2-Pyridyl thiazoles as novel anti-Trypanosoma cruzi agents: structural design, synthesis and pharmacological evaluation

The present work reports on the synthesis, anti-Trypanosoma cruzi activities and docking studies of a novel series of 2-(pyridin-2-yl)-1,3- thiazoles derived from 2-pyridine thiosemicarbazone. The majority of these compounds are potent cruzain inhibitors and showed excellent inhibition on the trypomastigote form of the parasite, and the resulting structure-activity relationships are discussed. Together, these data present a novel series of thiazolyl hydrazones with potential effects against Chagas disease and they could be important leads in continuing development against Chagas disease

Quercetin As An Inhibitor Of Snake Venom Secretory Phospholipase A2.

As polyphenolic compounds isolated from plants extracts, flavonoids have been applied to various pharmaceutical uses in recent decades due to their anti-inflammatory, cancer preventive, and cardiovascular protective activities. In this study, we evaluated the effects of the flavonoid quercetin on Crotalus durissus terrificus secretory phospholipase A2 (sPLA2), an important protein involved in the release of arachidonic acid from phospholipid membranes. The protein was chemically modified by treatment with quercetin, which resulted in modifications in the secondary structure as evidenced through circular dichroism. In addition, quercetin was able to inhibit the enzymatic activity and some pharmacological activities of sPLA2, including its antibacterial activity, its ability to induce platelet aggregation, and its myotoxicity by approximately 40%, but was not able to reduce the inflammatory and neurotoxic activities of sPLA2. These results suggest the existence of two pharmacological sites in the protein, one that is correlated with the enzymatic site and another that is distinct from it. We also performed molecular docking to better understand the possible interactions between quercetin and sPLA2. Our docking data showed the existence of hydrogen-bonded, polar interactions and hydrophobic interactions, suggesting that other flavonoids with similar structures could bind to sPLA2. Further research is warranted to investigate the potential use of flavonoids as sPLA2 inhibitors.1899-1

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

Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents

In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200-400 nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones. (C) 2010 Elsevier Ltd. All rights reserved.Pernambuco State Foundation for Science and Technology (FACEPE)[APQ-0123-4.03/08]Pernambuco State Foundation for Science and Technology (FACEPE)Brazilian National Council of Research (CNPq)[472880/2009-8]Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)CAPE

Structural Investigation of Anti-Trypanosoma cruzi 2-Iminothiazolidin-4-ones Allows the Identification of Agents with Efficacy in Infected Mice

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one S. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epirnastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.CNPq [471461/2011-3]CAPES [23038.003155/2011-37]FAPESB (PRONEX grant)European Union ChemBioFight [269301]CAPES-Fulbright Foundatio

Design, synthesis and structure-activity relationship of phthalimides endowed with dual antiproliferative and immunomodulatory activities

Soares, Milena Botelho Pereira. Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil “Documento produzido em parceria ou por autor vinculado à Fiocruz, mas não consta à informação no documento”. Marcos Veríssimo de Oliveira Cardoso a, *, Diogo Rodrigo Magalhães Moreira a, Gevanio Bezerra Oliveira Filho a, Suellen Melo Tiburcio Cavalcanti a, Lucas Cunha Duarte Coelho a, Jos e Wanderlan Pontes Espíndola a, Laura Rubio Gonzalez a, Marcelo Montenegro Rabello a, Marcelo Zaldini Hernandes a, Paulo Michel Pinheiro Ferreira b, Cl audia Pessoa c, d, Carlos Alberto de Simone e, Elisalva Teixeira Guimarães f, Milena Botelho Pereira Soares g, Ana Cristina Lima Leite a a Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520, Recife, PE, Brazil b Departamento de Biofísica e Fisiologia, Programa de P os-Graduação em Ciências Farmacêuticas, Universidade Federal do Piauí, 64049-550, Teresina, PI, Brazil c Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Cear a, 60430-270, Fortaleza, CE, Brazil d Fundação Oswaldo Cruz, 60180-900, Fortaleza, CE, Brasil e Departamento de Física e Inform atica, Instituto de Física, Universidade de São Paulo, 13560-970, São Carlos, SP, Brazil f Departamento de Ciências da Vida, Universidade do Estado da Bahia, 41150-000, Salvador, BA, Brazil g Hospital São Rafael, 41253-190, Salvador, BA, BrazilSubmitted by Ana Maria Fiscina Sampaio ([email protected]) on 2017-07-12T12:56:15Z No. of bitstreams: 1 Cardoso MVO Design, synthesis and structure activity.....pdf: 2327143 bytes, checksum: aed552566b61acc35f1c4ee5282c199d (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2017-07-12T13:12:17Z (GMT) No. of bitstreams: 1 Cardoso MVO Design, synthesis and structure activity.....pdf: 2327143 bytes, checksum: aed552566b61acc35f1c4ee5282c199d (MD5)Made available in DSpace on 2017-07-12T13:12:17Z (GMT). No. of bitstreams: 1 Cardoso MVO Design, synthesis and structure activity.....pdf: 2327143 bytes, checksum: aed552566b61acc35f1c4ee5282c199d (MD5) Previous issue date: 2015Múltipla - ver em NotasThe present work reports the synthesis and evaluation of the antitumour and immunomodulatory properties of new phthalimides derivatives designed to explore molecular hybridization and bioisosterism approaches between thalidomide, thiosemicarbazone, thiazolidinone and thiazole series. Twenty-seven new molecules were assessed for their immunosuppressive effect toward TNFα, IFNγ, IL-2 and IL-6 production and antiproliferative activity. The best activity profile was observed for the (6a-f) series, which presents phthalyl and thiazolidinone groups

Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-09-19T17:23:33Z No. of bitstreams: 1 Moreira DRM Structural Design....pdf: 1436389 bytes, checksum: d211240c01fd9449e4ca4a110e73acb7 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2014-09-19T17:23:43Z (GMT) No. of bitstreams: 1 Moreira DRM Structural Design....pdf: 1436389 bytes, checksum: d211240c01fd9449e4ca4a110e73acb7 (MD5)Made available in DSpace on 2014-09-19T17:47:58Z (GMT). No. of bitstreams: 1 Moreira DRM Structural Design....pdf: 1436389 bytes, checksum: d211240c01fd9449e4ca4a110e73acb7 (MD5) Previous issue date: 2014Universidade Federal de Pernambuco. Departamento de Química Fundamental. Recife, PE, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Química Fundamental. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, BrasilUniversidade de São Paulo. Departamento de Física e Inform ática. Instituto de F ísica. São Carlos, SP, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Universidade do Estado da Bahia. Departamento de Ciências da Vida. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhaes. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhaes. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhaes. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Centro de Biotecnologia e Terapia Celular. Hospital São Rafael. Salvador, BA, BrasilPharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti-Trypanosoma cruzi thiazolidinones (4 a-p). (2-[2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 h) and (2-[2-phenoxy-1-(4-phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 µM, while they did not display host cell toxicity up to 200 µM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti-T. cruzi thiazolidinones (4 a-p) led to the identification of compounds with enhanced potency and selectivity compared to first-generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

International audienceFourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC50 values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM)

Structural Investigation of Anti-<i>Trypanosoma cruzi</i> 2‑Iminothiazolidin-4-ones Allows the Identification of Agents with Efficacy in Infected Mice

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds <b>6</b>–<b>24</b>. Compounds with a phenyl at position N3, <b>15</b>–<b>19</b>, <b>22</b>–<b>24</b>, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one <b>5</b>. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one <b>18</b>, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles <b>26</b>–<b>45</b> and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with <b>18</b>, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease