Estela Maris Freitas Muri
@uff.br
Pharmaceutical Technology Department
Federal Fluminense University
Scopus Publications
Scopus Publications
Pedro Henrique Rodrigues de Alencar Azevedo, Bruna Rachel de Britto Peçanha, Luiz Augusto Pinheiro Flores-Junior, Tatiana Fialho Alves, Luiza Rosaria Sousa Dias, Estela Maris Freitas Muri, and Camilo Henrique da Silva Lima
Informa UK Limited
O-linked N-acetylglucosamine (O-GlcNAc) is a unique intracellular post-translational glycosylation at the hydroxyl group of serine or threonine residues in nuclear, cytoplasmic and mitochondrial proteins. The enzyme O-GlcNAc transferase (OGT) is responsible for adding GlcNAc, and anomalies in this process can lead to the development of diseases associated with metabolic imbalance, such as diabetes and cancer. Repurposing approved drugs can be an attractive tool to discover new targets reducing time and costs in the drug design. This work focuses on drug repurposing to OGT targets by virtual screening of FDA-approved drugs through consensus machine learning (ML) models from an imbalanced dataset. We developed a classification model using docking scores and ligand descriptors. The SMOTE approach to resampling the dataset showed excellent statistical values in five of the seven ML algorithms to create models from the training set, with sensitivity, specificity and accuracy over 90% and Matthew's correlation coefficient greater than 0.8. The pose analysis obtained by molecular docking showed only H-bond interaction with the OGT C-Cat domain. The molecular dynamics simulation showed the lack of H-bond interactions with the C- and N-catalytic domains allowed the drug to exit the binding site. Our results showed that the non-steroidal anti-inflammatory celecoxib could be a potentially OGT inhibitor.
Joana L.S. Ribeiro, Júlio C.A.V. Soares, Gisele B. Portapilla, Maiara V. Providello, Camilo H.S. Lima, Estela M.F. Muri, Sérgio de Albuquerque, and Luiza R.S. Dias
Elsevier BV
Despite the serious public health problems caused by Chagas disease in several countries, the available therapy remains with only two drugs that are poorly active during the chronic phase of the disease in addition to having severe side effects. In search of new trypanocidal agents, herein we describe the synthesis and biological evaluation of eleven new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine compounds containing the carbohydrazide or the 2,3-dihydro-1,3,4-oxadiazole moieties. Two of them showed promising in vitro activity against amastigote forms of T. cruzi and were evaluated in vivo in male BALB/c mice infected with T. cruzi Y strain. Our results suggest that the substitution at the C-2 position of the phenyl group connected to the carbohydrazide or to the 2,3-dihydro-1,3,4-oxadiazole moieties plays an important role in the trypanocidal activity of this class of compounds. Moreover, the compound containing the 2,3-dihydro-1,3,4-oxadiazole moiety has demonstrated more favorable structural requirements for in vivo activity than its carbohydrazide analog.
Suraby O. Albuquerque, Thalita G. Barros, Luiza R.S. Dias, Camilo H. da S. Lima, Pedro H.R. de A. Azevedo, Luiz A.P. Flores-Junior, Eldio G. dos Santos, Hector F. Loponte, Sergio Pinheiro, Wagner B. Dias,et al.
Elsevier BV
The vital enzyme O-linked β-N-acetylglucosamine transferase (OGT) catalyzes the O-GlcNAcylation of intracellular proteins coupling the metabolic status to cellular signaling and transcription pathways. Aberrant levels of O-GlcNAc and OGT have been linked to metabolic diseases as cancer and diabetes. Here, a new series of peptidomimetic OGT inhibitors was identified highlighting the compound LQMed 330, which presented better IC50 compared to the most potent inhibitors found in the literature. Molecular modeling study of selected inhibitors into the OGT binding site provided insight into the behavior by which these compounds interact with the enzyme. The results obtained in this study provided new perspectives on the design and synthesis of highly specific OGT inhibitors.
