Synthesis, Dna Binding, And Antiproliferative Activity Of Novel Acridine-thiosemicarbazone Derivatives.

In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a-h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 10(4) to 1.0 × 10(6) M(-1) and quenching constants from -0.2 × 10(4) to 2.18 × 10(4) M(-1) indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N- (4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties.1613023-1304

Development of a validated stability-indicating HPLC- DAD method for dasabuvir and the characterization of its degradation products using LC-QToF-MS/MS

A stability-indicating HPLC-DAD method was developed and validated for the simultaneous determination of dasabuvir and its degradation products in the pharmaceutical formulation. The proposed method utilized a Symmetry® C18 (4.6 x 75 mm, 3.5 µm) column, and the mobile phase consisted of an isocratic elution of formic acid (0.1%) and acetonitrile (55:45, v/v), at a flow of 1 mL min-1; analytes were detected at 244 nm. Dasabuvir was submitted to different stress degradation conditions, such as acidic, alkaline, neutral, thermal, oxidative and photolytic, and the structural elucidation of degradation products was performed using LC-QToF-MS/MS. The HPLC-DAD stability-indicating method was validated for selectivity, linearity, limit of detection and quantification, accuracy, precision and robustness, according to ICH guidelines. Dasabuvir produced two degradation products (DP1 and DP2) from the alkaline stress conditions, which were characterized in negative ion mode. Dasabuvir was linear in the range 9.78 to 136.92 µg mL-1, and DP and DP were linear in the range 2.9 to 20.2 µg mL-1 and 1.3 to 14.9 µg mL-1, respectively. The 1 2 recovery ranged between 99.16 and 100.86%, while precision ranged from 1.02 to 2.89%. As the method can effectively separate the dasabuvir from its degradation products and quantitate them, it may be employed as a stability-indicating method for the pharmaceutical formulation

Ability of two new thiazolidinediones to downregulate proinflammatory cytokines in peripheral blood mononuclear cells from children with asthma

Allergic asthma is a chronic, complex inflammatory disease of the airway. Despite extensive studies on the immunomodulation of T helper (Th) cell pathways (i.e., Th1 and Th2) in asthma, little is known about the effects of Th17 pathway modulation, particularly that involving peroxisome proliferator-activated receptors (PPARs). In response, two new thiazolidinedione derivatives-namely, LPSF-GQ-147 and LPSF-CR-35 were synthesized and evaluated for their immunomodulatory effects on Th17-related cytokines, including interferon γ (IFNγ), interleukin IL-6, IL-17, and IL-22 in the peripheral blood mononuclear cells of asthmatic children. Both compounds were nontoxic even at high concentrations (i.e., 100 µM). The LPSF-CR-35 compound significantly reduced the levels of IL-17A (p = .039) and IFNγ (p = .032) at 10 µM. For IL-22 and IL-6, significant reduction occurred at 100 µM (p = .039 and p = .02, respectively). Conversely, LPSF-GQ-147 did not significantly inhibit the production of the tested cytokines, the levels of all of which were more efficiently reduced by LPSF-CR-35 than methylprednisolone, the standard compound. Real-time polymerase chain reaction assay confirmed that LPSF-GQ-147 has significant PPARγ modulatory activity. Such data indicate that both LPSF-CR-35 and LPSF-GQ-147 are promising candidates as drugs for treating inflammation and asthma

Synthesis, in vitro and in vivo biological evaluation, COX-1/2 inhibition and molecular docking study of indole-N-acylhydrazone derivatives

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2018-12-13T12:58:18Z No. of bitstreams: 1 Moraes AD. Synthesis, in vitro... 2018.pdf: 3558449 bytes, checksum: 47595109fd43883dd3da4f7348667a6c (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2018-12-13T13:09:51Z (GMT) No. of bitstreams: 1 Moraes AD. Synthesis, in vitro... 2018.pdf: 3558449 bytes, checksum: 47595109fd43883dd3da4f7348667a6c (MD5)Made available in DSpace on 2018-12-13T13:09:51Z (GMT). No. of bitstreams: 1 Moraes AD. Synthesis, in vitro... 2018.pdf: 3558449 bytes, checksum: 47595109fd43883dd3da4f7348667a6c (MD5) Previous issue date: 2018Brazilian agencies Fundaçao de Amparo Pesquisa do Estado de Pernambuco (FACEPE, Brazil) and Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq).Universidade Federal de Pernambuco. Departamento de Antibióticos. Recife, PE, Brasil.Universidade Federal de Pernambuco. Departamento de Antibióticos. Recife, PE, Brasil.Universidade Federal de Pernambuco. Departamento de Antibióticos. Recife, PE, Brasil.Universidade Federal de Pernambuco. Departamento de Antibióticos. Recife, PE, Brasil.Universidade Estadual da Paraíba. Departamento de Farmácia. Campina Grande, PB, Brasil.Universidade Estadual da Paraíba. Departamento de Farmácia. Campina Grande, PB, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Engenharia Tecidual e Imunofarmacologia. Salvador, BA, Brasil.Universidade de Pernambuco. Faculdade de Ciências, Educação e Tecnologia de Garanhuns. Garanhuns, PE, BrasilUniversidade Federal Rural de Pernambuco. Unidade Acadêmica de Serra Talhada. Serra Talhada, PE, Brasil.Universidade Federal de Pernambuco. Departamento de Antibióticos. Recife, PE, Brasil.Universidade Federal de Pernambuco. Departamento de Antibióticos. Recife, PE, Brasil.Universidade Federal de Pernambuco. Departamento de Antibióticos. Recife, PE, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Engenharia Tecidual e Imunofarmacologia. Salvador, BA, Brasil.Universidade Federal de Pernambuco. Departamento de Antibióticos. Recife, PE, Brasil.The objective of this work was to obtain and evaluate anti-inflammatory in vitro, in vivo and in silico potential of novel indole-N-acylhydrazone derivatives. In total, 10 new compounds (3a-j) were synthesized in satisfactory yields, through a condensation reaction in a single synthesis step. In the lymphoproliferation assay, using mice splenocytes, 3a and 3b showed inhibition of lymphocyte proliferation of 62.7% (±3.5) and 50.7% (±2), respectively, while dexamethasone presented an inhibition of 74.6% (±2.4). Moreover, compound 3b induced higher Th2 cytokines production in mice splenocytes cultures. The results for COX inhibition assays showed that compound 3b is a selective COX-2 inhibitor, but with less potency when compared to celecoxib, and compound 3a not presented selectivity towards COX-2. The molecular docking results suggest compounds 3a and 3b interact with the active site of COX-2 in similar conformations, but not with the active site of COX-1, and this may be the main reason to the COX-2 selectivity of compound 3b. In vivo carrageenan-induced paw edema assays were adopted for the confirmation of the anti-inflammatory activity. Compound 3b showed better results in suppressing edema at all tested concentrations and was able to induce an edema inhibition of 100% after 5 h of carrageenan injection at the 30 mg kg-1 dosage, corroborating with the COX inhibition and lymphoproliferation results. I addition to our experimental results, in silico analysis suggest that compounds 3a and 3b present a well-balanced profile between pharmacodynamics and pharmacokinetics. Thus, our preliminary results revealed the potentiality of a new COX-2 selective derivative in the modulation of the inflammatory process