http://hdl.handle.net/11422/28 Mon, 20 Jul 2026 23:26:22 GMT 2026-07-20T23:26:22Z http://hdl.handle.net/11422/29608 Title: Avaliação do efeito sinérgico a partir da inibição simultânea de EGFR e PI3K/mTOR: uma nova alternativa terapêutica para o tratamento do glioblastoma Author(s)/Inventor(s): São José, Vitória Santório de Advisor: Lima, Lídia Moreira Abstract: Glioblastoma (GB) is a malignant and invasive tumor with a high proliferation profile, resulting in a poor prognosis. Due to the high lethality rate and limited therapeutic options, GB shows high mortality. Besides, TMZ-based chemotherapy has significant limitations, such as resistance. In this context, several studies have considered Tyrosine – Kinase Receptor inhibitors (TKRi) against GB. However, monotherapy with TKRi shows limited efficacy and safety. For this purpose, investigating synergistic effects appears as an alternative to increase the potency and safety of anti-tumor drugs. First, our study aims to demonstrate the synergistic effect of the combination of osimertinibe (an irreversible and BBB-permeable EGFR inhibitor) and gedatolisib (PI3K and mTOR dual inhibitor) in a phenotypic assay against five GB cell lines. Secondly, we searched for a synergistic effect on the combination of EGFR inhibitor LASSBio-1971 (planned and synthesized by our lab) and gedatolisib, which were BBB-permeable, considering in vitro prediction based on the HBMEC monolayer model. Although both combinations showed a synergistic effect, LASSBio-1971 appears as a more selective compound: both combinations showed reduced migration and proliferation and induced apoptosis. In conclusion, our in vitro results suggest that the triple inhibition of EGFR, PI3K/mTOR, is a promising therapeutic strategy for GB treatment to be tested in pre-clinical models. Publisher: Universidade Federal do Rio de Janeiro Type: Tese Tue, 14 Jan 2025 00:00:00 GMT http://hdl.handle.net/11422/29608 2025-01-14T00:00:00Z http://hdl.handle.net/11422/29607 Title: O primeiro estudo amplo da relação estrutura-atividade do benznidazol: atividades in vitro e in vivo contra Trypanosoma cruzi e na enzima nitroredutase Author(s)/Inventor(s): Menozzi, Cheyene Almeida Celestino Advisor: Boechat, Nubia Abstract: Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a significant public health challenge, particularly due to the limitations of current treatments. Benznidazole (BZN) is currently the only drug used in Brazil for the treatment of the disease and, despite its limitations, remains the best therapeutic alternative, as evidenced by recent clinical studies. Its well-established mechanism of action and consolidated efficacy make it a valuable prototype for the development of new molecules. In this context, this work proposed the synthesis and evaluation of 27 BZN derivatives, aiming to optimize their anti-T. cruzi activity and to carry out a preliminary structure–activity relationship (SAR) study, which has not yet been explored or documented in the literature. The derivatives were obtained through a simple and low-cost synthetic route, consisting of two steps performed using a one-pot system. In silico predictions indicated favorable physicochemical and pharmacokinetic properties, including good aqueous solubility, excellent gastrointestinal absorption potential, and compliance with major drug-likeness criteria. Biological activity was determined through in vitro assays against intracellular forms of the parasite (Tulahuen strain) and bloodstream trypomastigotes (Y strain), as well as cytotoxicity in L929 cells. Nine compounds exhibited greater potency and selectivity than BZN (EC50 = 2.52 ± 0.60 μM) against the intracellular form of the parasite, with three of them standing out as the most potent, showing EC50 values ranging from 1.01 to 2.52 μM. All compounds showed CC50 > 200 μM, indicating a high selectivity index and no cytotoxicity up to the maximum concentration tested, highlighting a favorable safety profile. Against bloodstream trypomastigotes, 8 of the 17 compounds tested showed EC50 values lower than BZN (5.8 μM), ranging from 2.37 to 5.18 μM. The in vitro evaluation on the nitroreductase enzyme (TcNTR) classified nine derivatives as artificial substrates. Enzymatic conversion rates, expressed relative to BZN (100%), were equal to or higher than this value for eight compounds, reinforcing the hypothesis of this pathway's involvement in the mechanism of action. The SAR analysis enabled the identification of structural patterns that enhance anti-T. cruzi activity, suggesting potential directions for the development of new compounds. Five of the most promising derivatives were evaluated in vivo, and the compound N-(2-methylbenzyl)-2- (2-nitro-1H-imidazol-1-yl)acetamide was able to reduce parasitemia