Sergio Pinheiro, Jaqueline C. Pessôa, Erick M.C. Pinheiro, Estela M.F. Muri, Eclair Venturini Filho, Laiza B. Loureiro, Maria Clara R. Freitas, Carlos M.D. Silva Junior, Rodolfo G. Fiorot, José Walkimar M. Carneiro,et al.
Elsevier BV
Prostate cancer is an important cause of death in the male population and for which there is no satisfactory chemotherapy. Herein a new series of chalcone hybrids containing 2H-1,2,3-triazole core as the ring B has been synthesized and evaluated in vitro against PC-3 prostate cancer cell line. Compounds 4a, 4c and 4e significantly reduced cell viability and showed IC50 of 28.55, 15.64 and 25.56 µM, respectively. The structure-activity relationship supported by computational chemistry points that the polarity of the molecular surface area should have some relevance to the efficiency of the compounds, in particular the ratio of the partial positive charge sites and the total molecular surface area exposed to the cell environment.
Sergio Pinheiro, Erick M. C. Pinheiro, Estela M. F. Muri, Jaqueline C. Pessôa, Mayara A. Cadorini, and Sandro J. Greco
Springer Science and Business Media LLC
The [1,2,4]triazolo[1,5-a]pyrimidines (TPs) comprise an important class of non-naturally occurring small molecules that aroused the interest of researches. This scaffold is present in diverse important structures in agriculture and medicinal chemistry, such as antibacterial, antifungal, antiviral, antiparasitic, and anticancer. As over the decades the development of the chemistry and application of 1,2,4-triazolo[1,5-a]pyrimidines has continued and even accelerated, in this review, we thoroughly discussed the applications of TPs in both agriculture and medicinal chemistry highlighting the significance of this nucleus.
Camilo Henrique da Silva Lima, Júlio César de Araujo Vanelis Soares, Joana Lucius de Sousa Ribeiro, Estela Maris Freitas Muri, Sérgio de Albuquerque, and Luiza Rosaria Sousa Dias
Bentham Science Publishers Ltd.
Background: Untargeted studies led to the development of some pyrazolopyridine derivatives for the antiparasitic profile, particularly the derivatives containing the structural carbohydrazide subunit. In this work, we proceeded in the biological screening of 27 N’- (substitutedphenylmethylene)- 4-carbohydrazide-3-methyl-1-phenyl-1H-pyrazolo[3, 4-b]pyridine derivatives against T. cruzi as well as the cytotoxic evaluation. To obtain more information about the trypanocidal activity of this class of compounds, we carried out molecular docking simulations to get an insight into putative targets in T. cruzi. Methods: The assays were evaluated against both trypomastigote and amastigote forms of T. cruzi and cytotoxicity assays on LLCMK2 cells. The predominant conformational compounds were analyzed and molecular docking simulations performed. Results: The results from trypanocidal activity screening of this series showed that just the compounds with phenyl group at C-6 position exhibited activity and the N’-4-hydroxyphenylmethylene derivative presented the best profile against both trypomastigote and amastigote forms of T. cruzi. Docking simulation results showed that this compound has a binding affinity with both CYP51 and cruzain targets of T. cruzi. Conclusion: Our results indicate that the hydroxyl substituent at the N’-substituted-phenylmethylene moiety and the phenyl ring at C-6 of 1H-pyrazolo[3,4-b]pyridine system are relevant for the trypanocidal activity of this class of compounds. Also, docking simulations showed that activity presented can be related to more than one target of the parasite.
Acácio S. de Souza, Barbara D.C. Pacheco, Sergio Pinheiro, Estela M.F. Muri, Luiza R.S. Dias, Camilo H.S. Lima, Rafael Garrett, Mariana B.M. de Moraes, Bruno E.G. de Souza, and Luciano Puzer
Elsevier BV
Human kallikreins 5 and 7 (KLK5 and KLK7) exhibit trypsin- and chymotrypsin-like activities and are involved in pathologies related to skin desquamation process. A series of new 3-acyltetramic acids were developed as a novel class of inhibitors of KLK5, KLK7 and trypsin enzymes. The nature and length of the acyl chain is crucial to the KLK5, KLK7 and trypsin inhibition activities, and the most potent compounds (but not the most selective) 2b, 2c and 2g showed low micromolar IC50 values. While very few of the compounds were selective for KLK5, the selective inhibition of trypsin against chymotrypsin was achieved. Our molecular modelling studies revealed that the double bond in 2g provided the best fit in the binding site of KLK5, while the hydrogen bonding interactions modulated the best fit of 2c in the binding site of KLK7 due to the hydrophobicity of the cavity.
