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  1. Article ; Online: It Takes Two to Tango, Part II

    Joyce C. Oliveira / Renato L. de Carvalho / Hugo G. S. Sampaio / João Honorato / Javier A. Ellena / Felipe T. Martins / João V. M. Pereira / Pedro M. S. Costa / Claudia Pessoa / Rafaela S. Ferreira / Maria H. Araújo / Claus Jacob / Eufrânio N. da Silva Júnior

    Molecules, Vol 28, Iss 2222, p

    Synthesis of A-Ring Functionalised Quinones Containing Two Redox-Active Centres with Antitumour Activities

    2023  Volume 2222

    Abstract: In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres ( ortho -quinone/ para -quinone or quinone/selenium-containing triazole) through a copper-catalyzed azide-alkyne ... ...

    Abstract In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres ( ortho -quinone/ para -quinone or quinone/selenium-containing triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of para -naphthoquinones and subsequent conjugation with different ortho -quinoidal moieties. As anticipated, our study identified several compounds with IC 50 values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para -quinones coupled with ortho -quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango!
    Keywords click chemistry ; triazoles ; quinones ; redox centres ; anticancer activity ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala

    Rafaela S Ferreira / Oliva Glaucius / Adriano D Andricopulo

    Química Nova, Vol 34, Iss 10, Pp 1770-

    oportunidades e desafios em P&D de fármacos

    2011  Volume 1778

    Abstract: High-throughput screening (HTS) and virtual screening (VS) are useful methods employed in drug discovery, allowing the identification of promising hits for lead optimization. The efficiency of these approaches depends on a number of factors, such as the ... ...

    Abstract High-throughput screening (HTS) and virtual screening (VS) are useful methods employed in drug discovery, allowing the identification of promising hits for lead optimization. The efficiency of these approaches depends on a number of factors, such as the organization of high quality databases of compounds and the parameterization of essential components of the screen process. This brief review presents the basic principles of the HTS and VS methods, as well as a perspective of the utility and integration of these drug design approaches, highlighting current opportunities and future challenges in medicinal chemistry.
    Keywords high-throughput screening ; virtual screening ; drug design ; Chemistry ; QD1-999
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher Sociedade Brasileira de Química
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: S. mansoni SmKI-1 Kunitz-domain

    Fábio Mambelli / Bruno P O Santos / Suellen B Morais / Enrico G T Gimenez / Duana C Dos S Astoni / Amanda D Braga / Rafaela S Ferreira / Flávio A Amaral / Mariana T Q de Magalhães / Sergio C Oliveira

    PLoS Neglected Tropical Diseases, Vol 15, Iss 1, p e

    Leucine point mutation at P1 site generates enhanced neutrophil elastase inhibitory activity.

    2021  Volume 0009007

    Abstract: The Schistosoma mansoni SmKI-1 protein is composed of two domains: a Kunitz-type serine protease inhibitor motif (KD) and a C-terminus domain with no similarity outside the genera. Our previous work has demonstrated that KD plays an essential role in ... ...

    Abstract The Schistosoma mansoni SmKI-1 protein is composed of two domains: a Kunitz-type serine protease inhibitor motif (KD) and a C-terminus domain with no similarity outside the genera. Our previous work has demonstrated that KD plays an essential role in neutrophil elastase (NE) binding blockage, in neutrophil influx and as a potential anti-inflammatory molecule. In order to enhance NE blocking capacity, we analyzed the KD sequence from a structure-function point of view and designed specific point mutations in order to enhance NE affinity. We substituted the P1 site residue at the reactive site for a leucine (termed RL-KD), given its central role for KD's inhibition to NE. We have also substituted a glutamic acid that strongly interacts with the P1 residue for an alanine, to help KD to be buried on NE S1 site (termed EA-KD). KD and the mutant proteins were evaluated in silico by molecular docking to human NE, expressed in Escherichia coli and tested towards its NE inhibitory activity. Both mutated proteins presented enhanced NE inhibitory activity in vitro and RL-KD presented the best performance. We further tested RL-KD in vivo in an experimental model of monosodium urate (MSU)-induced acute arthritis. RL-KD showed reduced numbers of total cells and neutrophils in the mouse knee cavity when compared to KD. Nevertheless, both RL-KD and KD reduced mice hypernociception in a similar fashion. In summary, our results demonstrated that both mutated proteins showed enhanced NE inhibitory activity in vitro. However, RL-KD had a prominent effect in diminishing inflammatory parameters in vivo.
    Keywords Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
    Subject code 570
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With In Vivo Activity and Favorable Pharmacokinetics

    Ivani Pauli / Celso de O. Rezende Jr. / Brian W. Slafer / Marco A. Dessoy / Mariana L. de Souza / Leonardo L. G. Ferreira / Abraham L. M. Adjanohun / Rafaela S. Ferreira / Luma G. Magalhães / Renata Krogh / Simone Michelan-Duarte / Ricardo Vaz Del Pintor / Fernando B. R. da Silva / Fabio C. Cruz / Luiz C. Dias / Adriano D. Andricopulo

    Frontiers in Pharmacology, Vol

    2022  Volume 12

    Abstract: Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite’s life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of ... ...

    Abstract Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite’s life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics. Extensive pharmacokinetic studies enabled the identification of metabolically stable and permeable compounds with high selectivity indices. CYP3A4 was found to be involved in the main metabolic pathway, and the identification of metabolic soft spots provided insights into molecular optimization. Compound 28, which showed a promising trade-off between pharmacodynamics and pharmacokinetics, caused no acute toxicity and reduced parasite burden both in vitro and in vivo.
    Keywords chagas disease ; cruzain ; medicinal chemistry ; drug design ; multiparameter optimization ; pharmacokinetics ; Therapeutics. Pharmacology ; RM1-950
    Subject code 540
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Schistosoma mansoni SmKI-1 serine protease inhibitor binds to elastase and impairs neutrophil function and inflammation.

    Suellen B Morais / Barbara C Figueiredo / Natan R G Assis / Debora M Alvarenga / Mariana T Q de Magalhães / Rafaela S Ferreira / Angélica T Vieira / Gustavo B Menezes / Sergio C Oliveira

    PLoS Pathogens, Vol 14, Iss 2, p e

    2018  Volume 1006870

    Abstract: Protease inhibitors have important function during homeostasis, inflammation and tissue injury. In this study, we described the role of Schistosoma mansoni SmKI-1 serine protease inhibitor in parasite development and as a molecule capable of regulating ... ...

    Abstract Protease inhibitors have important function during homeostasis, inflammation and tissue injury. In this study, we described the role of Schistosoma mansoni SmKI-1 serine protease inhibitor in parasite development and as a molecule capable of regulating different models of inflammatory diseases. First, we determine that recombinant (r) SmKI-1 and its Kunitz domain but not the C-terminal region possess inhibitory activity against trypsin and neutrophil elastase (NE). To better understand the molecular basis of NE inhibition by SmKI-1, molecular docking studies were also conducted. Docking results suggest a complete blockage of NE active site by SmKI-1 Kunitz domain. Additionally, rSmKI-1 markedly inhibited the capacity of NE to kill schistosomes. In order to further investigate the role of SmKI-1 in the parasite, we designed specific siRNA to knockdown SmKI-1 in S. mansoni. SmKI-1 gene suppression in larval stage of S. mansoni robustly impact in parasite development in vitro and in vivo. To determine the ability of SmKI-1 to interfere with neutrophil migration and function, we tested SmKI-1 anti-inflammatory potential in different murine models of inflammatory diseases. Treatment with SmKI-1 rescued acetaminophen (APAP)-mediated liver damage, with a significant reduction in both neutrophil recruitment and elastase activity. In the model of gout arthritis, this protein reduced neutrophil accumulation, IL-1β secretion, hypernociception, and overall pathological score. Finally, we demonstrated the ability of SmKI-1 to inhibit early events that trigger neutrophil recruitment in pleural cavities of mice in response to carrageenan. In conclusion, SmKI-1 is a key protein in S. mansoni survival and it has the ability to inhibit neutrophil function as a promising therapeutic molecule against inflammatory diseases.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2018-02-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Sequence analysis of the cDNA encoding for SpCTx

    Fábio L. S. Costa / Maria Elena De Lima / Suely G. Figueiredo / Rafaela S. Ferreira / Núbia S. Prates / Tetsu Sakamoto / Carlos E. Salas

    Journal of Venomous Animals and Toxins including Tropical Diseases, Vol 24, Iss 1, Pp 1-

    a lethal factor from scorpionfish venom (Scorpaena plumieri)

    2018  Volume 15

    Abstract: Abstract Background Lethal factors are multifunctional oligomeric proteins found in the venomous apparatus of Scorpaeniformes fish. These toxins elicit not only an array of biological responses in vitro but also cardiovascular disorders and strong ... ...

