Browsing by Author "Robledo, Sara M."
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Item In Silico, In Vitro, and Pharmacokinetic Studies of UBMC-4, a Potential Novel Compound for Treating against Trypanosoma cruzi(MDPI, 2022-06) Bustamante, Christian; Díez Mejía, Andrés Felipe; Arbeláez, Natalia; Soares, Maurilio José; Robledo, Sara M.; Ochoa, Rodrigo; Varela M., Rubén E.; Marín Villa, MarcelThe lack of therapeutic alternatives for the treatment of Chagas disease, a neglected disease, drives the discovery of new drugs with trypanocidal activity. Consequently, we conducted in vitro studies using UBMC-4, a potential Trypanosoma cruzi AKT-like pleckstrin homology (PH) domain inhibitory compound found using bioinformatics tools. The half effective concentration (EC50) on intracellular amastigotes was determined at 1.85 ± 1 µM showing low cytotoxicity (LC50) > 40 µM on human cell lines tested. In order to study the lethal effect caused by the compound on epimastigotes, morphological changes were assessed by scanning and transmission electron microscopy. Progressive alterations such as flagellum inactivation, cell size reduction, nuclear structure alteration, condensation of chromatin towards the nuclear periphery, vacuole formation, and mitochondrial swelling with kinetoplast integrity loss were evidenced. In addition, apoptosis-like markers in T. cruzi were assessed by flow cytometry, demonstrating that the effect of UBMC-4 on T. cruzi AKT-like kinase reduced the tolerance to nutritional stress-triggered, apoptosis-like events, including DNA fragmentation, mitochondrial damage, and loss of plasma membrane integrity. After this, UBMC-4 was formulated for oral administration and pharmacokinetics were analyzed in a mouse model. Finally, upon oral administration of 200 mg/kg in mice, we found that a UBMC-4 plasma concentration remaining in circulation beyond 24 h after administration is well described by the two-compartment model. We conclude that UBMC-4 has an effective trypanocidal activity in vitro at low concentrations and this effect is evident in T. cruzi cell structures. In mice, UBMC-4 was well absorbed and reached plasma concentrations higher than the EC50, showing features that would aid in developing a new drug to treat Chagas disease. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Item In vitro evaluation of the potential pharmacological activity and molecular targets of new benzimidazole-based schiff base metal complexes(2021) Aragón Muriel, Alberto; Liscano, Yamil; Upegui, Yulieth; Robledo, Sara M.; Ramírez-Apan, María Teresa; Morales Morales, David; Oñate Garzón, Jose; Polo Cerón, DorianMetal-based drugs, including lanthanide complexes, have been extremely effective in clinical treatments against various diseases and have raised major interest in recent decades. Hence, in this work, a series of lanthanum (III) and cerium (III) complexes, including Schiff base ligands derived from (1H-benzimidazol-2-yl)aniline, salicylaldehyde, and 2,4-dihydroxybenzaldehyde were synthesized and characterized using different spectroscopic methods. Besides their cytotoxic activities, they were examined in human U-937 cells, primate kidney non-cancerous COS-7, and six other, different human tumor cell lines: U251, PC-3, K562, HCT-15, MCF-7, and SK-LU-1. In addition, the synthesized compounds were screened for in vitro antiparasitic activity against Leishmania braziliensis, Plasmodium falciparum, and Trypanosoma cruzi. Additionally, antibacterial activities were examined against two Gram-positive strains (S. aureus ATCC® 25923, L. monocytogenes ATCC® 19115) and two Gram-negative strains (E. coli ATCC® 25922, P. aeruginosa ATCC® 27583) using the microdilution method. The lanthanide complexes generally exhibited increased biological activity compared with the free Schiff base ligands. Interactions between the tested compounds and model membranes were examined using differential scanning calorimetry (DSC), and interactions with calf thymus DNA (CT-DNA) were investigated by ultraviolet (UV) absorption. Molecular docking studies were performed using leishmanin (1LML), cruzain (4PI3), P. falciparum alpha-tubulin (GenBank sequence CAA34101 [453 aa]), and S. aureus penicillin-binding protein 2a (PBP2A; 5M18) as the protein receptors. The results lead to the conclusion that the synthesized compounds exhibited a notable effect on model membranes imitating mammalian and bacterial membranes and rolled along DNA strands through groove interactions. Interactions between the compounds and studied receptors depended primarily on ligand structures in the molecular docking study.Item Search of Allosteric Inhibitors and Associated Proteins of an AKT-like Kinase from Trypanosoma cruzi(International Journal of Molecular Sciences, 2018) Ochoa, Rodrigo; Rocha-Roa, Cristian; Marín-Villa, Marcel; Robledo, Sara M.; Varela-M, Rubén E.Proteins associated to the PI3K/AKT/mTOR signaling pathway are widely used targets for cancer treatment, and in recent years they have also been evaluated as putative targets in trypanosomatids parasites, such as Trypanosoma cruzi. Here, we performed a virtual screening approach to find candidates that can bind regions on or near the Pleckstrin homology domain of an AKT-like protein in T. cruzi. The compounds were also evaluated in vitro. The in silico and experimental results allowed us to identify a set of compounds that can potentially alter the intracellular signaling pathway through the AKT-like kinase of the parasite; among them, a derivative of the pyrazolopyridine nucleus with an IC50 of 14.25 ± 1.00 μM against amastigotes of T. cruzi. In addition, we built a protein–protein interaction network of T. cruzi to understand the role of the AKT-like protein in the parasite, and look for additional proteins that can be postulated as possible novel molecular targets for the rational design of compounds against T. cruzi.Item Synthesis of novel quinoline–based 4,5–dihydro–1H–pyrazoles as potential anticancer, antifungal, antibacterial and antiprotozoal agents(Elsevier Masson SAS, 2017-03-16) Ramírez Prada, Jonathan; Robledo, Sara M.; Velez, Ivan D.; Crespo, María del Pilar; Quiroga, Jairo; Abonia, Rodrigo; Montoya, Alba; Svetaz, Laura; Zacchino, Susana; Insuasty, BraulioA new series of Nesubstituted 2epyrazolines 9aef, 10aef, 11aef, 12aef and 13aef were obtained from the cyclocondensation reaction of [(7echloroquinoline4eyl)amino]chalcones 8aef with hydrazine hydrate and its derivatives. Fourteen of the synthesized compounds including the starting chalcones were selected by US National Cancer Institute (NCI) for testing their anticancer activity against 60 different human cancer cell lines, with the most important GI50 values ranging from 0.28 to 11.7 mM (0.13e6.05 mg/ mL) and LC50 values ranging from 2.6 to > 100 mM (1.2 to > 51.7 mg/mL), for chalcones 8a,d and pyrazolines 10c,d. All compounds were assessed for antibacterial activity against wild type and multidrug resistant gram negative and gram positive bacteria, with MIC values ranging from 31.25 to 500 mg/mL. Additionally, the novel compounds were tested for antifungal and antiparasitic properties. Although these compounds showed mild activity against Candida albicans, chalcones 8a and 8e showed high activity against Cryptococcus neoformans with MIC50 ¼ 7.8 mg/mL. For antiePlasmodium falciparum activity the 2epyrazoline 11b was the most active with EC50 ¼ 5.54 mg/mL. Regarding the activity against Trypanosoma cruzi, compound 10a was highly active with EC50 ¼ 0.70 mg/mL. Chalcone 8a had good activity against Leishmania panamensis amastigotes with EC50 ¼ 0.79 mg/mL.