Jaqueline Cavalcanti Pessoa, Roberto Faria Azevedo, Suellen Finamor Mota, Sergio Pinheiro, Estela Maris Freitas Muri, Elaine Aparecida de Souza, and Denilson Ferreira Oliveira
Bentham Science Publishers Ltd.
Sergio Pinheiro, Estela M.F. Muri, Rafael P. R. F. de Oliveira, Luiza R.S. Dias, and Sandro J. Greco
Bentham Science Publishers Ltd.
Aline C. Portela, Thalita G. Barros, Camilo H. da S. Lima, Luiza R.S. Dias, Pedro H.R. de A. Azevedo, Anna Sophia C.L. Dantas, Ronaldo Mohana-Borges, Gustavo T. Ventura, Sergio Pinheiro, and Estela M.F. Muri
Elsevier BV
Hepatitis C infection is a cause of chronic liver diseases such as cirrhosis and carcinoma. The current therapy for hepatitis C has limited efficacy and low tolerance. The HCV encodes a serine protease which is critical for viral replication, and few protease inhibitors are currently on the market. In this paper, we describe the synthesis and screening of novel isosorbide-based peptidomimetic inhibitors, in which the compounds 1d, 1e, and 1i showed significant inhibition of the protease activity in vitro at 100µM. The compound 1e also showed dose-response (IC50=36±3µM) and inhibited the protease mutants D168A and V170A at 100µM, indicating it as a promising inhibitor of the HCV NS3/4A protease. Our molecular modeling studies suggest that the activity of 1e is associated with a change in the interactions of S2 and S4 subsites, since that the increased flexibility favors a decrease in activity against D168A, whereas the appearance of a hydrophobic cavity in the S4 subsite increase the inhibition against V170A strain.
André L. Lourenço, Raquel R.S. Salvador, Leonardo A. Silva, Max S. Saito, Juliana F.R. Mello, Lúcio M. Cabral, Carlos R. Rodrigues, Maria A.F. Vera, Estela M.F. Muri, Alessandra M.T. de Souza,et al.
Elsevier BV
Cardiovascular diseases (CVDs) account for over 17 million deaths globally each year, with atherosclerosis as the underlying cause of most CVDs. Herein we describe the synthesis and in vitro mechanistic evaluation of novel N'-benzylidene-carbohydrazide-1H-pyrazolo[3,4-b]pyridines (3-22) designed as non-anionic antiplatelet agents and presenting a 30-fold increase in potency compared to aspirin. The mechanism underlying their antiplatelet activity was elucidated by eliminating potential targets through a series of in vitro assays including light transmission aggregometry, clot retraction, and quantitative ELISA, further identifying the reduction in biosynthesis of thromboxane B2 as their main mechanism of action. The intrinsic fluorescence of the compounds permits their binding to platelet membranes to be readily monitored. In silico structure-activity relationship, molecular docking and dynamics studies support the biological profile of the series revealing the molecular basis of their activity and their potential as future molecular therapeutic agents.
Thalita G. Barros, Jorge A.N. Santos, Bruno E.G. de Souza, Ana Carolina R. Sodero, Alessandra M.T. de Souza, Dayane P. da Silva, Carlos Rangel Rodrigues, Sergio Pinheiro, Luiza R.S. Dias, Bárbara Abrahim-Vieira,et al.
Elsevier BV
Human kallikrein 1 (KLK1) is the most extensively studied member of this family and plays a major role in inflammation processes. From Ugi multicomponent reactions, isomannide-based peptidomimetic 10 and 13 where synthesized and showed low micromolar values of IC50 for KLK1 The most active compound (10) presented competitive mechanism, with three structural modifications important to interact with active site residues which corroborates its KLK1 inhibition. Finally, the most active compound also showed good ADMET profile, which indicates compound 10 as a potential hit in the search for new KLK1 inhibitors with low side effects.