by 100% and ensure 100% survival of the treated animals. These findings reinforce the potential of these molecules as promising candidates for the development of new anti-Chagas agents. Publisher: Universidade Federal do Rio de Janeiro Type: Tese Wed, 07 May 2025 00:00:00 GMT http://hdl.handle.net/11422/29607 2025-05-07T00:00:00Z http://hdl.handle.net/11422/29595 Title: Identificação de novos inibidores de RHO kinase planejados como análogos estruturais do prototipo J0P Author(s)/Inventor(s): Oliveira, Daniela Rodrigues de Advisor: Lima, Lídia Moreira Abstract: Rho kinases (Rho-associated protein kinases - ROCK) are protein kinases involved in multiple biological processes. Given the accelerated aging of the global population, the development of ROCK inhibitors offers promising perspectives for interventions aimed at effectively managing age-related diseases. This work presents the synthesis and enzymatic evaluation of novel N-acylhydrazonebased ROCK inhibitors designed using aza-vinylogous principles. All synthesized compounds were assessed for their inhibitory profiles against both ROCK isoforms (ROCK1 and ROCK2), and their potential binding modes were explored through molecular dynamics simulations, particularly focusing on ROCK2. Additionally, the pharmacodynamic properties of the sixteen synthesized compounds were evaluated, including kinetic solubility at pH 7.4, chemical stability under gastric and plasma pH conditions, and permeability across the gastrointestinal tract and the blood-brain barrier. Among the sixteen compounds, LASSBio-2346, LASSBio-2348, LASSBio-2350, and LASSBio-2354 exhibited solubility above 50 µM at 4 and 24 hours, high in vitro gastrointestinal permeability, positive blood-brain barrier permeability, and stability under plasma pH conditions. These results guide further studies in disease models affecting the central nervous system associated with aging, such as Alzheimer's and Parkinson's diseases. Publisher: Universidade Federal do Rio de Janeiro Type: Tese Fri, 11 Apr 2025 00:00:00 GMT http://hdl.handle.net/11422/29595 2025-04-11T00:00:00Z http://hdl.handle.net/11422/29594 Title: Avaliação do efeito antitumoral e anticarcinogênico de análogos de simplificação estrutural da curcumina em modelos de câncer de pulmão humano Author(s)/Inventor(s): Chaves, Lorrane de Souza Advisor: Freire-de-Lima, Leonardo Abstract: Lung cancer is one of the leading causes of mortality worldwide, making the search for new, more selective and effective therapeutic agents essential. Curcumin, a polyphenol extracted from Curcuma longa, exhibits antitumor properties, but its low bioavailability limits its clinical use. In this study, curcumin analogs were synthesized and evaluated for their antiproliferative activity in human lung cancer cells (A549 and H460) and their selectivity toward healthy cells (PBMCs). The compounds were tested at increasing concentrations (0.190–200 μM), and IC₅₀ values were determined using the MTT assay. Analogs 8, 11, and 12 showed higher antiproliferative potency, with up to a 25-fold increase compared to the precursor compounds. Furthermore, cell cycle analysis revealed that these compounds induced arrest in the G2/M phase, suggesting inhibition of CDKs and cyclins. Flow cytometry-based cell death analysis indicated that analog 12 induced apoptosis, with a significant increase in cells in the sub-G0/G1 phase. Molecular docking studies revealed compound affinity for molecular targets associated with tumor progression, such as p53, KIT, EGFR, STAT3, and Bcl -2, corroborating the in vitro phenotypic data. Morphological analysis and wound healing assays were also conducted in the presence of TGF-β, demonstrating that the curcuminoids can attenuate the epithelial–mesenchymal transition process, especially when combined with inhibition of the TGF-β pathway. The in silico evaluation of ADME parameters indicated that the compounds possess good intestinal absorption and favorable physicochemical properties, although adjustments are needed to improve their oral bioavailability. Notably, analogs 11 and 12 showed high selectivity for tumor cells compared to PBMCs, suggesting a safer profile for future therapeutic applications. The results of this study indicate that structurally modified curcumin analogs exhibit enhanced antiproliferative activity, promote cell cycle arrest, and induce apoptosis in lung cancer cells, with lower toxicity toward healthy cells. Thus, these compounds emerge as potential candidates for the development of new chemotherapeutic agents, although further studies are necessary to validate their efficacy and safety. Publisher: Universidade Federal do Rio de Janeiro Type: Dissertação Fri, 13 Jun 2025 00:00:00 GMT http://hdl.handle.net/11422/29594 2025-06-13T00:00:00Z