Browsing by Author "Faundez, Mario"

Now showing 1 - 17 of 17
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    Biological activity of native Myrtaceae fruits from Chile as a potential functional food
    (2022) Velasquez, Patricia; Orellana, Jocelyn; Munoz-Carvajal, Eduardo; Faundez, Mario; Gomez, Miguel; Montenegro, Gloria; Giordano, Ady
    Myrtaceae fruits (Myrceugenia obtusa, Luma apiculata, and Luma chequen) were used as food and medicine by Chilean indigenous people. This study aimed to evaluate the bioactive properties of these berry-type fruits. The antioxidant capacity determined by the FRAP assay varied between 10.4 and 646.9 mmol Fe+2/g, while the antibacterial activity against Staphylococcus aureus and Salmonella typhi was 0 - 33 mm and 0 - 7.33 mm, respectively. All the extracts were rich in polyphenols and showed low cytotoxicity. Overall, M. obtusa presented dissimilar results compared to those of L. apiculata and L. chequen, encouraging the use of these native fruits as food, nutraceutical, or pharmacological ingredients.
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    Design of benzimidazoles, benzoxazoles, benzothiazoles and thiazolopyridines as leukotriene A4 hydrolase inhibitors through 3D-QSAR, docking and molecular dynamics
    (2023) Lorca, Marcos; Faundez, Mario; Pessoa-Mahana, C. David; Recabarren-Gajardo, Gonzalo; Diethelm-Varela, Benjamin; Millan, Daniela; Celik, Ismail; Mellado, Marco; Araque, Ileana; Mella, Jaime; Romero-Parra, Javier
    Human leukotriene A4 hydrolase enzyme (LTA4H) catalyses the biotransformation of the inactive precursor leukotriene A4 (LTA4) to the bioactive Leukotriene B4 (LTB4), which causes many inflammatory responses in the human body. Therefore, the selective inhibition of this enzyme becomes a useful strategy for the treatment of several illnesses such as asthma, allergic rhinitis, cardiovascular diseases, and cancer. Herein we report a 3D-QSAR/ /CoMFA and CoMSIA study on a series of 47 benzimidazoles, benzoxazoles, benzothiazoles and thiazolopyridines reported as potent LTA4H inhibitors. Good statistical parameters were obtained for the best model (q2 = 0.568, r2 ncv = 0.891 and r2 test = 0.851). A new series of 10 compounds capable of inhibiting leukotriene A4 hydrolase with high potency was presented. All designed inhibitors showed low IC50 in nano- and sub-nanomolar ranges, when they were evaluated in 3D-QSAR models. Subsequently, the designed molecules, as well as the least and most active compounds were subjected to docking and molecular dynamics studies into LTA4H. In conclusion, we summarised a thorough structure-activity relationship (SAR) of LTA4H inhibitors of heterocyclic structure. These models can be used for the rational proposal of new inhibitors.
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    Design, synthesis, cytotoxicity and 3D-QSAR analysis of new 3,6-disubstituted-1,2,4,5-tetrazine derivatives as potential antitumor agents
    (2017) Cañete Molina, Álvaro; Espinosa Bustos, Christian Marcelo; González Castro, Marcos; Faundez, Mario; Mella, Jaime; Tapia Apati, Ricardo; Cabrera Caballero, Alan Raúl; Brito, Iván; Aguirre, Adam; Salas Sánchez, Cristián Osvaldo
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    Effect of alpha lipoic acid on leukotriene A(4) hydrolase
    (2017) Torres, M.; Fierro Huerta, Angélica; Pessoa Mahana, Carlos David; Romero, J.; Cabrera, G.; Faundez, Mario
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    Effect of substituents and chain length in amino-1,4-naphthoquinones on glutathione-S-transferase inhibition: molecular docking and electrochemical perspectives: a structure-activity study
    (2022) Faundes, Judith; Munoz-Osses, Michelle; Morales, Pilar; Tasca, Federico; Zuniga Loyola, Cesar; Faundez, Mario; Mascayano, Carolina; Ibacache, Juana A.