L.V.B. Hoelz, V.F. Leal, C.R. Rodrigues, P.G. Pascutti, M.G. Albuquerque, E.M.F. Muri, and L.R.S. Dias
Informa UK Limited
The major cysteine protease of Trypanosoma cruzi, cruzain (CRZ), has been described as a therapeutic target for Chagas’ disease, which affects millions of people worldwide. Thus, a series of CRZ inhibitors has been studied, including a new competitive inhibitor, Nequimed176 (NEQ176). Nevertheless, the structural and dynamic basis for CRZ inhibition remains unclear. Hoping to contribute to this ever-growing understanding of timescale dynamics in the CRZ inhibition mechanism, we have performed the first study using 100 ns of molecular dynamics (MD) simulations of two CRZ systems in an aqueous solvent under pH 5.5: CRZ in the apo form (ligand free) and CRZ complexed to NEQ176. According to the MD simulations, the enzyme adopts an open conformation in the apo form and a closed conformation in the NEQ176–CRZ complex. We also suggest that this closed conformation is related to the hydrogen-bonding interactions between NEQ176 and CRZ, which occurs through key residues, mainly Gly66, Met68, Asn69, and Leu160. In addition, the cross-correlation analysis shows evidence of the correlated motions among Ala110–Asp140, Leu160–Gly189, and Glu190–Gly215 subdomains, as well as, the movements related to Ala1–Thr59 and Asp60–Pro90 regions seem to be crucial for CRZ activity.
Lucas V.B. Hoelz, Bruna C. Zorzanelli, Pedro Henrique R.de A. Azevedo, Silvia G. Passos, Lucas R. de Souza, Marcelo Zani, Sergio Pinheiro, Luciano Puzer, Luiza R.S. Dias, and Estela M.F. Muri
Elsevier BV
Human kallikrein 5 (KLK5) is a potential target for the treatment of skin inflammation and cancer. A new series of statine based peptidomimetic compounds were designed and synthesized through simple and efficient reactions. Some KLK5 inhibitors (2a-c compounds) were identified with nanomolar affinity showing Ki values of 0.12-0.13 μM. Our molecular modeling studies suggest that the inhibitors binding at the KLK5 through H-bond interactions with key residues (mainly His108, Gln242, Gly243, Ser245, and Ser260), disrupting the correlated motions mainly among the Ile67-Tyr127, Glu128-Val187, and Gly237-Ser293 subdomains, which seems to be crucial for KLK5 activity. Therefore, we believe that these findings will significantly facilitate our understanding of the conformational dynamics in the course of KLK5 inhibition and, consequently, the development of more potent molecules as alternative for cancer treatment.
RAQUEL R.S. SALVADOR, MURILO L. BELLO, IGOR R.L. BARRETO, MARIA A.F. VERA, ESTELA M.F. MURI, SÉRGIO DE ALBUQUERQUE, and LUIZA R.S. DIAS
FapUNIFESP (SciELO)
This paper reports the in vitro trypanocidal activity evaluation of new carbohydrazide derivatives from 3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine, substituted at C-6 position by phenyl, methyl or trifluoromethyl group. These compounds were evaluated in order to identify the antiparasitic profile against trypomastigote and amastigote forms of Trypanosoma cruzi. The 4-carbohydrazide derivatives presented different profiles of activity. In the investigation of the chemical structure influence in the trypanocidal activity, the results indicated there are large lipophilicity and volume differences among these derivatives. The complementarities of their stereoelectronic and physical-chemical aspects seem to be relevant for the biological activity against T. cruzi.
Bruna C. Zorzanelli and Estela M. F. Muri
Sociedade Brasileira de Quimica (SBQ)
With the advent of green chemistry, the industry becomes more and more attempting to reverse the pollution releasing state of its process, combining progress with the development of technologies and processes less harmful to the planet. The synthetic chemists are improving the methodologies of synthesis in order to generate fewer residues. The oxidation of alcohols, one of the most important chemical transformations in the industry, already presents various techniques according to the philosophy of green chemistry. This article will show some of the new techniques used for the oxidation of alcohols, including a brief review of the main conventional
Jocelia P. C. Oliveira, Renato F. Freitas, Leandro Silva de Melo, Thalita G. Barros, Jorge A. N. Santos, Maria A. Juliano, Sérgio Pinheiro, Michael Blaber, Luiz Juliano, Estela M. F. Muri,et al.
