| Congresso Brasileiro de Microbiologia 2023 | Resumo: 246-1 | ||||
Resumo:Bacterial infections are a major health problem worldwide, including the impacts of resistance to antibacterial drugs. Natural products have been the start point of discovery of innovative bioactive compounds. Curcumin has demonstrated several therapeutic properties, however with some therapeutic limitations. In this context, molecular simplification can lead to more potent analogs. In this work, a series of monocarbonyl curcuminoids was designed, synthesized and investigated against Gram-positive and Gram-negative bacteria with human health relevance. Out of 14 compounds, 13 are new chemical identities. The 1
H NMR and 13 C NMR spectra data were able to identify all curcumin analogs. Thee log Po/w value evaluations were established from 1.55 to 3.36. Purity ranging from 95.9 to 99.0%. Compound GRM12 displayed a broad-spectrum of action, exhibiting activity against Gram-positive and Gram-negative bacteria, with MIC values from 3.0 to 60 然. These MIC values included drug-resistant strains. GRM12 exhibited a MIC of 1 to 79 然, equal to or close to tetracycline. Against Pseudomanas aeruginosa (ATCC 27453), GRM12 was weakly active with a MIC of 1000 然.In silico studies predicted the physicochemical properties and target of GRM12. We used SwissTargetPrediction, a computational platform, to elucidate possible mechanisms of action, which suggested a strong interaction with proteases, eraser enzyme and kinases. With this investigation, we explain points that are justifiable for such a low MIC. In the membrane permeation test, GRM12 showed 75% damage to the membrane of Staphylococcus aureus (ATCC 29213), which may associate the action of this analogue in the rupture of the bacterial membrane. In vivo toxicity test against Galleria mellonella larvae, GRM12 did not demonstrate toxicity at all tested concentrations, contributing to the follow-up of other assays. The biofilm is a barrier to conventional antibiotics due to its very well-organized matrix, making its eradication rigid. However, GRM12 was able to inhibit the biofilm formed by 50% against Gram-positive and Gram-negative bacteria, having a bacteriostatic action against biomass. In contrast, the bacterial death curve caused by GRM12 was equal to or lower than vancomycin and tetracycline, validating GRM12 as a promising candidate for future trials. Among the series of monocarbonyl curcuminoids, other compounds were strongly active. GRM01 showed activity against Helicobacter pylori (ATCC43526) with a MIC value of 44 然, GRM03 and GRM11 demonstrated antibacterial activity against H. pylori (ATCC43526) and the Methicillin-Resistant Staphylococcus aureus (BAA44) with MIC value of 39 and 177 然, respectively. Therefore, we concluded that molecular simplification leads to active curcumin analogs, corroborating the potential of this natural product as a prototype in the design of novel antibacterial agents. Palavras-chave: Curcumin, Synthesis, antibacterial, bacterial membrane, antibiofilm Ag瘽cia de fomento:Coordination for the Improvement of Higher Education Personnel (CAPES) | |||||