    In this study, new homodimers and monoamination products based on the pharmacophore amino-1,4-naphthoquinone were synthesized. To perform a structure-activity study, three precursor quinones (2,3-dichloro-1,4-naphthoquinone, 1,4-naphthoquinone, and 2-hydroxy-1,4-naphthoquinone) and four diamines (4,40-diaminodiphenylmethane, 4,40-ethylenedianiline, ethylenediamine and 1,3-diaminopropane) were used. The reactions of the compounds were accomplished in the presence or the absence of Lewis acid as a catalyst. The new derivatives were evaluated as potential inhibitors of the enzyme glutathione-S-transferase (GST) by conjugating reduced glutathione (GSH) with the substrate 1-chloro-2,4-dinitrobenzene (CDNB). The study of the GST activity showed a clear structure-activity relationship in which the chlorinated compound 8 was the best inhibitor, with inhibition percentage values of 57%, being in the inhibition range as other GST inhibitors such as hexachlorophene and ethacrynic acid. These experimental results are consistent with molecular docking studies which show that compound 8 binds to the enzyme close to the catalytic site (G-site) and the chlorine group shows up to be essential for the stability of the ligand. Additionally, from the in silico exploration, a directly proportional trend between lipophilicity and enzyme affinity was noted, correlating with the experimental results of GST activity where the chlorine atom contributes positively to it. Finally, the electrochemical characterization provided another significant insight: the compounds with higher formal potential values (E-0) had the electron-withdrawing group chlorine being the most active against GST.
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    In vitro activity and mechanism of action against the protozoan parasite Trypanosoma cruzi of 5-nitrofuryl containing thiosemicarbazones
    (2004) Aguirre, Gabriela; Boiani, Lucia; Cerecetto, Hugo; Fernandez, Marcelo; Gonzalez, Mercedes; Denicola, Ana; Otero, Lucia; Gambino, Dinorah; Rigol, Carolina; Faundez, Mario; Olea-Azar, Claudio
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    Melatonin protects the cytochrome P450 system through a novel antioxidant mechanism
    (ELSEVIER IRELAND LTD, 2010) Eugenia Letelier, Maria; Jara Sandoval, Jose; Molina Berrios, Alfredo; Faundez, Mario; Aracena Parks, Paula; Aguilera, Felipe
    Melatonin, an endogenous hormone, is used as an antioxidant drug in doses quite higher than the endogenous circulating levels of this hormone. Hepatic endoplasmic reticulum contains the cytochrome P450 (CYP450) system, which catalyzes one biotransformation pathway of melatonin; this organelle is also one of the main sources of reactive oxygen species in cells. Therefore, we proposed that the antioxidant activity of this hormone may have a biological relevance in the organelle where it is biotransformed. To evaluate this postulate, we used Fe3+/ascorbate, an oxygen free radical generating system that leads to lipid peroxidation, loss of protein-thiol content, and activation of UDP-glucuronyltransferase in rat liver microsomes. We found that mM concentrations of melatonin prevented all these oxidative phenomena. We also found that Fe3+/ascorbate leads to structural alterations in the CYP450 monooxygenase, the enzyme that binds the substrate in the CYP450 system catalytic cycle, probably through direct oxidation of the protein, and also inhibited p-nitroanisole O-demethylation, a reaction catalyzed by the CYP450 system. Notably, melatonin prevented both phenomena at mu M concentrations. We provide evidence suggesting that melatonin may be oxidized by oxygen free radicals. Thus, we postulate that melatonin may be acting as an oxygen free radical scavenger, and Fe3+/ascorbate-modified melatonin would be directly protecting the CYP450 system through an additional specific mechanism. Pharmacological relevance of this phenomenon is discussed. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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    Microencapsulation of Chilean Papaya Waste Extract and Its Impact on Physicochemical and Bioactive Properties
    (2023) Fuentes, Yihajara; Giovagnoli-Vicuna, Claudia; Faundez, Mario; Giordano, Ady
    The microencapsulation of bioactive extracts of Chilean papaya waste, including both seeds and skin, was investigated. Papaya waste extract microcapsules utilizing maltodextrin at 10% (MD10), 20% (MD20), and 30% (MD30) (w/v) as the wall material through the freeze-drying process were obtained, and subsequently their physicochemical, antioxidant, and antimicrobial properties were evaluated. The TPC efficiency and yield values achieved were more than 60% for the microencapsulated seed and skin extracts, respectively. The best results for phenolic and antioxidant compounds were found in the microencapsulated seed extract with MD20, with a value of 44.20 +/- 3.32 EAG/g DW for total phenols and an antioxidant capacity of 12.0 +/- 0.32 mol ET/g DW for the DPPH and 236.3 +/- 4.1 mol ET/g DW for the FRAP assay. In addition, the seed and skin samples reduced ROS generation in H2O2-treated Hek293 cells. In terms of antimicrobial activity, values ranging from 7 to 15 mm of inhibitory halos were found, with the maximum value corresponding to the inhibition of S. aureus, for both microencapsulated extracts. Therefore, the successful microencapsulation of the waste bioactive extracts (seed and skin) with the demonstrated antimicrobial and antioxidant properties highlight the bioactivity from Chilean papaya waste resources.