American Chemical Society (ACS)
Human kallikrein 5 (KLK5) and 7 (KLK7) are potential targets for the treatment of skin inflammation and cancer. Previously, we identified isomannide derivatives as potent and competitive KLK7 inhibitors. The introduction of N-protected amino acids into the isomannide-based scaffold was studied. Some KLK5 inhibitors with submicromolar affinity (K i values of 0.3-0.7 μM) were identified, and they were 6- to 13-fold more potent than our previous hits. Enzyme kinetics studies and the determination of the mechanism of inhibition confirmed that the new isomannide-based derivatives are competitive inhibitors of both KLK5 and KLK7. Molecular docking and MD simulations of selected inhibitors into the KLK5 binding site provide insight into the molecular mechanism by which these compounds interact with the enzyme. The promising results obtained in this study open new prospects on the design and synthesis of highly specific KLK5 and KLK7 inhibitors.
Bárbara Abrahim-Vieira, Emmerson C. B. da Costa, Pedro H. R. de A. Azevedo, Aline C. Portela, Luiza R. S. Dias, Sergio Pinheiro, Amilcar Tanuri, Anne M. Capaccia, Gustavo T. Ventura, Ronaldo Mohana-Borges,et al.
Springer Science and Business Media LLC
Hepatitis C viral infection is a cause of chronic liver disease, and current therapies are only effective in 50 % of patients. Serine proteases, which are present in both hepatitis C virus (HCV) and the dengue virus, are the most studied class of proteolytic enzymes and are the primary targets for drug development in this field. In this paper, we describe the synthesis of a novel class of isomannide-based peptide mimetic compounds based on a tartaric acid backbone. Our data showed that substitutions at position 168 (D168A) and 170 (V170A) conferred low-level resistance against compound 5a3, whereas substitutions at position 155 (R155K) and 156 (A156V) conferred no resistance. These data suggest that even though compound 5a3 is a noncompetitive inhibitor; it is able to interact with important residues located near the catalytic site. In addition, this novel compound class exhibits potent antiviral activity against variants carrying resistance mutations to boceprevir and telaprevir. Our docking studies showed important interactions, including hydrogen bonds and a π–π interaction, between compound 5a3 and residues of the allosteric site of NS3/4A. Biological and theoretical results indicate that 5a3 is a promising lead compound for the development of new drugs targeting HCV infection.
Estela Maris Freitas Muri
GN1 Genesis Network
Proteases catalyze the hydrolysis of peptide bonds of proteins and peptides to produce smaller peptides and free amino acids. These enzymes are involved in physiologic processes such as blood coagulation and cellular death, and are related to life cycle of several viruses, such as hepatitis C, dengue, and AIDS. These features make most of proteases very important therapeutic targets for new pharmaceutical compounds. The development of peptidemimetics with improved pharmacokinetic properties is driving extensive research in the field of viral protease inhibitors. The present paper aims to highlight the design and synthesis of peptidemimetics that are able to inhibit viral proteases related to hepatitis C, dengue, and AIDS.
Simone Santos de Sousa Oliveira, Sorele Batista Fiaux, Igor Ramon Lomba Barreto, Estela Maris Freitas Muri, Maria da Conceição Klaus V. Ramos, Francisco Radler de Aquino Neto, and Luiza Rosária Sousa Dias
GN1 Genesis Network
In this work, we report a new method for obtaining racemic β-hydroxyesters by reduction of β-ketoesters. The use of glycerol as a reactional medium in selective reduction of β-ketoesters into the corresponding alcohols was shown to be a viable and more efficient alternative compared with the conventional methodology, taking into account green chemistry prerogatives.