    Abstract Abstract Background Lethal factors are multifunctional oligomeric proteins found in the venomous apparatus of Scorpaeniformes fish. These toxins elicit not only an array of biological responses in vitro but also cardiovascular disorders and strong hemolytic, nociceptive and edematogenic activities in vivo. This work describes the cloning and molecular identification of two toxin subunits, denominated Sp-CTx-α and Sp-CTx-β, from scorpionfish venom (Scorpaena plumieri). Methods The primary structures were deduced after cDNA amplification by PCR with primers from conserved sequences described in Scorpaeniformes toxins. Following DNA sequencing and bioinformatic analysis, the tridimensional structures of both subunits were modeled. Results The translated sequences (702 amino acids, each subunit) show homology with other lethal factors, while alignment between Sp-CTx-α and Sp-CTx-β shows 54% identity. The subunits lack N-terminal signal sequences and display masses of approximately 80 kDa each. Both Sp-CTx subunits display a B30.2/SPRY domain at the C-terminal region with typically conserved motifs as described in these toxins. Secondary structure prediction identified six α-helices 18 residues long in both α and β subunits, some of them amphiphilic with their N-terminal flanked by many basic residues, creating a cationic site associated with the cytolytic activity of these toxins. Antimicrobial potential sites were identified in Sp-CTx and share some features with other peptides presenting variable and broad-spectrum activity. A phylogenetic tree built to represent these toxins supports the proximity between scorpionfish, lionfish and stonefish. Conclusion The study identified a putative toxin protein whose primary structure is similar to other fish toxins and with potential for production of antivenom against scorpionfish envenomation in Brazil. As a prelude to structure-function studies, we propose that the toxin is structurally related to pore-forming marine toxins.
    Keywords cDNA ; Lethal factor ; Scorpaena plumieri ; Scorpionfish ; Venom gland ; Arctic medicine. Tropical medicine ; RC955-962 ; Toxicology. Poisons ; RA1190-1270 ; Zoology ; QL1-991
    Subject code 572
    Language English
    Publishing date 2018-08-01T00:00:00Z
    Publisher SciELO
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Structure-Based and Molecular Modeling Studies for the Discovery of Cyclic Imides as Reversible Cruzain Inhibitors With Potent Anti-Trypanosoma cruzi Activity

    Rafael A. A. Ferreira / Ivani Pauli / Thiago S. Sampaio / Mariana L. de Souza / Leonardo L. G. Ferreira / Luma G. Magalhães / Celso de O. Rezende / Rafaela S. Ferreira / Renata Krogh / Luiz C. Dias / Adriano D. Andricopulo

    Frontiers in Chemistry, Vol

    2019  Volume 7

    Abstract: Chagas disease causes ~10,000 deaths each year, mainly in Latin America, where it is endemic. The currently available chemotherapeutic agents are ineffective in the chronic stage of the disease, and the lack of pharmaceutical innovation for Chagas ... ...

    Abstract Chagas disease causes ~10,000 deaths each year, mainly in Latin America, where it is endemic. The currently available chemotherapeutic agents are ineffective in the chronic stage of the disease, and the lack of pharmaceutical innovation for Chagas disease highlights the urgent need for the development of new drugs. The enzyme cruzain, the main cysteine protease of Trypanosoma cruzi, has been explored as a validated molecular target for drug discovery. Herein, the design, molecular modeling studies, synthesis, and biological evaluation of cyclic imides as cruzain inhibitors are described. Starting with a micromolar-range cruzain inhibitor (3a, IC50 = 2.2 μM), this molecular optimization strategy resulted in the nanomolar-range inhibitor 10j (IC50 = 0.6 μM), which is highly active against T. cruzi intracellular amastigotes (IC50 = 1.0 μM). Moreover, most compounds were selective toward T. cruzi over human fibroblasts, which were used as host cells, and are less toxic to hepatic cells than the marketed drug benznidazole. This study enabled the discovery of novel chemical diversity and established robust structure-activity relationships to guide the design of optimized cruzain inhibitors as new trypanocidal agents.
    Keywords Chagas disease ; Trypanosoma cruzi ; cruzain ; SAR ; medicinal chemistry ; synthesis ; Chemistry ; QD1-999
    Subject code 540
    Language English
    Publishing date 2019-11-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Síntese, avaliação biológica e modelagem molecular de arilfuranos como inibidores da enzima tripanotiona redutase Synthesis, biological evaluation and molecular modeling of arylfurans as potential trypanothione reductase inhibitors

    Renata B. de Oliveira / Carlos L. Zani / Rafaela S. Ferreira / Rodrigo S. Leite / Tânia M. A. Alves / Thaís H. A. da Silva / Alvaro J. Romanha

    Química Nova, Vol 31, Iss 2, Pp 261-

    2008  Volume 267

    Abstract: Trypanosoma cruzi is a protozoan parasite that causes a severe disease (Chagas'disease) in Central and South America. The currently available chemotherapeutic agents against this disease are still inadequate. The enzyme trypanothione reductase (TR) is ... ...

    Abstract Trypanosoma cruzi is a protozoan parasite that causes a severe disease (Chagas'disease) in Central and South America. The currently available chemotherapeutic agents against this disease are still inadequate. The enzyme trypanothione reductase (TR) is considered a validated molecular target for the development of new drugs against this parasite. In this regard, a series of arylfurans based on 2,5-bis-(4-acetamidophenyl)furan was synthesized and tested for their in vitro inhibitory activity against TR. Molecular modeling studies of putative enzyme-inhibitor complexes revealed a possible mechanism of interaction. From synthesized compounds, a benzylaminofuran derivative was found to be more active than the lead compound.
    Keywords trypanothione reductase ; molecular modeling ; arylfurans ; Chemistry ; QD1-999
    Language English
    Publishing date 2008-01-01T00:00:00Z
    Publisher Sociedade Brasileira de Química
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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