Navegando por Autor "Varotti, Fernando de Pilla"
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Item Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle : mode of action, mutagenicity profile, and Caco-2 cell-based permeability.(2019) Guimarães, Daniel Silqueira Martins; Luz, Letícia Silveira de Sousa; Nascimento, Sara Batista do; Silva, Lorena Rabelo; Martins, Natália Rezende de Miranda; Almeida, Heloísa Gonçalves de; Reis, Vitória de Souza; Maluf, Sarah El Chamy; Budu, Alexandre; Marinho, Juliane Aparecida; Abramo, Clarice; Carmona, Adriana Karaoglanovic; Silva, Marina Goulart da; Silva, Gisele Rodrigues da; Kemmer, Victor Matheus; Butera, Anna Paola; Viana, Renato Márcio Ribeiro; Gazarini, Marcos Leoni; Nascimento Júnior, Clébio Soares; Guimarães, Luciana; Santos, Fabio Vieira dos; Castro, Whocely Victor de; Ribeiro, Gustavo Henrique; Brito, Cristiana Ferreira Alves de; Varotti, Fernando de PillaThe development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to‑lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7 μM, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50 mg/kg. In silico and UV–vis approaches determined that compound 3 acts impairing hemozoin crystallization and confocal microscopy experiments corroborate these findings as the compound was capable of diminishing food vacuole acidity. The assay of uptake using human intestinal Caco-2 cell line showed that compound 3 is absorbed similarly to chloroquine, a standard antimalarial agent. Therefore, we present here compound 3 as a potent new lead antimalarial compound.Item Nanoemulsion composed of 10-(4,5-dihydrothiazol-2-yl)thio)decan-1-ol), a synthetic analog of 3-alkylpiridine marine alkaloid : development, characterization, and antimalarial activity.(2020) Silva, Marina Goulart da; Cardoso, Jéssica Ferreira; Perasoli, Fernanda Barçante; Branquinho, Renata Tupinambá; Mourão, Renata Silva; Tavares, Harley da Silva; Xocaira, Maria Luiza Costa Trench; Guimarães, Daniel Silqueira Martins; Viana, Gustavo Henrique Ribeiro; Varotti, Fernando de Pilla; Silva, Gisele Rodrigues daMalaria treatment is based on a reduced number of antimalarial drugs, and drug resistance has emerged, leading to the search for new antimalarial drugs incorporated into pharmaceutical formulations. In this study, 10-(4,5- dihydrothiazol-2-yl)thio)decan-1-ol) (thiazoline), a synthetic analog of 3-alkylpiridine marine alkaloid, and a potent antimalarial substance, was incorporated into O/W nanoemulsion. This formulation was prepared by a 23 factorial design. It was characterized by globule diameter, polydispersity index, zeta potential, encapsulation efficiency, in vitro thiazoline release at pH 2 and 6.86, and accelerated stability. In vitro and in vivo antimalarial activity was determined against P. falciparum and P. berghei, respectively. Thiazoline nanoemulsion showed 248.8 nm of globule diameter, 0.236 of polydispersity index, -38.5 mV of zeta potential, 96.92% encapsulation efficiency, and it was stable for 6 months. Thiazoline release profiles differed in acidic and neutral media, but in both cases, the nanoemulsion controlled and prolonged the thiazoline delivery. Thiazoline nanoemulsion exerted in vitro antimalarial activity against the parasite (IC50 = 1.32 µM), and it significantly reduced the in vivo parasitemia for 8 days without increasing the survival time of animals. Therefore, the thiazoline nanoemulsion represents a strategy to treat malaria combining an antimalarial candidate and a new nanocarrier.Item Spiramyin-loaded PLGA implants for the treatment of ocular toxoplasmosis : development, characterization, biocompatibility, and anti-toxoplasma activity.(2021) Tavares, Harley da Silva; Cardoso, Jéssica Ferreira; Almeida, Tamires Cunha; Marques, Maria Betânia de Freitas; Mussel, Wagner da Nova; Lopes, M. C. P.; Oréfice, Rodrigo Lambert; Andrade, Silmara Nunes; Varotti, Fernando de Pilla; Silva, Glenda Nicioli da; Silva, Gisele Rodrigues daOcular toxoplasmosis is the major cause of infectious posterior uveitis worldwide, inducing visual field defect and/or blindness. Despite the severity of this disease, an effective treatment is still lacking. In this study, spiramycin-loaded PLGA implants were developed aiming at the treatment of ocular toxoplasmosis. Implants were manufactured by a hot-molding technique, characterized by Fourier Transform Infrared Spectroscopy, X-Ray Diffraction, Differential Scanning Calorimetry, Scanning Electron Microscopy; evaluated in terms of ocular biocompatibility by immunofluorescence, flow cytometry, cell migration, Hen’s egg test-chorioallantoic membrane (HET-CAM) irritation test; and investigated in terms of in vitro efficacy against Toxoplasma gondii. Characterization techniques indicated that spiramycin was dispersed into the polymeric chains and both substances preserved their physical structures in implants. The HET-CAM test indicated that implants did not induce hemorrhage or coagulation, being non-irritant to the CAM. ARPE-19 cells showed viability by MTT assay, and normality in cell cycle kinetics and morphology, without stimulating cell death by apoptosis. Finally, they were highly effective against intracellular parasites without inducing human retinal pigment epithelial cell death. In conclusion, spiramycin-loaded PLGA implants represent a promising therapeutic alternative for the local treatment of ocular toxoplasmosis.