Bruna PEÇANHA, Luiza DIAS, Eliani SPINELLI, and Estela F. MURI
FapUNIFESP (SciELO)
Polimeros de impressao molecular (Molecularly Imprinted Polymers, MIPs) foram sintetizados e aplicados como adsorventes na tecnica de extracao em fase solida (EFS). O metodo de polimerizacao por precipitacao foi usado para sintetizar os polimeros, devido a simplicidade de preparo, altos rendimentos e obtencao de particulas mais uniformes uma vez que o polimero nao e triturado. Os MIPs foram sintetizados com acido metacrilico como monomero funcional, trimetacrilato de trimetilolpropano como agente de reticulacao e cloridrato de amilorida como molecula molde. O solvente de elevada polaridade empregado na sintese (THF:MeOH:H2O) possibilita empregar a tecnica para moleculas polares como o cloridrato de amilorida. O controle no volume de solvente permitiu obter particulas maiores, de modo que a EFS foi realizada nas condicoes usuais, o que confere um potencial para aplicacao dessa tecnica de polimerizacao na preparacao de adsorventes para EFS.
E. M. F. Muri and T. G. Barros
Springer Berlin Heidelberg
Helicobacter pylori (H. pylori) is a microaerophilic spiral bacterium and infection by it in the human stomach causes gastritis and is considered to be involved in the pathogenesis of peptic ulcer and in the development of gastric carcinoma. It produces a nickel-dependent enzyme called urease which catalyzes the hydrolysis of urea to produce ammonia and carbamate. This ammonia produced by urease elevates the level of pH in the stomach, breaks gastric mucus, inhibits the consumption of oxygen, and reduces the production of ATP in gastric mucus cells or in mitochondria. In order to stop the pathogenesis of these disorders in the body, it is therefore essential that potent inhibitors of H. pylori urease be developed. The present chapter discusses the role of hydroxamic acids as inhibitors of this enzyme.
Renato F. Freitas, Thiago S.P. Teixeira, Thalita G. Barros, Jorge A.N. Santos, Marcia Y. Kondo, Maria A. Juliano, Luiz Juliano, Michael Blaber, Octávio A.C. Antunes, Odonírio Abrahão,et al.
Elsevier BV
Human kallikrein 7 (KLK7) is a potential target for the treatment of skin inflammation and cancer. Despite its potential, few KLK7-specific small-molecule inhibitors have been reported in the literature. As an extension of our program to design serine protease inhibitors, here we describe the in vitro assays and the investigation of the binding mechanism by molecular dynamics simulation of a novel class of pseudo-peptide inhibitors derived from isomannide. Of the inhibitors tested, two inhibited KLK7 with K(i) values in the low micromolar range (9g=1.8μM; 9j=3.0μM). Eadie-Hofstee and Dixon plots were used to evaluate the competitive mechanism of inhibition for the molecules. Calculated binding free energies using molecular MM/PB(GB)SA approach are in good agreement with experimental results, suggesting that the inhibitors share the same binding mode, which is stabilized by hydrophobic interactions and by a conserved network of hydrogen bonds. The promising results obtained in this study make these compounds valid leads for further optimization studies aiming to improve the potency of this new class of kallikrein inhibitors.
Thalita G. Barros, Bruna C. Zorzanelli, Sergio Pinheiro, Monique A. de Brito, Amilcar Tanuri, Vitor F. Ferreira, and Estela M.F. Muri
Bentham Science Publishers Ltd.
Thalita G. Barros, Sergio Pinheiro, J. S. Williamson, Amílcar Tanuri, M. Gomes, Helena S. Pereira, R. M. Brindeiro, José B. A. Neto, O. A. C. Antunes, and Estela M. F. Muri
Springer Science and Business Media LLC
In this paper, we describe the synthesis of a novel class of pseudo-peptides derived from isomannide and several oxazolones as potential inhibitors of serine proteases as well as preliminary pharmacological assays for hepatitis C. Hepatitis C, dengue and West Nile fever are among the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes and are a primary target in the drug development field. Several pseudo-peptides were obtained in good yields from the reaction of isomannide and oxazolones, and their anti-HCV potential using the HCV replicon-based assay was shown.