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    Microwave Assisted Synthesis of Novel Six-Membered 4-C, 4-O and 4-S Lactams Derivatives: Characterization and in vitro Biological Evaluation of Cytotoxicity and Anticoagulant Activity
    (2017) Núñez Navarro, Nicolás Ernesto; Segovia Bonnemaison, Gerardine Francoise; Burgos, Renato; Lagos, Carlos; Fuentes, Nataly; Faundez, Mario; Zacconi, Flavia C. M.
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    Motifs in Natural Products as Useful Scaffolds to Obtain Novel Benzo[d]imidazole-Based Cannabinoid Type 2 (CB2) Receptor Agonists
    (2023) Cho, Analia Young Hwa; Chung, Hery; Romero-Parra, Javier; Kumar, Poulami; Allara, Marco; Ligresti, Alessia; Gallardo-Garrido, Carlos; Pessoa-Mahana, Hernan; Faundez, Mario; Pessoa-Mahana, Carlos David
    The endocannabinoid system (ECS) constitutes a broad-spectrum modulator of homeostasis in mammals, providing therapeutic opportunities for several pathologies. Its two main receptors, cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mediate anti-inflammatory responses; however, their differing patterns of expression make the development of CB2-selective ligands therapeutically more attractive. The benzo[d]imidazole ring is considered to be a privileged scaffold in drug discovery and has demonstrated its versatility in the development of molecules with varied pharmacologic properties. On the other hand, the main psychoactive component of Cannabis sativa, delta-9-tetrahydrocannabinol (THC), can be structurally described as an aliphatic terpenoid motif fused to an aromatic polyphenolic (resorcinol) structure. Inspired by the structure of this phytocannabinoid, we combined different natural product motifs with a benzo[d]imidazole scaffold to obtain a new library of compounds targeting the CB2 receptor. Here, we synthesized 26 new compounds, out of which 15 presented CB2 binding and 3 showed potent agonist activity. SAR analysis indicated that the presence of bulky aliphatic or aromatic natural product motifs at position 2 of the benzo[d]imidazoles ring linked by an electronegative atom is essential for receptor recognition, while substituents with moderate bulkiness at position 1 of the heterocyclic core also participate in receptor recognition. Compounds 5, 6, and 16 were further characterized through in vitro cAMP functional assay, showing potent EC50 values between 20 and 3 nM, and compound 6 presented a significant difference between the EC50 of pharmacologic activity (3.36 nM) and IC50 of toxicity (30-38 & mu;M).
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    NADPH oxidase activity: Spectrophotometric determination of superoxide using pyrogallol red
    (2017) Cortes, J.; Torres, M.; Campos, M.; Romero, J.; Letelier, M.; Pessoa Mahana, Carlos David; Chung, H.; Faundez, Mario
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    New imidoyl-indazole platinum (II) complexes as potential anticancer agents: Synthesis, evaluation of cytotoxicity, cell death and experimentaltheoretical DNA interaction studies
    (2017) Cabrera Caballero, Alan Raúl; Espinosa Bustos, Christian Marcelo; Faundez, Mario; Meléndez Rojel, Jaime Gumercindo; Jaque Olmedo, Pablo César; Daniliuc, Constantin G.; Aguirre Ducler, Adam Jesús; Rojas Guerrero, René; Salas Sánchez, Cristián Osvaldo
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    New NADPH Oxidase 2 Inhibitors Display Potent Activity against Oxidative Stress by Targeting p22phox-p47phox Interactions
    (2023) Treuer, Adriana V.; Faundez, Mario; Ebensperger, Roberto; Hovelmeyer, Erwin; Vergara-Jaque, Ariela; Perera-Sardina, Yunier; Gutierrez, Margarita; Fuentealba, Roberto; Gonzalez, Daniel R.
