Síntese de chalconas, triagem in silico e in vitro e avaliação da adesão de Helicobacter pylori por docking molecular
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Data
2024-05-29
Autores
Romagna, Rodrigo de Almeida
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Universidade Federal do Espírito Santo
Resumo
Helicobacter pylori is a Gram-negative bacterium that chronically infects the human stomach, a risk factor for the development of inflammatory gastrointestinal diseases, including cancer, being defined as group I carcinogen. It is estimated that H. pylori infects around 40% of the global population and that the persistence of the infection is related to various virulence factors, including adhesion proteins of the bacteria in the gastric epithelium. The progression of gastric lesions to cancer is related to the activation of the NF-κB and MAPK pathways, especially in cagA+ strains, which are related to increased expression of metalloproteinases, such as MMP 9. The activation of these metalloproteinases contributes to the adhesion of the bacterium in gastric cells and the evolving stages of cancer, such as enabling metastasis. Due the increasing resistance to the current therapy protocols, the search for alternative targets and candidate molecules are necessary. In this way the objective was synthetize 10 hydroxylated and methoxylated chalcones, asses their anti-H. pylori potential through the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) and evaluate their cytotoxicity in gastric adenocarcinoma cells and L929 to determine the selectivity index. Also, in silico studies were performed to evaluate potential anti-adhesive properties for the chalcones against H. pylori. Ten chalcones were synthetized by Claisen-Schmidt condensation using Ba(OH)2 or LiOH as catalysts with yields of 10 to 52% and were characterized by 1H and 13C Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). Predictive in silico assays using PASS Online, Tanimoto similarity, ADME properties and molecular docking in MMP-9 (PDB code: 6ESM) were performed and revealed the possibility of anti-H. pylori, anti inflammatory and MMP-9 inhibitors for the chalcones. All chalcones exhibited strong activity against H. pylori, specially 2,4'-dihydroxy-4-methoxychalcone 9, that showed the best growth inhibition values for MIC and MBC, being 1 μg/mL and 2 μg/mL, respectively. The 2'-hydroxy 4'-methoxy-2-chlorochalcone 14 and 2',3',4'-trimethoxychalcone 15 also showed significant inhibition results, being 2 μg/mL for both MIC and MBC. Also, 15 presented the best MMP-9 inhibition score, in silico. Despite not corroborating the in silico data, 2'-hydroxy-4'-methoxy 2-methoxychalcone 10, 2'-hydroxy-4'-methoxy-2-methoxy-5-bromochalcone 13, and 2' hydroxy-2-chloronaphthalenone 18 showed notewhorthy cytotoxicity and the best selectivity indices. The predicted MMP-9 inhibition by molecular docking added by the MIC, MBC, SI and the CI50 values for 18 revealed that this substance may be a drug candidate by acting synergically to reduce the inflammatory response and the possibilities for developing a tumor by inhibiting both bacteria growth, it's adhesion and malignant cells proliferation.
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Helicobacter pylori , Chalconas , MMP-9 , NF-κB