-acylated at the C2 and C3 positions and a di-acylated product (12-17). After being isolated, each compound was subjected to the removal of the acetal protecting group to yield the papulacandin D analogues 18-23. Three compounds showed low antifungal activity against two species: C. albicans (compounds 7 and 23) and C. tropicalis (compound 17) at 200 µg mL−1

Capillary zone electrophoresis method to assay tipranavir capsules and identification of oxidation product and organic impurity by quadrupole-time of flight mass spectrometry.

Tipranavir (TPV) is one of the most recently developed protease inhibitors (PI) and it is specially recommended for treatment-experienced patients who are resistant to other PI drugs. In this work, a simple and friendly environmental CZE stability-indicating method to assay TPV capsules was developed and two TPV organic impurities were identified by high resolution mass spectrometry (HRMS). The optimized analytical conditions were: background electrolyte composed of sodium borate 50 mM, pH 9.0 and 5% of methanol; voltage + 28 kV; hydrodynamic injection of 5 s (100 mbar), detection wavelength 240 nm, at 25 ?C. The separation was achieved in a fused silica capillary with 50 ?m ? 40 cm (inner diameter ? effective length), using furosemide as internal standard. All the validation parameters were met and the method was specific, even in the presence of degradation products and impurities. Oxidation was indicated as the main degradation pathway among those evaluated in this study (acidic, alkaline, thermal, photolytic and oxidative) and it showed a second order degradation kinetic, under the conditions used in this study. The main oxidation product and an organic impurity detected in the standard were characterized by Q-TOF, and both of them correspond to oxidation products of TPV

Phenylpropanoid-based sulfonamide promotes cyclin D1 and cyclin E downregulation and induces cell cycle arrest at G1/S transition in estrogen positive MCF-7 cell line.

Cancer is one of the most critical problems of public health in the world and one of the main challenges for medicine. Different biological effects have been reported for sulfonamide-based compounds including antibacterial, antifungal, and antitumor activities. Herein, a series of phenylpropanoid-based sulfonamides (4a, 4a?, 4b, 4b?, 5a, 5a?, 5b and 5b?) were synthesized and their cytotoxic activity was evaluated against four cell lines derived from human tumours (A549 ? lung, MCF-7 ? breast, Hep G2 - hepatocellular carcinoma, and HT-144-melanoma). Cell viability was significantly reduced in the MCF-7 cell line when compounds 4b, 4b? and 5a were used; IC50 values were lower than those found for their precursors (eugenol and dihydroeugenol) and sulfanilamide. We observed that 4b induced cell cycle arrest at G1/S transition. This is probably due to its ability to reduce cyclin D1 and cyclin E expression. Moreover, 4b also induced apoptosis in MCF-7 cells as demonstrated by an increase in the cell population positive for annexin V in treated cultures in comparison to the control group. Taken together, the data showed that 4b is a promising antitumor agent and it should be considered for further in vivo studies

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells

Piplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. In the present study, we synthesized a novel platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh3)2]PF6 (where, PIP-OH = piplartine demethylated derivative; and PPh3 = triphenylphosphine) with enhanced cytotoxicity in different cancer cells, and investigated its apoptotic action in human promyelocytic leukemia HL-60 cells. The structure of PIP-OH ligand was characterized by X-ray crystallographic analysis and the resulting platinum complex was characterized by infrared, molar conductance measurements, elemental analysis and NMR experiments. We found that the complex is more potent than piplartine in a panel of cancer cell lines. Apoptotic cell morphology, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HL-60 cells. Treatment with the complex also caused a marked increase in the production of reactive oxygen species (ROS), and the pretreatment with N-acetyl-L-cysteine, an antioxidant, reduced the complex-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. Important, pretreatment with a p38 MAPK inhibitor (PD 169316) and MEK inhibitor (U-0126), known to inhibit ERK1/2 activation, also prevented the complex-induced apoptosis. The complex did not induce DNA intercalation in cell-free DNA assays. In conclusion, the complex exhibits more potent cytotoxicity than piplartine in a panel of different cancer cells and triggers ROS/ERK/p38-mediated apoptosis in HL-60 cells. Keywords: Piplartine, Piperlongumine, Platinum complex, Leukemia, Apoptosis, ROS, p38, ER