Síntese de novos isoxazóis 3,5-dissubstituídos como potenciais inibidores da enzima urease

Abstract

Urease is a nickel-dependent metalloenzyme widely distributed in nature, whose activity is associated both with nitrogen metabolism in plants and with the pathogenicity of microorganisms such as Helicobacter pylori. Due to its clinical and agricultural relevance, the search for effective urease inhibitors represents an area of intense scientific interest. In this work, fourteen functionalized isoxazole derivatives were synthesized and characterized, thirteen of which represent novel chemical structures not previously described in the literature, with the aim of evaluating their potential as urease inhibitors. Classical organic synthesis methodologies were employed, having as the key step the 1,3-dipolar [3+2] cycloaddition reaction, responsible for constructing the isoxazole core. The hypervalent iodine reagent [bis(trifluoroacetoxy)iodo]benzene (PIFA) was used as a sustainable and metal-free oxidizing agent. Its use offers significant advantages over traditional metal-based protocols, such as greater stability to air and humidity, broad tolerance to functional groups, and economic efficiency. The synthesized compounds were characterized by ¹H and ¹³C NMR, COSY, infrared spectroscopy (IR), and high-resolution mass spectrometry (HRMS), confirming their proposed molecular structures. Molecular docking studies performed against Canavalia ensiformis urease (Jack Bean Urease, JBU) revealed that several of the synthesized compounds exhibited promising inhibitory profiles, allowing the evaluation of the interactions of the isoxazole derivatives with the enzyme active site. The results highlighted the role of hydrogen bonds and hydrophobic contacts in stabilizing the enzyme–ligand complex. To experimentally assess the biological potential of the synthesized compounds, enzyme inhibition assays against C. ensiformis urease were performed. The results indicated that some derivatives exhibited significant inhibitory activity, supporting the potential of this class of compounds as a starting point for the development of new urease inhibitors. The findings demonstrate that structural modifications on the isoxazole scaffold can modulate inhibitory activity, reinforcing the potential of this heterocyclic framework as a promising platform for designing new urease inhibitor candidates. Furthermore, the integration of synthetic, spectroscopic, and computational approaches proved to be an effective strategy for identifying molecules with potential applications in both medicinal chemistry, aimed at combating urease-related bacterial infections, and agrochemistry, focused on reducing nitrogen losses in urea-fertilized soils. Thus, this dissertation contributes to advancing the understanding of isoxazole-based chemistry and its application as urease inhibitors, providing a foundation for future studies directed toward structural optimization, expanded biological evaluation, and exploration of potential practical applications in health and agriculture.