Is bismuth(iii) able to inhibit the activity of urease? Puzzling results in the quest for soluble urease complexes for agrochemical and medicinal applications

Abstract

Bismuth(III) complexes have been reported to act as inhibitors of the enzyme urease, ubiquitously present in soils and implicated in the pathogenesis of several microorganisms. The general insolubility of Bi(III) complexes in water at neutral pH, however, is an obstacle to their utilization. In our quest to improve the solubility of Bi(III) complexes, we selected a compound reported to inhibit urease, namely [Bi(HEDTA)]·2H₂O, and co-crystallized it with (i) racemic DL-histidine to obtain the conglomerate [Bi₂(HEDTA)₂(μ-D-His)₂]·6H₂O + [Bi₂(HEDTA)₂(μ-L-His)₂]·6H₂O, (ii) enantiopure L-histidine to yield [Bi₂(HEDTA)₂(μ-L-His)₂]·6H₂O, and (iii) cytosine to obtain [Bi(HEDTA)]·Cyt·2H₂O. All compounds, synthesised by mechanochemical methods and by slurry, were characterized in the solid state by calorimetric (DSC and TGA) and spectroscopic (IR) methods, and their structures were determined using powder X-ray diffraction (PXRD) data. All compounds show an appreciable solubility in water, with values ranging from 6.8 mg mL⁻¹ for the starting compound [Bi(HEDTA)]·2H₂O to 36 mg mL⁻¹ for [Bi₂(HEDTA)₂(μ-L-His)₂]·6H₂O. The three synthesized compounds as well as [Bi(HEDTA)]·2H₂O were then tested for inhibition activity against urease. Surprisingly, no enzymatic inhibition was observed during in vitro assays using Canavalia ensiformis urease and in vivo assays using cultures of Helicobacter pylori, raising questions on the efficacy of Bi(III) compounds to counteract the negative effects of urease activity in the agro-environment and in human health.