    NADPH oxidase (NOX2) is responsible for reactive oxygen species (ROS) production in neutrophils and has been recognized as a key mediator in inflammatory and cardiovascular pathologies. Nevertheless, there is a lack of specific NOX2 pharmacological inhibitors. In medicinal chemistry, heterocyclic compounds are essential scaffolds for drug design, and among them, indole is a very versatile pharmacophore. We tested the hypothesis that indole heteroaryl-acrylonitrile derivatives may serve as NOX2 inhibitors by evaluating the capacity of 19 of these molecules to inhibit NOX2-derived ROS production in human neutrophils (HL-60 cells). Of these compounds, C6 and C14 exhibited concentration-dependent inhibition of NOX2 (IC50-1 mu M). These molecules also reduced NOX2-derived oxidative stress in cardiomyocytes and prevented cardiac damage induced by ischemia-reperfusion. Compound C6 significantly reduced the membrane translocation of p47(phox), a cytosolic subunit that is required for NOX2 activation. Molecular docking analyses of the binding modes of these molecules with p47(phox) indicated that C6 and C14 interact with specific residues in the inner part of the groove of p47(phox), the binding cavity for p22(phox). This combination of methods showed that novel indole heteroaryl acrylonitriles represent interesting lead compounds for developing specific and potent NOX2 inhibitors.
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    New Pyridone-Based Derivatives as Cannabinoid Receptor Type 2 Agonists
    (MDPI, 2021) Faundez Parraguez, Manuel; Alarcon Miranda, Carlos; Cho, Young Hwa; Pessoa Mahana, Hernan; Gallardo Garrido, Carlos; Chung, Hery; Faundez, Mario; Pessoa Mahana, David
    The activation of the human cannabinoid receptor type II (CB2R) is known to mediate analgesic and anti-inflammatory processes without the central adverse effects related to cannabinoid receptor type I (CB1R). In this work we describe the synthesis and evaluation of a novel series of N-aryl-2-pyridone-3-carboxamide derivatives tested as human cannabinoid receptor type II (CB2R) agonists. Different cycloalkanes linked to the N-aryl pyridone by an amide group displayed CB2R agonist activity as determined by intracellular [cAMP] levels. The most promising compound 8d exhibited a non-toxic profile and similar potency (EC50 = 112 nM) to endogenous agonists Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) providing new information for the development of small molecules activating CB2R. Molecular docking studies showed a binding pose consistent with two structurally different agonists WIN-55212-2 and AM12033 and suggested structural requirements on the pyridone substituents that can satisfy the orthosteric pocket and induce an agonist response. Our results provide additional evidence to support the 2-pyridone ring as a suitable scaffold for the design of CB2R agonists and represent a starting point for further optimization and development of novel compounds for the treatment of pain and inflammation.
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    Novel FXa Inhibitor identification through integration of ligand- and structure-based approaches
    (2017) Lagos, C.; Segovia Bonnemaison, Gerardine Francoise; Núñez Navarro, Nicolás Ernesto; Faundez, Mario; Zacconi, Flavia C. M.
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    Synthesis, binding assays, cytotoxic activity and docking studies of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor
    (2016) Romero Parra, Javier Hernán; Mella Raipán, Jaime Alberto; Palmieri, Vittoria; Allarà, Marco; Torres Torres, María José; Pessoa Mahana, Hernán; Iturriaga Vásquez, Patricio; Escobar, Rossy; Faundez, Mario; Di Marzo, Vicenzo; Pessoa Mahana, Carlos David
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    Trypanosoma cruzi: In vitro effect of aspirin with nifurtimox and benznidazole
    (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2010) Lopez Munoz, Rodrigo; Faundez, Mario; Klein, Sebastian; Escanilla, Sebastian; Torres, Gloria; Lee Liu, Dasfne; Ferreira, Jorge; Kemmerling, Ulrike; Orellana, Myriam; Morello, Antonio; Ferreira, Arturo; Maya, Juan D.
    Nifurtimox and benznidazole are the only active drugs against Trypanosoma cruzi; however, they have limited efficacy and severe side effects. During primoinfection, T cruzi infected macrophages mount an antiparasitic response, which the parasite evades through an increase of tumor growth factor beta and PGE(2) activation as well as decreased iNOS activity. Thus, prostaglandin synthesis inhibition with aspirin might increase macrophage antiparasitic activity and increase nifurtimox and benznidazole effect.